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UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549

FORM 10-K

(Mark One)
ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the fiscal year ended December 31, 20192021
OR
TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
Commission File Number 001-36751

OCUGEN, INC.
(Exact Name of Registrant as Specified in its Charter)

___________________________________________________________
Delaware04-3522315
(State or other jurisdiction of
incorporation or organization)
(I.R.S. Employer
Identification No.)
5263 Great Valley Parkway Suite 160
Malvern, Pennsylvania 19355
(Address of principal executive offices, including zip code)
(484) 328-4701
(Registrant’s telephone number, including area code)

Securities registered pursuant to Section 12(b) of the Act
Act:
Title of each classTrading
symbol(s)
Name of each exchange
on which registered
Common StockOCGN
The Nasdaq Stock Market LLC
(The Nasdaq Capital Market)
Securities registered pursuant to section 12(g) of the Act: None
___________________________________________________________
Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities ActAct.
Yes o No x
Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the ActAct.
Yes o No x

Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days.    Yes  x   No  o

Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§ 232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files).    Yes x    No  o
Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller
reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act
Act.
Large accelerated fileroAccelerated filero
Non-accelerated filerxSmaller reporting company
Emerging growth company
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 7(a)(2)(B)13(a) of the SecuritiesExchange Act.   

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. o

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes   No  x

As of June 30, 2019,2021, the last day of the registrant's most recently completed second fiscal quarter, the aggregate market value of the common stock held by non-affiliates of the registrant was approximately $18.1 million,$1.6 billion, based upon the closing price of the registrant's common stock on June 30, 2019.2021.

As of March 20, 2020,February 21, 2022, there were 52,625,228199,488,183 outstanding shares of the registrant’s common stock, $0.01 par value per share.

DOCUMENTS INCORPORATED BY REFERENCE

Part III of this Annual Report on Form 10-K incorporates certain information by reference from the registrant’s proxy statement for the 20202022 annual meeting of stockholders to be filed no later than 120 days after the end of the registrant’s fiscal year ended December 31, 2019.
2021.




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As previously announced, on September 27, 2019, Ocugen, Inc. (formerly known as Histogenics Corporation) (referred to herein as "Ocugen" or the "Company", completed its reverse merger with Ocugen Opco, Inc. (formerly known as Ocugen, Inc.) (“Former Ocugen”), in accordance with the terms of the Agreement and Plan of Merger and Reorganization, dated as of April 5, 2019 by and among Ocugen, Former Ocugen and a wholly owned subsidiary of Ocugen (“Merger Sub”), as amended (the “Merger Agreement”), pursuant to which Merger Sub merged with and into Former Ocugen, with Former Ocugen surviving as a wholly owned subsidiary of Ocugen (the “Merger”).
For accounting purposes, the Merger is treated as a “reverse asset acquisition” under generally acceptable accounting principles in the United States (“U.S. GAAP”) and Former Ocugen is considered the accounting acquirer. Accordingly, Former Ocugen’s historical results of operations will replace the Company’s historical results of operations for all periods prior to the Merger and, for all periods following the Merger, the results of operations of the combined company will be included in the Company’s financial statements.
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This Annual Report on Form 10-K relates to the Company’s fiscal year ended December 31, 2019, which includes the date of the completion of the Merger and is therefore the Company’s first annual report that includes results of operations for the combined company, including Former Ocugen.
Unless the context otherwise requires, references to the “Company,” the “combined company” “we,” “our”“our,” or “us” in this report refer to Ocugen, Inc. (formerly known as Histogenics Corporation) and its subsidiaries, references to “Ocugen” refer to the Company following the completion of the Merger, references to “Histogenics” refer to the Company prior to the completion of the Merger and references to “OpCo” refer to Ocugen OpCo, Inc., the Company’s wholly owned subsidiary following the Merger.
subsidiary.
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DISCLOSURE REGARDING FORWARD-LOOKING STATEMENTS
This Annual Report on Form 10-K and the documents incorporated by reference herein contain forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts contained in this Annual Report on Form 10-K or the documents incorporated by reference herein, regarding our strategy, future operations, future financial position, future revenues, projected costs, prospects, plans, and objectives of management are forward-looking statements. These statements involve known and unknown risks, uncertainties, and other important factors that may cause our actual results, performance, or achievements to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “will,” “would”“would,” or the negative of such terms and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are based on assumptions and expectations that may not be realized and are inherently subject to risks, uncertainties, and other factors, many of which cannot be predicted with accuracy and some of which might not even be anticipated.
The forward-looking statements in this Annual Report on Form 10-K and the documents incorporated herein by reference include, among other things, statements about:
our estimates regarding expenses, future revenue, capital requirements, and the timing and availability of and the need for additional financing;
our ability to obtain sufficient additional capitalfunding to continue to advance theseour product candidates;
our activities with respect to BBV152, known as COVAXIN outside the United States, our vaccine candidate for the prevention of COVID-19 caused by SARS-CoV-2 in humans, in collaboration with Bharat Biotech International Limited (“Bharat Biotech”), including our plans and expectations regarding clinical development, manufacturing, pricing, regulatory review and compliance, reliance on third parties, and commercialization, if authorized or approved in the United States and Canada;
our plans regarding the submission of a Biologics License Application ("BLA") to the U.S. Food and Drug Administration ("FDA") for adults ages 18 years and older, including the need for the Phase 2/3 immuno-bridging and broadening clinical trial and a safety-bridging clinical trial to support a BLA submission;
our submission of a request to the FDA for Emergency Use Authorization ("EUA") for COVAXIN for pediatric use in children ages two to 18 years in the United States, which was based on the results of a Phase 2/3 immuno-bridging pediatric clinical trial conducted by Bharat Biotech in India;
our activities with respect to resolving the deficiencies communicated by Health Canada in its Notice of Deficiency ("NOD") on our New Drug Submission ("NDS") for COVAXIN, including our responses provided to Health Canada;
our ability to successfully obtain adequate supply of COVAXIN from Bharat Biotech and to complete a technology transfer to our third-party manufacturer, Jubilant HollisterStier, and engage such manufacturer on commercially acceptable terms;
anticipated market demand for COVAXIN in the United States and Canada, including for both the pediatric and adult populations;
our ability to successfully continue and complete the Phase 1/2 clinical trial for OCU400 pursuant to the Investigational New Drug ("IND") accepted by the FDA;
the uncertainties associated with the clinical development and regulatory authorization or approval of our product candidates, including potential delays in the initiation, commencement, enrollment, and its preclinical programs;completion of clinical trials;
our ability to realize any value from product candidates and preclinical programs being developed and anticipated to be developed in light of inherent risks and difficulties involved in successfully bringing product candidates to market and the risk that products will not achieve broad market acceptance;
uncertainties in obtaining successful clinical trial results for product candidates and unexpected costs that may result therefrom;
our ability to comply with regulatory schemes applicable to our business and other regulatory developments in the United States, Canada, and other foreign countries;
our ability including the extent to operate under increased leverage and associated lending covenants;
which developments with respect to the uncertainties associated withCOVID-19 pandemic will affect the clinical development and regulatory approval of product candidates, including potential delayspathway available for COVID-19 vaccines in the commencement, enrollment and completion of clinical trials;United States, Canada, or other jurisdictions;
the performance of third-parties upon which we depend, including third-party contract researchdevelopment and manufacturing organizations (“CROs”("CDMOs"), and third-party suppliers, manufacturers, group purchasing organizations, distributors, and logistics providers;
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the pricing and reimbursement of our product candidates, if authorized or approved;
our ability to obtain and maintain patent protection, or obtain licenses to intellectual property and defend our intellectual property rights against third-parties;
our ability to maintain our relationships, profitability, and contracts with our key collaborators and commercial partners; including with Bharat Biotech and CanSino Biologics, Inc. ("CanSinoBIO"), and our ability to establish additional collaborations and partnerships;
our ability to recruit or retain key scientific, technical, commercial, and management personnel or to retain our executive officers; and
our ability to comply with stringent U.S., Canada, and other foreign government regulation in the manufacture of pharmaceutical products, including current Good Manufacturing Practice (“cGMP”("cGMP") compliance and U.S. Drug Enforcement Agency compliance, and other relevant regulatory authorities.authorities; and
the extent to which health epidemics and other outbreaks of communicable diseases, including the COVID-19 pandemic, could disrupt our business and operations including impacts on our development programs, global supply chain, and collaborators and manufacturers, including Bharat Biotech and CanSinoBIO.
We may not actually achieve the plans, intentions, or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions, and expectations disclosed in the forward-looking statements we make. We have included important factors in the cautionary statements included in this Annual Report on Form 10-K, particularly under “Risk Factors,” that we believe could cause actual results or events to differ materially from the forward-looking statements that we make. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures, collaborations, or investments we may make.
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You should read this Annual Report on Form 10-K and the documents that we incorporate by reference herein and have filed as exhibits to this Form 10-K, completely and with the understanding that our actual future results may be materially different from what we expect. We do not assume any obligation to update any forward-looking statements.
In addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of the date of this Annual Report on Form 10-K, and while we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an exhaustive inquiry into, or review of, all relevant information. These statements are inherently uncertain and investors are cautioned not to unduly rely upon these statements.
Solely for convenience, tradenames and trademarks referred to in this Annual Report on Form 10-K appear without the ® symbol,or TM symbols, but those references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights or that the applicable owner will not assert its rights, to these tradenames.tradenames or trademarks, as applicable. All tradenames, trademarks, and service marks and tradenames included or incorporated by reference in this Annual Report on Form 10-K are the property of their respective owners. Further, for ease of reference, the name "COVAXIN" is used throughout this Annual Report on Form 10-K to refer to the vaccine candidate, BBV152. The name COVAXIN has not been evaluated or cleared by the FDA or Health Canada.

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PART I
Item 1.    BusinessBusiness.
OVERVIEW
We are a clinical-stage biopharmaceutical company focused on discovering, developing and commercializing transformativegene therapies to treat the whole eye.cure blindness diseases and developing a vaccine to save lives from COVID-19.
Our cutting-edge technology pipeline includes:
COVID-19 Vaccine Candidate — COVAXIN is a whole-virion inactivated COVID-19 vaccine candidate being developed to prevent COVID-19 infection in humans. We are focused on three waves of technological innovations that targetco-developing COVAXIN with Bharat Biotech for the backU.S. and front of the eye:
Potential therapies that target the back of the eye:Canadian markets.
Modifier Gene Therapy Platform—Based on nuclear hormone receptors ("NHRs"), we believe our modifier gene therapy platform has the potential to address many retinal diseases, including retinitis pigmentosa ("RP") with one product., Leber congenital amaurosis ("LCA"), and dry age-related macular degeneration (“AMD”).
Novel Biologic TherapiesTherapy for Retinal Diseases—We are developing OCU200, which is being developeda novel biologic product candidate, to treat diabetic macular edema (“DME”), diabetic retinopathy (“DR”), and wet age-related macular degeneration (“AMD”).AMD.
Potential therapy that targetsCOVID-19 Vaccine Candidate
In February 2021, we entered into a Co-Development, Supply and Commercialization Agreement with Bharat Biotech, pursuant to which we obtained an exclusive right and license under certain of Bharat Biotech’s intellectual property rights, with the frontright to grant sublicenses, to develop, manufacture, and commercialize COVAXIN for the prevention of COVID-19 in the eye:United States, its territories, and possessions. In June 2021, we entered into an amendment to the Co-Development, Supply and Commercialization Agreement (as so amended, the "Covaxin Agreement") pursuant to which we and Bharat Biotech agreed to expand our rights to develop, manufacture, and commercialize COVAXIN to include Canada in addition to the United States, its territories, and possessions (the "Ocugen Covaxin Territory").
Small Molecule Phase 3 Rare Disease Asset—Our OCU300 product candidateCOVAXIN is formulated with the inactivated SARS-CoV-2 virus, an antigen, and an adjuvant. COVAXIN requires a two-dose vaccination regimen given 28 days apart and is stored in standard vaccine storage conditions (2-8°C). COVAXIN has been authorized or approved in more than a dozen countries and was granted an Emergency Use Listing ("EUL") by the World Health Organization ("WHO") in November 2021. Over 295 million doses globally have been administered to date.
The Phase 3 clinical developmenttrial conducted by Bharat Biotech in India in 25,798 adults, who were healthy or had stable chronic medical conditions ages 18 years and older, reported an overall estimated vaccine efficacy of COVAXIN against COVID-19 infection of 77.8%, with efficacy against severe COVID-19 infection of 93.4%, and efficacy against asymptomatic COVID-19 infection of 63.6%. Approximately 30% of participants were seropositive at baseline in each dosing group and were excluded from the per protocol analysis but contributed to the safety dataset. COVAXIN was generally well tolerated, with no clinically or statistically significant differences in reported adverse events in the vaccine and placebo groups. Additionally, a Phase 2/3 immuno-bridging clinical trial was conducted by Bharat Biotech in India to assess the protective immunity of COVAXIN in children ages two to 18 years. The results demonstrated a robust neutralizing antibody response comparable to that of the adults studied in the Phase 3 clinical trial, and that COVAXIN was generally well tolerated. This study demonstrated a favorable safety profile, including no hospitalizations, myocarditis, or vaccine-induced thrombotic thrombocytopenia. Additionally, data from the clinical trials and from research conducted by third parties has shown that COVAXIN has neutralizing potential against multiple variants of concern including both the Omicron (B.1.1.529) and Delta (B.1.617.2) variants.
In June 2021, the FDA provided feedback to us regarding the data and information contained in a "Master File" that we previously submitted to the FDA and recommended that we pursue a BLA submission instead of the EUA application for COVAXIN for adults ages 18 years and older in the United States. As part of the feedback provided, the FDA requested additional information and data. In October 2021, we submitted an IND application to the FDA to initiate a Phase 2/3 immuno-bridging and broadening clinical trial evaluating COVAXIN for ages 18 years and older. The clinical trial is designed to evaluate whether the immune response experienced in participants in the aforementioned completed Phase 3 clinical trial in India is similar to a demographically representative, adult population in the United States. In November 2021, we were notified that the FDA issued a clinical hold on our IND application. In December 2021, the FDA sent us a letter setting forth the reasons for the treatmentclinical hold and specific guidance on steps that must be taken to have the clinical hold lifted. We provided the FDA responses to their comments and the FDA lifted its clinical hold in February 2022. We plan to initiate the Phase 2/3 immuno-
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bridging and broadening clinical trial for COVAXIN as soon as we are able to. We also plan to initiate a safety-bridging clinical trial in the first half of 2022, subject to discussions with ocular graft-versus-host disease (“oGVHD”the FDA. Subject to the foregoing, we anticipate submitting a BLA with the FDA near the end of 2022. In November 2021, we also submitted a request to the FDA for EUA for COVAXIN for pediatric use in ages two to 18 years in the United States. The EUA submission was based on the results of the aforementioned Phase 2/3 immuno-bridging pediatric clinical trial conducted by Bharat Biotech in India. Our EUA submission is currently under review by the FDA. In February 2022, Delta and Omicron neutralization results along with a safety database of more than 36 million teenagers who had been vaccinated with COVAXIN were submitted to the FDA to support our EUA submission.
We are also pursuing approval for COVAXIN in Canada. In July 2021, we completed our rolling submission to Health Canada for COVAXIN. The rolling submission process, which permits companies to submit safety and efficacy data and information as they become available, was recommended and accepted under the Minister of Health’s Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 (the "Interim Order") and transitioned to a NDS. The submission was conducted through our Canadian subsidiary, Vaccigen Ltd. ("Vaccigen"). We are in discussions with Health Canada regarding our NDS submission for COVAXIN. In December 2021, we were provided with a NOD from Health Canada regarding our NDS submission. Health Canada requested further analyses of the COVAXIN preclinical and clinical data, as well as additional information regarding chemistry, manufacturing, and controls ("CMC"). We have responded to and provided proposed resolutions for the deficiencies included in the NOD. Our responses are currently under review by Health Canada.
Modifier Gene Therapy Platform
We are developing a modifier gene therapy platform to generate therapies designed to fulfill unmet medical needs in the area of retinal diseases, including inherited retinal diseases (“IRDs”("IRDs")., such as RP and LCA, and dry AMD. Our modifier gene therapy platform is based on nuclear hormone receptors (“NHRs”),NHRs, which have the potential to restore homeostasis, the basic biological processes in the retina. Unlike single-gene replacement therapies, which only target one genetic mutation, we believe that our modifier gene therapy platform, through its use of NHRs, represents a novel approach in that it mayhas the potential to address multiple retinal diseases caused by mutations in multiple genes with one product. product; and potentially address complex diseases, such as dry AMD, that are potentially caused by imbalances in multiple gene networks.
IRDs, such as RP and LCA, can lead to visual impairment and blindness and affect over 1.5two million people worldwide. Over 150 gene mutations have been associated with RP and this number represents only 60%LCA are rooted in mutations of more than 175 different genes. We believe that OCU400, our first product candidate being developed with our modifier gene therapy platform, has the potential to be broadly effective in restoring retinal integrity and function across a range of IRDs, including RP population. The remaining 40% of RP patients cannot be genetically diagnosed, making it difficult to develop individual treatments.and LCA. For example, we believe OCU400 has the potential to eliminate the need for developing more than 150175 individual products and provide one treatment option for all RP and LCA patients. Our first gene therapy candidate, OCU400 has received two orphan drug designationsfour Orphan Drug Designations ("ODDs") from the U.S. Food and Drug Administration ("FDA"), oneFDA for the treatment of certain disease genotypes: nuclear receptor subfamily 2 group E member 3 ("NR2E3"), centrosomal protein 290 ("CEP290"), rhodopsin ("RHO"), and phosphodiesterase 6B ("PDE6ß") mutation-associated inherited retinal diseases anddegenerations. In November 2021, we submitted an IND application to the otherFDA for OCU400 for the treatment of centrosomal protein 290 ("the CEP290")NR2E3 mutation-associated retinal diseases.and RHO disease genotypes. Our IND application was accepted by the FDA in December 2021. We have initiated a Phase 1/2 clinical trial in the United States for the treatment of these disease genotypes and the first patient is expected to be dosed in the first half of 2022. This Phase 1/2 clinical trial is a multicenter, open-label, dose ranging study to assess the safety of unilateral subretinal administration of OCU400 in subjects with NR2E3-related RP. OCU400 has additionally received Orphan Medicinal Product Designation ("OMPD") from the European Commission ("EC"), based on the recommendation of the European Medicines Agency ("EMA"), for RP and LCA. We believe OCU400 has the potential for broad-spectrum application to treat many IRDs. We are planningcurrently evaluating options to initiate a Phase 1/2aOCU400 clinical trial for OCU400trials in 2021. Europe.
Our second gene therapy candidate, OCU410, is being developed to utilize the nuclear receptor genes RAR-related orphan receptor A (“("RORA") for the treatment of dry AMD. This candidate isWe are currently in preclinical development.executing pre-IND studies consistent with FDA discussions to support a Phase 1/2 clinical trial.
Novel Biologic TherapiesTherapy for Retinal Diseases
We are in preclinical development for a novelOur pipeline also includes our biologic product candidate, OCU200. OCU200, is a novel fusion protein designed to treat severely sight-threatening diseases such as DME, DR, and wet AMD. We expectare currently establishing a cGMP process for the production of clinical trial materials and executing pre-IND studies consistent with FDA discussions to initiatesupport a Phase 1/22a clinical trial for OCU200 within the next two years. We plan to expand the therapeutic applications of OCU200 beyond DME, DR and wet AMD to potentially include macular edema following retinal vein occlusion (“RVO”) and myopic choroidal neovascularization (“mCNV”).
Small Molecule Phase 3 Rare Disease Asset
We are also developing OCU300, which is a small molecule therapeutic currently in Phase 3 clinical development for patients with oGVHD. OCU300 is a brimonidine tartrate eye drop formulated as a topical nanoemulsion. As of March 20, 2020, we had completed over 95% of planned enrollment of our Phase 3 clinical trial for OCU300. OCU300 has received ODD from the FDA, and it is the first and only product candidate to receive that designation for the treatment of symptoms associated with oGVHD. oGVHD, a severe chronic autoimmune disease that occurs in up to 60% of patients receiving hematopoietic stem cell transplantation (“HSCT”) from donors, referred to as allogeneic HSCT, can result in light sensitivity, excessive ocular redness, severe ocular pain and, ultimately, vision impairment. We estimate the current prevalence of patients suffering from oGVHD in the United States to be approximately 63,000. OCU300 is formulated using our proprietary nanoemulsion technology, OcuNanoE—Ocugen’s ONE Platform™ (“OcuNanoE™”), which we believe represents an effective drug delivery mechanismtrial.
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to treat ocular surface disorders. We believe that OcuNanoE™ provides additional protection to the ocular surface and the potential for enhanced efficacy compared to traditional formulations. OcuNanoE nanoemulsion was developed to decrease the drainage rate, prolong precorneal residence time and increase the drug concentration in the lacrimal gland, which is critical for tear film production. We are the first and only company to use nanoemulsion technology in the ophthalmology space.
We are headquartered in Malvern, Pennsylvania, and our common stock trades on The NASDAQ Capital Market (“Nasdaq”) under the symbol “OCGN.” On September 27, 2019, we completed our reverse merger with Ocugen OpCo Inc. (formerly known as Ocugen, Inc. (“Former Ocugen”)) in accordance with the terms of the Agreement and Plan of Merger and Reorganization, dated as of April 5, 2019, by and among Histogenics, Former Ocugen and Restore Merger Sub, Inc., a wholly owned subsidiary of Histogenics (“Merger Sub”), as amended (the “Merger Agreement”), pursuant to which Merger Sub merged with and into Former Ocugen, with Former Ocugen surviving as a wholly owned subsidiary of Histogenics (the “Merger”). Immediately after completion of the Merger, Histogenics changed its name to Ocugen, Inc. and the business conducted by Ocugen, Inc. became the business conducted by Former Ocugen.
OUR STRATEGY
We are developing novel solutions to medical challenges, approaching healthcare innovation with purpose and agility to deliver new options for people facing disease. Our current product candidates have the potential to address unmet medical needs in both retinalsave lives from COVID-19 and ocular surfacecure blindness diseases. We are committed to developing these product candidates and bringing them to market to serve patients. Key elements of the strategy we employ to accomplish this objectivemission include:
EstablishingAdvancing our COVID-19 vaccine candidate in North America towards commercialization, if authorized or approved.We have continued discussions about the regulatory pathway for COVAXIN with the FDA and Health Canada and we intend to advance COVAXIN towards authorization or approval in both jurisdictions to augment the North American arsenal of vaccines against COVID-19 and expand the COVID-19 vaccine choices for individual patients. We will continue to expand our headcount, infrastructure, and partnerships to support commercialization in both the United States and Canada.
Advancing our modifier gene therapy platform and advancing OCU400 and OCU410 intothrough clinical development. We intend to advance OCU400 and OCU410 through clinical development for the treatment of multiple IRDs, such as RP and LCA, and dry AMD, respectively. We have initiated a Phase 1/2 clinical trial for OCU400 for the treatment of the NR2E3 and RHO disease genotypes and are executing pre-IND studies consistent with FDA discussions to support a Phase 1/2 clinical trial for OCU410. We will continue to explore additional NHR-based product candidates to bring our cutting-edge modifier gene therapy platform technology to a broad range of patients to address rare and complex diseases.
Advancing our preclinical biological program into clinical development. We intend to advance OCU200, our biologic product candidate, into and through clinical development for the treatment of multiple IRDsseverely sight-threatening diseases such as DME, DR, and for the treatment of dry AMD, respectively. In additionWet AMD. We are currently executing pre-IND studies consistent with FDA discussions to OCU400 and OCU410, we will also explore additional NHR-based product candidates for multiple eye disease indications.support a Phase 1/2a clinical trial.
Advancing the development of OCU300 to approval. We have initiated Phase 3 registration trials using OCU300 as a first-in-class treatment for ocular rednessExpanding and discomfort in patients with oGVHD. While the clinical trials are progressing and successful completion of such trials is a prerequisite for the submission of a New Drug Application (“NDA”) to the FDA, we have concurrently begun development of chemistry, manufacturing and controls (“CMC”) for OCU300, including process validation and stability studies of registration batches. OCU300 has been granted ODD, and accordingly it may be eligible for seven-year market exclusivity.
Exploring potentialexploring partnerships with leading pharmaceuticalcurrent and biotechnology companiesfuture key collaborators and commercial partners to maximize patient access, global reach, and the value of its product candidates. We currently plan to explore licensing the commercialization rights to our product candidates, or other forms of collaboration with qualified potential partners in certain key markets outside of the United States, including Europe, Japan and emerging markets, including potentially partnering commercialization rights for OCU300. During 2019, we entered into a co-development commercialization agreement with CanSino Biologics Inc. ("CanSinoBIO") with respectas well as to the development and commercialization of our initial gene therapy product candidate, OCU400.
Advancing preclinical biological programs into clinical development. Within the next two years, we intend to advance OCU200,expand our product candidate targeting DME, DRpipeline. We intend to explore strategic licensing, acquisition, and wet AMD into clinical development. Thiscollaboration opportunities with qualified partners to maximize the benefit of our product candidates on patients globally and to expand our product candidate is currently in preclinical development.pipeline to support our future growth.
COMPETITIVE STRENGTHS
Our key competitive strengths include:
Gene Therapy Manufacturing. We have established a strategic partnership with CanSinoBIO for CMC development and manufacturing of clinical supplies for our gene therapy candidate, OCU400. The partnership secures hard-to-find manufacturing capacity and expertise for gene therapy product development. This will help with the development timeline and significant reduction in associated costs.
Intellectual Property Portfolio. We hold the worldwide commercial rights for our current product candidates. Our intellectual property portfolio contains patents and pending patent applications related to composition of matter, pharmaceutical compositions and methods of use for our product candidates, which have been licensed from leading institutions. We strive to protect the proprietary technology that we believe is important to our business, including seeking and maintaining patents for our product candidates and OcuNanoE platform. We have patent protection for OCU300 in the United States through at least 2036.
We seek to protect our proprietary and intellectual property positions by filing U.S. and foreign applications for our clinical program, OCU300, preclinical development programs, OCU400, and OCU200, as well as technology
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platforms critical to the development and implementation of our business strategy. We have built a strong global patent portfolio with 34 U.S. or foreign issued patents and 30 patent applications, including patents licensed from The Schepens Eye Research Institute ("SERI"), the University of Colorado ("CU"), and the University of Illinois at Chicago ("UIC"). As of March 2020, we had exclusive rights or owned rights to: (i) three issued patents and 11 pending U.S. and foreign patent applications related to OCU300; (ii) one issued patent and four pending applications related to OCU400; and (iii) 25 issued U.S. and foreign patents and three pending patent applications related to OCU200.
Licensing Arrangements with Leading Institutions. We have three licensing agreements with leading academic and medical institutions that cover our four product candidates. In December 2017, we entered into an exclusive worldwide license agreement with SERI, an affiliate of Harvard Medical School, pursuant to which we acquired patent rights for NHRs, including those used in our OCU400 and OCU410 programs. In March 2014, we entered into an exclusive worldwide license agreement with the CU pursuant to which we acquired rights to the transferrin-tumstatin fusion protein technology used in OCU200 as well as other technology. In February 2016, we entered into an exclusive worldwide license agreement with UIC pursuant to which we acquired rights develop brimonidine tartrate for the treatment of ocular surface diseases, which is the compound used in our OCU300 program.
Experienced Management Team.Team and Esteemed Scientific Advisory Boards. Our management team has a combinedand key advisors have extensive experience of over 200 years with a proven track record of success in developing, launching, and managing the life cycle of many vaccines and biopharmaceuticals at leading pharmaceutical companies (including Pfizer and Merck) and biotechnology companies. Our vaccine and retina scientific advisory boards are composed of leading academic and industry experts with extensive experience in the infectious disease and ocular fields. We believe that the experience of our management team, our scientific advisory board members, and our broad network of relationships with leaders within the industry and the medical community provides us with insight into product development andthe identification of product candidate opportunities as well as supports us in advancing the development and commercialization of our product candidates.
Product Candidate Manufacturing. We have established partnerships for the clinical and commercial manufacturing of our product candidates, including partnerships with Jubilant HollisterStier and Bharat Biotech for COVAXIN and CanSinoBIO for our modifier gene therapy platform. These partners have state-of-the-art facilities and proven expertise in the fields of vaccines and gene therapy, which is critical to address underserved eye diseases.advancing our product candidates into and through clinical trials and commercialization as well as accelerating development timelines, reducing our associated costs, and increasing the reliability of our product candidate manufacturing.
Orphan Medicinal Product Designations and Orphan Drug Designations. OCU400 has received OMPD from the EC, based on the recommendation of the EMA, for RP and LCA. The OMPD demonstrates the potential broad spectrum application of OCU400, through its use of NHRs, to treat the more than 175 gene mutations associated with RP and LCA with one product rather than developing individual treatments for each gene mutation. OCU400 has additionally received four ODDs from the FDA for the treatment of certain disease genotypes: NR2E3, CEP290, RHO, and PDE6ß mutation-associated inherited retinal degenerations.
Licensing and Development Arrangements and Intellectual Property Portfolio. We have licensing and development arrangements with leading companies, academic institutions, and medical institutions that cover all of our product candidates. These licensing and development arrangements include the Covaxin Agreement with Bharat Biotech with respect to the development and commercialization of COVAXIN in the United States and Canada, the licensing agreement with The Schepens Eye Research Institute ("SERI"), an affiliate of Harvard Medical School, through which
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we acquired the technology used in our modifier gene therapy platform as well as access to technologies for other NHR genes, and the license agreement with the University of Colorado ("CU") pursuant to which we acquired rights to the transferrin-tumstatin fusion protein technology used in our OCU200 product candidate. Our global intellectual property portfolio contains 46 patents and 10 pending patent applications related to composition of matter, pharmaceutical compositions, and methods of use for our product candidates, including those under our licensing and development arrangements. We will leverage these domestic and global partnerships and our intellectual property portfolio to advance our near- and long-term product pipeline opportunities.
OUR PRODUCT CANDIDATE PIPELINE
Our current product candidate pipeline candidates areis summarized in the following chart:
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COVID-19 VACCINE PRODUCT CANDIDATE FOR THE TREATMENT OF OCULAR SURFACE DISEASES
OCU300COVAXIN is a whole-virion inactivated COVID-19 vaccine candidate being developed for the Treatmentprevention of Ocular RednessCOVID-19. COVAXIN is manufactured using a Vero cell manufacturing platform. We are co-developing COVAXIN with Bharat Biotech, a global leader in vaccine innovation, for the Ocugen Covaxin Territory. COVAXIN has been authorized or approved in more than a dozen countries and Discomfortwas granted an EUL by the WHO in PatientsNovember 2021. Over 295 million doses globally have been administered to date. See "—License and Development Agreements—Covaxin Agreement" and Note 3 in the notes to the consolidated financial statements included in this elsewhere in this Annual Report on Form 10-K for additional information about our partnership with oGVHDBharat Biotech.
OCU300Overview of COVID-19
COVID-19 infection, caused by SARS-CoV-2, was first reported to have surfaced in Wuhan, China in December 2019 and was declared a global pandemic by the WHO in March 2020. COVID-19 is a late-stage product candidate for which we have initiated a randomized, double-masked, placebo-controlled, Phase 3 trial for the treatment of ocular redness and discomfort in patients with oGVHD. There currently are no FDA-approved products for oGVHD. oGVHD is a severe chronic autoimmunehighly transmissible disease that occursspreads from person to person through respiratory droplets that are produced when an infected person coughs, sneezes, or talks. Common symptoms of COVID-19 include cough, shortness of breath or difficulty breathing, fever or chills, muscle or body aches, sore throat, congestion, or loss of taste or smell. Certain people are at an increased risk for severe COVID-19 infection including those over the age of 65 and with underlying medical conditions, including cancer, heart conditions, obesity, and diabetes, along with many other underlying conditions. Those at increased risk for severe COVID-19 infection are more likely to be hospitalized, need intensive care, require a ventilator, or die. Since being discovered, new variants of SARS-CoV-2 have emerged. New variants of a virus emerge when a mutation to the virus' genes occurs. In November 2021, the Omicron variant (B.1.1.529) was identified in upSouth Africa and has been deemed a variant of concern by the WHO. Current research suggests that the Omicron variant (B.1.1.529) is more contagious and there is an increased risk of reinfection with the Omicron variant (B.1.1.529), i.e., people who previously had COVID-19 could become reinfected more easily with the Omicron variant (B.1.1.529) as compared to 60%the other variants of allogeneic HSCT recipients and represents a critical unmet medical need.concerns, including those who received authorized or approved vaccines. In addition to the Omicron variant (B.1.1.529), the WHO has deemed four other SARS-CoV-2 variants to be variants of concern: the Alpha variant
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OCU300(B.1.1.7), the Beta variant (B.1.351), the Gamma variant (P.1), and the Delta variant (B.1.617.2). All of the aforementioned variants have at least one of the following characteristics resulting in the WHO to deem them variants of concern: an increase in transmissibility or detrimental change in COVID-19 epidemiology, an increase in virulence or change in clinical disease presentation, or a decrease in the effectiveness of public health and social measures or available diagnostics, vaccines, or therapeutics.
COVAXIN for the Prevention of COVID-19
COVAXIN is formulated with the inactivated SARS-CoV-2 virus, an antigen, and an adjuvant, which is a twice-daily eye drop of brimonidine tartrate (0.18%) OcuNanoE nanoemulsion. OCU300common approach to vaccine design. COVAXIN is sterile-filtered, preservative-free, and steroid-free, and it has been designed as such to avoid certain side effects. In addition to the existing ODD for oGVHD, we are eligible to utilize the streamlined Section 505(b)(2) regulatory pathway forwhole-virion inactivated SARS-CoV-2 virus to trigger the approvalimmune response to create antibodies against multiple antigens. Inactivated vaccines do not replicate and are therefore unlikely to revert and cause pathological effects. COVAXIN has an antigen concentration of OCU300six micrograms and utilizes a toll-like receptor 7/8 agonist molecule (IMDG) adsorbed to alum (Algel) as an adjuvant designed to boost COVAXIN's immunogenicity and increase COVAXIN's effectiveness. The toll-like receptor 7/8 plays a vital role in the immune response to COVID-19 infection. The adjuvant used in the formulation of COVAXIN was developed in the United States. We believe that the Section 505(b)(2) regulatory pathway provides usStates with a potential path to market by allowing us to rely on certain informationfunding from studies conducted by third parties. As of March 20, 2020, we have enrolled over 95% of the planned sample size into the first pivotal, Phase 3 trial of OCU300.
oGVHD is a disease driven by the invasion of HSCT-derived leukocytes onto the ocular surface, resulting in fibrosis and excessive production of extracellular matrix (“ECM”) proteins. The donor leukocytes subsequently launch an autoimmune assault on the tear-producing glands, cornea, conjunctiva and eyelid of the recipient. oGVHD can cause irreparable damage to these ocular tissues, thereby decreasing the secretion and stability of tear film. Prolonged inflammation can result in ocular pain and discomfort, corneal ulceration, cicatricial conjunctivitis, blepharitis, and vision loss.
In order to treat oGVHD, a viable product must have the ability to interrupt the pathological process of the disease, which can involve the local infiltration of inflammatory cells, the activation of leukocytes, fibrosis, the production of ECM proteins and the disruption of tear production. Brimonidine tartrate, which is approved for other ophthalmic indications, is an imidazoline compound that acts as a specific α2-adrenergic agonist. It has 1,000 times higher selectivity for α2-adrenergic receptors than α-1 adrenergic receptors. We believe brimonidine tartrate can treat oGVHD in the following ways:
Reducing ocular surface blood flow,
Disrupting leukocyte extravasation to the ocular tissue,
Suppressing leukocyte activation,
Providing analgesic properties, and
Reducing fibrosis and suppressing excessive ECM protein formation.
By potentially attenuating autoimmune activity and inflammation, brimonidine tartrate may allow the ocular surface and tear film producing glands to avoid further atrophy and to heal from damage sustained during the HSCT pre-conditioning regimen. In addition, brimonidine tartrate may alleviate heightened ocular pain through its antinociceptive and anti-inflammatory properties, which in turn, may potentially make the drug more tolerable and more effective. Brimonidine tartrate is approved for other indications by the FDA and has demonstrated a favorable safety profile via topical ocular delivery.
Overview of Ocular Graft-versus-Host Disease
oGVHD, which occurs exclusively in allogeneic HSCT recipients, is recognized by the National Institutes of Health ("NIH") and clinical experts as a distinct organ manifestation of chronic graft-versus-host disease. oGVHD is driven by an autoimmune mechanism and initiates immediately after bone marrow transplant completion with the encroachment of autoimmune cells onto the ocular surface. HSCT-derived leukocytes (i.e., T lymphocytes and neutrophils) invade the ocular surface of allogeneic HSCT recipients, resulting in excessive production of ECM proteins, and fibrosis. The donor leukocytes subsequently launch an autoimmune assault on the recipient eye’s tear producing glands, cornea, conjunctiva, and eyelid. The disease typically affects all major ocular surface tear film glands (i.e., the lacrimal gland, conjunctiva, and meibomian gland), as well as the cornea.
If left untreated, oGVHD can cause irreparable ocular surface damage and significant vision loss, leading to an overall decrease in their quality of life. The disease is most commonly associated with severe dry eye signs and symptoms, including visual hazing, reduction in visual acuity, light sensitivity (referred to as photophobia), excessive ocular redness, foreign body sensation and heightened ocular pain. Of the clinical symptoms reported with oGVHD, ocular pain is the one that most severely impactsfirst adjuvant in an authorized or approved vaccine against an infectious disease to activate toll-like receptor 7/8. In addition, the quality of life. In fact, the pain scores in oGVHD patients are comparable to those of patients suffering from ocular chemical burns. In severe cases, oGVHD can cause lens opacification, significant corneal epithelium degeneration and melting, including the development of corneal ulcers and corneal perforation, and may require multiple corneal grafts or surgeries to improve visual acuity. Furthermore, patients with oGVHD have difficulties in performing both near-vision activities and distance-vision activities, both centrally and peripherally, and suffer from cases of vision-related mental health decline.
The majority of patients with oGVHD become disabled and are unable to work and have reduced social functioning. As a result, the disease is associated with a significant economic impact on both patients and society. It has been estimated that the combined direct medical costs (e.g., prescription therapy, procedures, physician visits) and indirect costs (e.g., lost wages/productivity) resulting from oGVHDalum in the United States aggregateadjuvant stimulates the immune system to approximately $18,000 per patient per year.
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Absence of Approved Treatmentssearch for oGVHD Providesan invading pathogen. Molecules that activate toll-like receptor 7/8 provide a Market Opportunity
Up to 60% of patients that receive allogeneic HSCT in the United States are expected to develop oGVHD. We estimate the current prevalence of patients suffering from oGVHD in the United States to be approximately 63,000, which is anticipated to grow to approximately 140,000 patients by 2030. There are currently no FDA-approved drug products for the treatment of oGVHD.
Ongoing OCU300 Phase 3 Clinical Trials
As of March 20, 2020, we have enrolled over 95%powerful stimulation of the planned sample size into the first registration trial for OCU300. We planimmune system.
The rise of COVID-19 genetic variants has raised concerns that these variants may be able to conduct two identical trials. These studies will test OCU300 brimonidine tartrate (0.18%) OcuNanoE Ophthalmic Solution against placebo (ophthalmic buffered saline) for safetyescape neutralization by vaccines. The data from clinical trials conducted in India suggest that COVAXIN elicits a broad-spectrum immune response (including spike and efficacy in patients with oGVHD after 84 days of treatment. The study has two primary endpoints, ocular rednessnucleocapsid proteins) and ocular discomfort.
The pivotal trials have a planned sample size of approximately 60 patients in each study, randomized 2:1 (active: placebo). Subjects will be permitted to continue their existing ocular treatments. The trials are designed to measure the efficacy of OCU300 compared to placebo, dosed twice daily for approximately three months. After a baseline visit, patients will be observed during three additional visits, at Day 28, Day 56,induces both humoral and Day 84.
The co-primary endpoints of the Phase 3 trials are:
Ocular redness based on a 100-point Validated Bulbar Redness scale measuring change in appearance from baseline to Day 84; and
Ocular discomfort based on a 10-point Visual Analog Scale measuring change in intensity from baseline to Day 84. This scalecellular responses. In addition, COVAXIN is designed to capturegenerate memory T cell responses for its multiple epitopes, potentially indicating longevity of response, and a rapid antibody response to future infections. Furthermore, data suggests that COVAXIN may potentially generate robust immune memory to SARS-CoV-2 and certain variants of concern for at least six months after vaccination. We believe COVAXIN has certain characteristics that may be beneficial as compared to the typecurrently authorized or approved messenger RNA ("mRNA") and adenovirus-based vaccines. The beneficial characteristics of severe discomfort or pain often seen with oGVHD patients and has been validated as an assessment of pain intensity in multiple populations. Moreover, it has been recommended as the primary endpoint for use in clinical trials for chronic pain.
Severe ocular inflammation is a key factorCOVAXIN are described in the pathogenesis oGVHD. Ocular inflammation,figure below (Figure 1).
Figure 1: Beneficial characteristics of COVAXIN.
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Figure 1 describes the beneficial characteristics of COVAXIN including COVAXIN's design for broad spectrum immune response, efficacy results, known safety profile, and transportation and storage ease.
The inactivated SARS-CoV-2 virus in turn, contributes to ocular redness and discomfort.COVAXIN is inactivated using β-propiolactone treatment at a low temperature. As a result, ocular redness and discomfort are markers of inflammation in patients with oGVHD. By choosing ocular redness and ocular discomfort as co-primary endpoints,an inactivated virus vaccine, we are indirectly assessing brimonidine tartrate’s anti-inflammatory properties. In addition to its potential overall anti-inflammatory properties, brimonidine tartrate may have a direct effect on both ocular redness and discomfort. First, as an α2-adrenergic agonist, brimonidine tartrate may cause significant vasoconstriction leading tobelieve COVAXIN can use all the reduction of blood flow to the ocular surface and thereby reducing redness. Second, brimonidine tartrate may act as an ocular analgesic by interrupting pain pathways. Brimonidine tartrate has been shown to significantly suppress the stimulation of pain receptorsproteins in the murine cerebral cortex by antagonizing the effects of norepinephrine and phenylephrine. Nociceptive neuron activation in ocular surface tissue is linkedvirus to elevated ocular pain, photophobia and ocular discomfort. Accordingly, we believe that a treatment that can reduce ocular redness (and hence inflammation) while relieving ocular discomfort would significantly enhance the quality of life for patients suffering from oGVHD.
We expect to have top-line data available from the first trial in the second half of 2020. We will meet with the FDA to discuss top-line results and finalize our regulatory strategy for approval. We will conduct a pharmacokinetics study on OCU300 before submittingelicit an NDA to the FDA for product candidate approval.

Our Proprietary OcuNanoE—Ocugen’s ONE Platform™
We have core capabilities in ophthalmic drug delivery and plan to leverage our proprietary OcuNanoE nanoemulsion formulation to deliver drugs more efficiently to relevant ocular tissues. We believe that our proprietary drug delivery system is suitable for the delivery of drugs to the target tissues of the anterior segment of the eye for the treatment of ocular surface diseases such as oGVHD and dry eye disease ("DED"). OcuNanoE is also designed to provide protection to the ocular surface. Our proprietary OcuNanoE nanoemulsion formulation has shown positive results in preclinical studies and enhanced lacrimal gland drug distribution. It is manufactured as a sterile-filtered, preservative-free and steroid-free product, which is designed to avoid the side effects related to the use of steroids and preservatives.
We have applied this technology to create a nanoemulsion formulation of brimonidine tartrate, resulting in the development of OCU300. Data from a preclinical study suggests that brimonidine formulated with OcuNanoE may enhance drug distribution and penetration into the lacrimal gland, which is critical for tear film production. We believe this is significant given that approximately 90% of topical drugs applied to the anterior segment of the eye, such as eye drops, are lost into systemicimmune response, rather than
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circulation. We also believe our technology may be leveraged to formulate additional active molecules and to treat additional ocular surface disorders.
targeting the spike protein alone. We believe an inactivated whole-virion vaccine can produce a more robust response that our proprietary OcuNanoE™ formulation hascan elicit memory and cross-react with mutated strains. Once vaccinated with COVAXIN, the following attributes:
Oil in water nanoemulsion;
Capableimmune system can respond to a live infection of formulating water-soluble drug molecules inSARS-CoV-2. COVAXIN is intended for administration into the aqueous portiondeltoid muscle of the nanoemulsion;upper arm, in two doses occurring 28 days apart, and has a shelf life of 12 months from the date of manufacture at 2-8°C, which is standard vaccine storage conditions.
CapablePhase 1 and Phase 2 clinical trials were conducted by Bharat Biotech in India to evaluate the safety and immunogenicity of formulating water insoluble (lipiphilic) drug molecules inCOVAXIN. These clinical trials reported a favorable safety profile and strong Immunoglobulin G ("IgG") responses against the oil portion ofspike protein, the nanoemulsion;
Capable of delivering drug molecules to ocular tissues based upon a preclinical study;
Defined narrow range globules with average diameter of less than 100 nanometers;
Capable of filter sterilization without having to use non-scalable processes and/or preservatives; and
Suitable for commercial scale manufacturing.
As illustrated in Figure 1 below, tear film is composed of the inner mucin layer, the middle aqueous componentreceptor-binding domain, and the outer lipid layer. The mucin layer is derived from goblet cells from the conjunctiva and lacrimal glands; the aqueous layer is derived from the lacrimal glands; and the lipid layer is derived from the meibomian glands. Since 90%nucleocapsid protein of topical drugs applied to the anterior segment of the eye is lost into systemic circulation, the rest of the drug must reach a minimum threshold concentration in the target tissues, such as the lacrimal glands, conjunctiva and cornea, in order to exert the functional characteristics of the therapeutic. Therefore, treatment of diseases associatedSARS-CoV-2 along with the front of the eye, such as oGVHD, requires the stabilization of tear film and targeting the drug molecule at sufficient concentrations to the lacrimal functional unit which is primarily responsible for the tear film production and stability.
Figure 1 Tear film in Human Eye
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Given the structure of tear film and the human eye, we believe that our formulation has several novel properties, which may enable it to improve drug distribution and penetration:
it contains lipid components that may act as the lipid layer of the tear film both in its functional characteristics and its charge distribution;
it may mimic the charge characteristics of mucin and glycocalyx components present in the inner mucin layer, thus, potentially allowing the drug molecules to be carried to the site of action without binding to the mucin layer; and
it is a reproducible nanosized (less than 100 nanometers) emulsion which may enable the drug molecules to be transported through the interstitial cells to reach the specific target tissues.
In a DED mouse model study, we demonstrated that our nanoemulsion technology significantly reduced corneal epitheliopathy using brimonidine tartrate formulated with OcuNanoE as compared to brimonidine formulated without OcuNanoE. While a significant portion of conventionally formulated ophthalmic drugs are rapidly eliminated via the tear film, we believe that our nanoemulsion technology is capable of achieving higher concentration on the surface of the eye, thereby potentially enabling the active drug substance to reach cells in the underlying ocular tissue at higher therapeutic levels.
As shown in strong cellular responses (Figure 2 below,). Strong cellular responses are necessary for memory and long-term durability of vaccines.
Figure 2: Demonstration of broad-spectrum response of COVAXIN.
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Figure 2 demonstrates the protective effectSARS-CoV-2 virus. COVAXIN demonstrates a strong IgG response against the spike protein, the receptor-binding domain, and the nucleocapsid protein of OCU300the SARS-CoV-2 virus. Current mRNA and adenovirus-based vaccines only elicit responses against corneal epithelial damagethe spike protein.
A Phase 3, randomized, placebo-controlled clinical trial was conducted in comparisonIndia by Bharat Biotech to brimonidine tartrate 0.2% is demonstratedevaluate the efficacy of COVAXIN. The Phase 3 clinical trial enrolled 25,798 adults, who were healthy or had stable chronic medical conditions ages 18 years and older in India, including 10.7% of participants over the age of 60 and 27.5% of participants with at least one coexisting condition, including cardio-vascular, diabetes, or any other chronic stable condition. Participants with no serological evidence of previous exposure to SARS-CoV-2 received two doses of either COVAXIN or the placebo administered four weeks apart. The Phase 3 clinical trial reported an overall estimated vaccine efficacy of COVAXIN against COVID-19 infection of 77.8%, with efficacy against severe COVID-19 infection of 93.4%, and efficacy against asymptomatic COVID-19 infection of 63.6%. Approximately 30% of participants were seropositive at baseline in each dosing group and were excluded from the per protocol analysis but contributed to the safety dataset. The aforementioned efficacy results represent point estimates of vaccine efficacy with a mouse DED model. OCU30095% confidence interval of 65.2% to 86.4% against COVID-19 infection, 57.1% to 99.8% against severe COVID-19 infection, and 29.0% to 82.4% against asymptomatic COVID-19 infection. Adverse events in the COVAXIN and control arms of the Phase 3 clinical trial were observed in 12.4% of subjects, with less than 0.5% of subjects experiencing serious adverse events. The majority of the symptomatic cases identified in aggregate in the COVAXIN and control arms in the Phase 3 clinical trial were COVID-19 variants, the majority of which were identified to be the Delta variant (B.1.617.2) (Figure 3). Subjects vaccinated with COVAXIN in the Phase 3 clinical trial showed statistically significant protection against cornealthe Delta variant (B.1.617.2), showing a vaccine efficacy of 65.2%, which represents a point estimate of vaccine efficacy with a 95% confidence interval of 33.1% to 83.0%. Data from the clinical trials and from research conducted by third parties has shown that COVAXIN has neutralizing potential against multiple variants of concern including both the Omicron (B.1.1.529) and Delta (B.1.617.2) variants. Further, recent studies have shown that individuals receiving a COVAXIN booster dose six months following the second dose of COVAXIN saw a significant increase in neutralizing titers, an important predictor of vaccine efficacy. The increase in neutralizing titers was higher than that achieved after the primary two-dose series.
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epithelial cell damageFigure 3: Composition of COVID-19 variants in comparison to a commercial brimonidine tartrate solution (p<0.01). These results indicate that OCU300 may provide significantly better protection for corneal epithelial damage than placebo (vehicle) and a commercial brimonidine tartrate. The difference between OCU300 and brimonidine tartrate 0.2% provides support forsymptomatic infections identified in the potential importance of its nanoemulsion formulationadult Phase 3 clinical trial in contributing to the treatment of oGVHD. In addition, OCU300 significantly reduced the lacrimal gland pathology compared to the untreated control group (p<0.01). Goblet cell data, though not statistically significantly, showed a numerical improvement trend compared to the untreated control group.India.
Figure 2 Effect of OCU300 OcuNanoE against corneal epithelial damage in comparison to a commercial brimonidine tartrate using a mouse DED model. **P<0.01
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In 2018, we completed a preclinical ocular distribution study in dutch-belted rabbits that analyzed the distribution of brimonidine tartrate after the topical treatment with OCU300 in comparison to a brimonidine tartrate 0.2% solution.ocgn-20211231_g4.jpg
Figure 3 indicates brimonidine tartrate concentrationdisplays the COVID-19 variants that caused symptomatic infections in the lacrimal gland following a single dose with OCU300 versus brimonidine tartrate 0.2% solution. Dutch-belted rabbitsadult Phase 3 clinical trial conducted by Bharat Biotech in India. The majority of the cases were dosed with either OCU300 or a brimonidine tartrate 0.2% solutionidentified to be the Delta variant (B.1.617.2), followed by undisclosed variants, the Kappa variant (B.1.617.1), and the lacrimal glandsAlpha variant (B.1.1.7).
In June 2021, the FDA provided feedback to us regarding the data and information contained in a "Master File" that we previously submitted to the FDA and recommended that we pursue a BLA submission instead of an EUA application for COVAXIN for ages 18 years and older in the United States. As part of the feedback provided, the FDA requested additional information and data. In October 2021, we submitted an IND application to the FDA to initiate a Phase 2/3 immuno-bridging and broadening clinical trial evaluating COVAXIN for adults ages 18 years and older, intended to demonstrate a bridge to the Phase 3 clinical trial conducted in adult participants in India. In November 2021, we were removed at various intervals of time and analyzednotified that the FDA issued a clinical hold on our IND application. In December 2021, the FDA sent us a letter setting forth the reasons for the content of brimonidine tartrate. Resultsclinical hold and specific guidance on steps that must be taken to have the clinical hold lifted. We provided the FDA responses to their comments and the FDA lifted its clinical hold in February 2022. We plan to initiate the Phase 2/3 immuno-bridging and broadening clinical trial for COVAXIN as soon as we are represented as ng/gable to. We also plan to initiate a safety-bridging clinical trial in the Y-axis.first half of 2022, subject to discussions with the FDA. Subject to the foregoing, we anticipate submitting a BLA with the FDA near the end of 2022.
In November 2021, we also submitted a request to the FDA for EUA for COVAXIN for pediatric use in ages two to 18 years in the United States. The preclinicalEUA submission was based on the results of a Phase 2/3 immuno-bridging pediatric clinical trial conducted by Bharat Biotech in India, which included 526 children ages two to 18 years. The study indicated comparable immunogenicity data to the large Phase 3 adult clinical trial for COVAXIN in India. COVAXIN was evaluated in three age groups: ages two to six years, ages six to 12 years, and ages 12 to 18 years. All participants received two doses of COVAXIN 28 days apart. Immunogenicity against key COVID-19 proteins was measured using geometric mean titer ("GMT"), a test that measures the amount of antibodies in the blood in response to the presence of the SARS-CoV-2 virus. GMT was measured across the three age groups. The results showed that after a single dose, brimonidine tartrate levelsthe neutralizing antibody responses against the wild-type strain in the dutch-belted rabbitspediatric population ages two to 18 years were numerically highercomparable to those experienced in Bharat Biotech’s Phase 3 adult clinical trial in India. More than 90 percent of the seroconversion rates were observed for up to six hoursantibody titers against the spike protein, the receptor-binding domain, the nucleocapsid protein, and wild-type neutralizing antibodies. Among the 526 study subjects in the group treated with OCU300 compared to brimonidine tartrate levelspediatric clinical trial, no serious adverse events, such as deaths, hospitalizations, myocarditis, pericarditis, Guillain-Barre syndrome, vaccine-induced thrombotic thrombocytopenia, or anaphylactic reactions were reported. All other adverse events were mild or moderate in nature and were generally resolved within 24 hours. As aforementioned, COVAXIN is manufactured using a Vero cell manufacturing platform, which has been used in the group treated with brimonidine tartrate 0.2% solution, which provides supportproduction of the inactivated polio vaccine for the relative increased distributionpast 35 years, as well as for other traditional childhood vaccines. Our EUA submission is currently under review by the FDA. In February 2022, Delta and Omicron neutralization results along with a safety database of OCU300 in the lacrimal gland.
Figure 3 Brimonidine tartrate content (ng/g) in the lacrimal gland after a single dose
administration of OCU300 versus brimonidine tartrate 0.2%
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In summary, our data reported in the preclinical study supports the thesis that OCU300 distributes brimonidine tartratemore than 36 million teenagers who had been vaccinated with COVAXIN were submitted to the lacrimal glandFDA to a greater extent than a formulation without OcuNanoE.support our EUA submission.
We are also pursuing approval for COVAXIN in Canada. In July 2021, we completed our rolling submission to Health Canada for COVAXIN under the Minister of Health's Interim Order. Our submission was recommended and accepted under the Interim
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OCU310 for Dry Eye Disease
We were developing OCU310 for patients with DED, which is also formulated using OcuNanoE. We completedOrder and transitioned to a Phase 3 clinical trial for OCU310 in 2019. Although the trial showed that OCU310 is safe and well-tolerated, it did not meet its co-primary endpoints for symptom and sign.However, a pre-specified exploratory efficacy endpoint of reduction in redness (sign) from the baseline visit, measured by Validated Bulbar Redness score,NDS. The submission was statistically significantly better for OCU310 relative to placebo at both Day 14 and Day 28. This is consistent with the mechanism of action of brimonidine tartrate as an α2-agonist with anti-inflammatory properties.conducted through our Canadian subsidiary, Vaccigen. We are no longer pursuingin discussions with Health Canada regarding our NDS submission for COVAXIN. In December 2021, we were provided with a NOD from Health Canada regarding our NDS submission. Health Canada requested further analyses of the development of this product candidate.COVAXIN preclinical and clinical data, as well as additional information regarding CMC. We have responded to and provided proposed resolutions for the deficiencies included in the NOD. Our responses are currently under review by Health Canada.
OUR MODIFIER GENE THERAPY PLATFORM AND GENE THERAPY PRODUCT CANDIDATES
We are developing OCU400 which has received ODD for both the treatment of NR2E3 mutation-associated retinal diseases and CEP290 mutation-associated retinal diseases. We plan to initiate a Phase 1/2a clinical trial of OCU400 for the treatment of NR2E3 mutation-associated retinal degenerative disease in 2021. OCU400 is the first product candidate being developed by us withOCU410 using our modifier gene therapy platform utilizing NHRs. We are also utilizing our modifier gene therapy platform forto fulfill unmet medical needs in the developmentarea of OCU410, a product candidate designed to treatretinal diseases, including IRDs, such as RP and LCA, and dry AMD.
Breakthrough Platform Therapy Based on Nuclear Hormone Receptors
NHRs have long been known to play a critical role in modulating cellular homeostasis by regulating basic biological processes including development, metabolism, circadian cycle, and energy homeostasis. Our modifier gene therapy platform is being designed to target NHRs, which have the potential to restore homeostasis to the retina and accordingly to provide therapeutic benefit to patients sufferinga cutting-edge technology licensed from IRDs. Moreover, unlike single-gene replacement therapies, which only target one genetic mutation, we believe that our NHR-based approach represents a breakthrough modifier gene therapy platform that has the potential to restore retinal integrity and function across a range of genetically diverse IRDs and other degenerative retinal diseases, leading to multiple potential product opportunities. This approach has shown potential to rescue many genetic defects and may lead to vision-sparing therapies for rare IRDs including a broad spectrum of RP, as well as other forms of retinal and macular degeneration, providing us with significant potential long-term value.
NHR-based gene therapy platform encompasses the targeted delivery and expression of certain NHRs that are expressed naturally in retinal tissue. Preclinical studies conducted by Dr. Neena Haider and others have shown that NR2E3, a member of the NHR family, is a dual activator/repressor and that, with other transcription factors, modulates cell fate and differentiation of rod and cone photoreceptor cells in the eye (Figure 4). The delivery of Nr2e3 in a mouse, lacking a functional Nr2e3 gene, restored the retina structure and function. We believe that NR2E3 may partially or fully rescue photoreceptors, which are responsible for light detection in the retina, from degeneration in patients with IRDs and improve patients' vision.
Figure 4 Schematic representation of the potential mechanism
impactingNR2E3retinal degeneration.
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coR/coA—corepressor or coactivator; ESCS—Enhanced S-cone syndrome; GFS—Goldman Favre syndrome; adRP—autosomal dominant retinitis pigmentosa; rod photoreceptors in grey and cone photoreceptors are in blue, green, and red.
Dr. Haider’s lab at SERI, an affiliate of Harvard Medical School, and others have showninvolves the preclinical phenotypic outcome resultstargeted delivery and expression of one or more NHRs in the disease tissues and is designed to introduce a functional gene to modify the expression of multiple genes and gene-networks, which potentially enables it to address multiple retinal diseases with one product.
Modifier Gene Therapy Platform Based on NHRs
NHRs are modulators of retinal development and function, acting as master regulator genes in the retina. NHRs play a vital role in regulating retinal cell development, maturation, metabolism, visual cycle function, survival, and maintaining the cellular and molecular homeostasis in retinal tissues. Our modifier gene therapy platform is designed to target NHRs to potentially provide therapeutic benefit to patients suffering from a mutational load on a biological system that includes the primary mutationgenetically diverse IRDs and other factors such as modifier alleles impacting the normal homeostatic state. dry AMD. The use of genetic modifiers represents a broadened means of potentially treating a variety of retinal degenerative diseases, as compared to single-gene replacement therapy. While single-gene
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replacement therapies have shown tremendous promise in rare retinal diseases, they are highly specific and cannot improve a multitude of disease-causing genetic defects. OnOur modifier gene therapy platform has the potential to restore retinal integrity and function across a range of genetically diverse IRDs and other hand, NHRs play a vital role in regulatingdegenerative retinal cell development, maturation, metabolism, visual cycle function and survival (Figure 5).diseases providing us with significant potential long-term value.
Figure 5 InteractingOur modifier gene therapy platform encompasses the targeted delivery and expression of certain NHRs that are expressed naturally in retinal tissue. Preclinical studies have shown that NR2E3andRORA Associated Gene Networks.
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(a) IPA analysis, a member of E18 targets identified nine gene networksthe NHR family, is a dual activator and repressor that, with seven biological classifications. (b) IPA analysisother transcription factors, modulates cell fate and differentiation of P30 targets identified nine gene networks with six biological classifications. Venn Diagrams show uniquerod and overlapping gene targets of NR2E3 and RORA at E18 and P30. Comparisons of RORA E18/P30 or NR2E3 E18/P30 show less overlap than RORA/NR2E3 at E18 or RORA/NR2E3 at P30.
cone photoreceptor cells, specialized cells for detecting light, in the eye. Disease outcome is a result of a primary mutation as well as modifier alleles. NR2E3 is a master regulator of several key pathways in retinal development and function. NR2E3 potentially prevents and reduces diseaserescues degenerating retina by resetting the homeostatic state of key gene networks in the presence of a primary mutation (Figure 6).mutation.
Figure 6 Schematic representationThe delivery of potentialNr2e3 in a mouse lacking a functional Nr2e3 gene restored the retina structure and function. We believe that NR2E3 mediated therapy.
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NR2E3 potentially resets key gene networks that contribute to retinalmay partially or fully rescue photoreceptors from degeneration in RP. RP—retinitis pigmentosa; PR—photoreceptor cells; Gene networks: M—Metabolism; I—Inflammation; O—oxidative stress; P—photoreceptor genes; S—cell survival.
In summary, NR2E3 regulates multiple transcriptional networks, such as cell survival, metabolism, inflammationpatients with IRDs and phototransduction, that impact retinal diseases, such as RP.improve patients' vision. It was also demonstrated preclinically thatRORA RORA offers a protective allele in AMD where the loss of photoreceptor cells leads to blindness. NR2E3regulates the expression of both Nuclear Receptor Subfamily 1 Group D Member 1 ("NR1D1") and RORA. Thus, the nuclear receptors work in overlapping networks to modulate normal retinal development and function. These receptors impact gene expression of hundreds of genes and numerous networks and, as such, may be potent modifiers of retinal disease and degeneration.
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NR2E3 Modifier Gene Therapy Demonstrated Efficacy in many IRD models
Preclinical Studies Support the Potential Efficacy of Nr2e3 NR2E3 Modifier Gene Therapy
The efficacy of Nr2e3was evaluated in five RP models: FVB-Pde6ßrd1/NJ (rd1unique mouse models of IRDs in which treatment with the adeno-associated viral ("AAV"), Rhodopsin null allele (Rho−/−), B6.129S6(Cg)-Rhotm1.1Kpal/J (RhoP23H), BXD24/TyJ-Cep290rd16/J (rd16) and 8-Nr2e3rd7/J (rd7) followinggene by subretinal delivery.injection effectively rescued multiple genetically diverse IRDs by protecting photoreceptors from further damage after disease onset. These models represent a heterogeneous group of RP diseases in humans and are relevant in establishing the modifier role of NR2E3. The effect offive IRD models evaluated were: FVB-Pde6ßrd1/NJ ("rd1"), Rhodopsin null allele ("Rho−/−"), B6.129S6(Cg)-Rhotm1.1Kpal/J ("RhoP23H"), BXD24/TyJ-Cep290rd16/J ("rd16"), and Nr2e3 gene therapy was evaluated at both early and late disease states in these animal models.
These animals were dosed with AAV8-rd7Nr2e3 /J ("inrd7"). rd1 is rod cGMP-specific 3', 5'-cyclic thePDE6β subretinal spaceat post-natal day 0 (P0) and evaluated at P30 (B6 and rd1) or P90-P120 (associated RP, Rho−/−, and RhoP23H, are both RHO associated RP, rd16, is LCA, and rd7 is enhanced S-cone syndrome. C57BL6/J ("B6") in these models represents the control. The results were evaluated using fundus imaging, electroretinogram ("ERG"), histology, and immunostaining of retinal layers. Considerable improvementThis preclinical data was observedpublished in Nature Gene Therapy.
This study showed that the clinical phenotype for administration of AAV8RhoP23H, rd16, and rd7-Nr2e3 micetherapy improved clinical, histological, functional, and molecular disease outcomes in fundus imaging, though not alleach of the five models haveof IRDs. These studies demonstrated that the mechanism of Nr2e3 therapy involves resetting key retinal transcription factors and key biological networks that work in concert with Nr2e3 to modulate the homeostatic state of the retina. The study is based on the principle that disease outcome is rarely due to a contrasting clinical phenotypesingle gene mutation; rather, it is a result of the combinatorial mutational load on the biological system, which is often strongly influenced by other factors such as modifier genes. The models demonstrate the potential potency of a novel modifier gene therapy to elicit broad-
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spectrum therapeutic benefits in early (Figure 74). Further histological analyses of retinal sections demonstrated improvement in the integrity of the retinal layers, , Figure 6,and overall anatomy and morphology of the retina in all of these models (Figure 8). Immunohistochemistry analyses of retina showed that and advanced stages (Nr2e3Figure 5, delivery enhanced the expression of opsin proteins (blue and green) in treated mice in all the models exceptFigure 7, rd7. In the rd7 model, the disease phenotype starts with a higher number of S-cone and a higher expression of opsin proteins. In this model, Nr2e3 treatments restored the physiological level of opsin proteins in photoreceptors (Figure 9) needed for normal vision. Similarly, treated animals showed improvement inof IRDs and serve as a broad-spectrum gene therapy to reduce retinal ERG signal, both in photopic (light-adapted) and scotopic (dark-adapted) conditions (Figure 10).degeneration.
Figure 7:4: AAV8-Nr2e3 rescues clinical phenotype in multiple mouse models of RP. Fundus of P0 injected AAV8-Nr2e3 treated and untreated animals evaluated at P30 (B6 and early-stage ord1) or P90-P120 (Rho−/−, RhoP23H, rd16, and rd7). N = 7.
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Figure 8: AAV8-Nr2e3 treatment preserves retinal morphology and retinal integrity in RP models. B6, rd1, Rho−/−, RhoP23H, rd16, and rd7 animals injected at P0, evaluated at P30 (B6 and rd1) or P90-P120 (Rho−/−, RhoP23H, rd16, and rd7). (a) Hematoxylin/eosin staining of AAV8-Nr2e3 treated and untreated retinas with white boxes indicating location of cell count. (b) Rescued and un-rescued regions in retinas treated with AAV8-Nr2e3. (c) Cell layer numbers of outeruter nuclear layer ("ONL") rescue in IRD mouse models.
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Figure 4 displays the cell layer numbers of the ONL from AAV8-Nr2e3AAV8-Nr2e3 treated and untreated animalsmice in different RPearly-stage IRD models. Results are mean ± SEM. N = 7.
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Figure 9: AAV8-Nr2e3 preserves cone and rod opsin expression in multiple mouse models of RP. Immunohistochemistry of P0 injected AAV8-Nr2e3 treated and untreated retinas labeled with green opsin, blue opsin and rhodopsin evaluated at P30 (rd1) or P90-P120 (Rho−/−, RhoP23H, rd16, and rd7) and B6 control (Left panel). Semiquantitative analysis of cell counts of blue and green opsin-positive photoreceptor cells per 100 μm (Right panels). Results are mean SEM. N = 7.
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Figure 10: Improved ERG responses in AAV8-Nr2e3 treated RP retinas.(a) Scotopic and photopic ERG B-wave amplitudes were evaluated at P30 (rd1) or P90-P120 (Rho−/−, RhoP23H, and rd16) AAV8-Nr2e3 treated and untreated animals; B6 control ERGs shown. (b) Percent increase in ERG B-wave responses in the treated RP models. Results are mean ± SEM. N = 7.
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The efficacy of Nr2e3 was also evaluated in these animal models at a late disease stage. AAV8-Nr2e3 was injected subretinally at P21 and evaluated 2–3 months post injection in Rho−/−, RhoP23H, rd16, and rd7 mice. Fundus imaging and histological analyses indicated a reduction in retinal degeneration in these models (Figure 11). The improvement in the rescue of retinal layers were between approximately 30% to 80% of the retina, depending on the delivery location and distribution of Nr2e3 following dosing. Approximately 3-5 layers of ONL cells were preserved in Nr2e3 treated animals compared with 0-1 layer for untreated animals. These ONL photoreceptors induce phototransduction in the retina and thereby initiate the vision process. Immunohistochemistry labelingThe normal mouse retina is comprised of 10 to 12 layers of rod and cone photoreceptor nuclei in the ONL. rd1 retinas showed enhanced expressiona profound rescue of blue and green cone opsins and rhodopsin in photoreceptorsphotoreceptor cells (six to eight layers of treated groupsONL) compared to the untreated groups (eyes. Figure 12Rho)−/−, RhoP23H, and rd16 mice showed a more moderate increase (three to six layers of ONL) compared to the untreated eyes of each model. ONL cell layer numbers in the rd7 model do not start degenerating until four to five months of age. Although only partial rescue was observed in these models, results of research conducted by third parties suggests that retention of only a single layer of photoreceptor cells can maintain minimal visual function suggesting preservationthat an increase of photoreceptors with light absorbing opsins.even 20% is significant. We believe Nr2e3 therapy has great promise in potentially restoring retinal development.
Figure 11: AAV8-Nr2e35: rescues RP degeneration after disease onset.AAV8-Nr2e3 Animals injected with AAV8advanced stage ONL rescue in IRD mouse models.
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-Nr2e3Figure 5 at P21displays the cell layer numbers of the ONL from AAV8-Nr2e3 treated and evaluated at 2–3 months post injection. (a) Fundusuntreated mice in different advanced stage IRD models. Improvement varied from ~30 to 80% of the retina in the Rho−/−, RhoP23H, rd16, and rd7. (b) Hematoxylin/eosin staining shows partial preservation of photoreceptor cells inrd16 AAV8-Nr2e3 treated mutant animals. (c) Cell layer numbersmice, depending on distribution efficiency throughout the retina. Approximately three to five layers of ONL cells were preserved in Nr2e3 treated mice compared between AAV8-Nr2e3 treated andwith untreated animals in the four RP models and B6 control. Results are mean SEM. N = 7.mice that show less than or equal to one layer of ONL remaining.
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ocgn-20191231_g12.jpgFigure 6: Fundus imaging of AAV8-Nr2e3 early-stage rescues in IRD mouse models.
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Figure 12: 6 displays the fundus imaging results from AAV8-Nr2e3 treated and untreated mice in different early-stage IRD models. Although not all models have a clinical phenotype, considerable improvements were observed in the fundus of RhoP23H, rd16, and rd7 mice. The rd16 mice were observed to have a red fundus with increased and pronounced vessels and this fundus observation resolves with Nr2e3 administration. Improvement was observed in the rd7 phenotype, with reduction of retinal spots in AAV8-Nr2e3 treated eyes compared with untreated eyes.
Figure 7: Fundus imaging of AAV8-Nr2e3 advanced stage rescues in IRD mouse models.
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Figure 7 displays the fundus imaging results from AAV8-Nr2e3 treated and untreated mice in different advanced stage IRD models. The fundus imaging shows the reduction of retinal degeneration in the AAV8-Nr2e3 treated eyes compared with untreated eyes.
Figure 8: Hematoxylin/eosin ("H/E") staining of AAV8-Nr2e3 early-stage rescues in IRD mouse models.
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Figure 8 displays the H/E staining results from AAV8-Nr2e3 treated and untreated mice in different early-stage IRD models. The H/E staining revealed that subretinal delivery of AAV8-Nr2e3 rescued photoreceptor cells and helped maintain retinal integrity of IRD retinas in all models. Additionally, the rd7 model presents with increased cone cells with whorls and rosettes in the ONL. These retinal whorls and rosettes, that are characteristics of the rd7 phenotype, resolved following Nr2e3 treatment, suggesting that the delivery of Nr2e3 can restore normal retinal development.
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Figure 9: H/E staining of AAV8-Nr2e3 advanced stage rescues in IRD mouse models.
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Figure 9 displays the H/E staining results from AAV8-Nr2e3 treated and untreated mice in different advanced stage IRD models. The H/E staining shows the reduction of retinal degeneration by Nr2e3 therapy in each model.
Improved ERG results were also observed in AAV8-Nr2e3 treated IRD retinas in addition to the above results that displayed the rescue of ONL layers, improvement in fundus imaging, and improvement in H/E staining. Human vision is enabled by three primary modes: scotopic vision, photopic vision, and mesopic vision. Scotopic vision is monochromatic vision in very low light, which functions primarily due to rod cells in the eye. Photopic vision is vision under well-lit conditions, which provides for color perception and functions primarily due to cone cells in the eye. Mesopic vision is a combination of scotopic and photopic vision in low lighting, which functions due to a combination of rod and cone opsin expression aftercells in the eye. IRD disease onset.progression results in the loss of rod and cone function that is assessed by abnormal ERG responses. In the below study, the visual function of Nr2e3 Animalstreated IRD retinas was examined in four out of five IRD strains, excluding rd7, by recordingscotopic and photopic ERGs to evaluate rod- and cone-driven responses. Treated mice showed improvement in retinal ERG signal, both in scotopic and photopic conditions (Figure 10).
Figure 10: Improved ERG responses in AAV8-Nr2e3 treated IRD retinas.
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Analysis A within Figure 10 above displays the evaluation ofscotopic and photopic ERG B-wave amplitudes, which were injected with AAV8-Nr2e3 at P21 and evaluated at 2–3 months after injection. Immunohistochemistry of green opsin, blue opsinpost-natal day 30 (B6 and rhodopsin ofrd1) or post-natal day 90 to 120 (Rho−/−, RhoP23H, and rd16) in AAV8-Nr2e3 treated and untreated animalsmice. Analysis B above displays the percent increase in ERG B-wave responses in the treated IRD models.
Rho−/−, RhoP23H, rd16, and rd7 (left panel). Semiquantitative analysisResults of cell counts of blue and green opsin-positive photoreceptor cells per 50 μm ofPreclinical Studies Support the retina (right panels). Results are mean ± SEM. N = 7.
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Safety of NR2E3 in Rodent Model
SafetyThe safety of Nr2e3 was evaluated in healthy mice following subretinal administration. C57BL6/J (B6)B6 mice were treated with AAV8-Nr2e3-GFP-green fluorescent protein ("GFP") fusion construct at P0post-natal day zero and evaluated after both seven days and one month for any toxic effect as well as expression of Nr2e3-GFPNr2e3-GFP fusion protein in the retina. The expression of the Nr2e3 protein in a mouse retina did not show any detrimental effect on retinal cells, including photoreceptors (Figure 1311). Also, there was no difference in retinal anatomy (asas indicated by fundus),fundus, histology (cell(the cell layers), expression of opsin and rhodopsin proteins (immunohistochemistry), and retinal function (as indicated by ERG recording) between treated and untreated mice (Figure 1311).
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Expression of EGFP-Nr2e3enhanced GFP-Nr2e3 fusion protein was observed at P30post-natal day 30 in treated animals. These results confirm thatIn this Study, overexpression of the Nr2e3 protein following subretinal injection of AAV8-Nr2e3 was well-tolerated and safe to the retina.well-tolerated.
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Figure 13:11: Overexpression of AAV8-Nr2e3 has no detrimental effects on the retina.
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The analysis in Figure 11 above utilized a population size of five mice and displays the B6 control AAV8-AAV8-Nr2e3 treated mice showing no abnormalities. Analysis A above displays the following: fundus, Nr2e3H/E staining treated animals show no abnormalities in a. Fundus, hematoxylin/eosin histology staining, and, blue opsin, green opsin, and rhodopsin labeling of photoreceptor cells; and bcells. Analysis B above displays the ERG response of the B6 control B6in both treated and untreated. Animalsuntreated mice. The mice were injected at P0,post-natal day zero and tissue was collected at P30. cpost-natal day 30. Analysis C above displays the GFP label of AAV8-Nr2e3-GFPAAV8-Nr2e3-GFP injected at P0,post-natal zero with GFP expression assessed at P7both post-natal day seven and P30. N = 5.post-natal day 30.
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Overview of Inherited Retinal DiseasesIRDs and Current Treatment Options
IRDs are caused by genetic mutations that are passed down within families and lead to progressive disease, severe visual impairment, and blindness. Treating these conditions has been a significant challenge due to the sheer volume of potential therapeutic gene targets. Gene replacement therapy is a promising approach to provide a sustained restoration effect of normal retinal function for a mutated gene, but such therapies can only address one gene at a time, limiting their effectiveness.potential therapeutic use. Developing a custom gene therapy for genetic defects in each of the more than 150 known gene defects175 mutations linked to RP and LCA would not only be expensive but also may not be possible due to size, class, or localization that will impact delivery of the gene. Not all genes and disease expressions are amenable to gene therapy, and fortherapy. For example, the genetic mutations of approximately 40% of RP patients whose genetic mutations remain unknown there arewith few or no known therapeutic options.options available. Modifier gene therapy to ameliorate multiple forms of RP and LCA without requiring knowledge of the mutated gene, may provide a potentially robust and feasible treatment for RP.RP and LCA.
RP is a group of heterogeneous, pleiotropic IRDsrare, genetic disorders that affectinvolve a breakdown and loss of cells in the retina that affects approximately one in every 4,000 individuals. ItCommon symptoms of RP include difficulty seeing in poor lighting or in the dark, loss of central vision or side (peripheral) vision, and difficulty reading print and deciphering detailed images. RP is associated with over 150 gene mutations that affect over 1.5two million individuals worldwide. Currently, there is no cure for RP and over 40% of RP cannot be genetically diagnosed. RP is heterogeneous and varies greatly in age of onset, rate of progression, and even genetic etiology, yet a common pathology of photoreceptor cell degeneration develops.
There is currently no approved treatment which slows or stops the progression of multiple forms of RP. Proposed treatments for RP include gene-replacement therapy, retinal implant devices, retinal transplantation, stem cells, vitamin therapy, and other pharmacological treatments. Gene-replacement therapies are promising but are limited to treating just a single mutation and therefore cannot address the multiple mutations implicated by RP. In addition, while genegene-replacement therapies may provide a new functional gene, they do not necessarily eliminate the underlying genetic defect, which may still cause stress and toxic effects. Therefore, the development of gene specific replacement therapy is highly challenging, especially when multiple and unknown genes are involved.
In addition
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Similar to RP, no effective treatmentsor minimal treatment options are available for a large number of other retinal degenerative diseases, including treatments specifically for dry AMD.AMD and LCA. AMD is a degenerationattributed to the thinning of the macula of the retina, thatwhich leads to impairment and loss of central vision. The macula is the part of the retina responsible for clear vision in one's direct line of sight. AMD is characterized by thickening and loss of normal architecture within the Bruch’s membrane, lipofuscin accumulation in the retinal pigment epithelium ("RPE"), and drusen formation beneath the RPE in the Bruch’s membrane. These deposits consist of complement components, other inflammatory molecules, lipids, lipoproteins B and E, and glycoproteins. Dry AMD, which affects approximately 10 million individuals in the United States, involves the slow deterioration of the retina with submacular drusen (small white or yellow dots on the retina), atrophy, loss of macular function, and central vision impairment. Common symptoms of dry AMD include visual distortions, reduced central vision in one or both eyes, increased difficulty adapting to low levels of light, and a well-defined blind spot in one's field of vision. LCA is a group of IRDs characterized by severe impairment of vision or blindness at birth. LCA is caused by a degeneration and/or dysfunction of photoreceptors in the eye. Luxturna, developed by Spark Therapeutics, Inc., has been approved by the FDA to treat IRDs caused by retinoid isomerohydrolase ("RPE65") gene mutations. The RPE65 gene represents just one of more than 175 mutations linked to RP and LCA. No treatment options have been approved by the FDA for RP and LCA caused by mutations in other RP and LCA causing genes.
As a result, there remains a significant unmet medical need for a treatment with application across multiple genetic forms of RP and LCA as well as other ocular degenerative diseases such as dry AMD.
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OCU400 for the Treatment of Retinitis PigmentosaIRDs
OCU400 is theour first product candidate being developed with our modifier gene therapy platform. OCU400 is compriseda novel gene therapy product candidate with the potential to restore retinal integrity and function across a range of genetically diverse IRDs. OCU400 consists of a functional copy of the NHR gene, NR2E3, delivered to target cells in the retina using an NHR gene expressed in adeno-associated viralAAV8 vector that has the potential to be used as a gene therapeutic not only for the treatment of retinal diseases associated with mutationmutations in genes such as NR2E3 RHO, CEP290, and, PDE6RHOß, CEP290, and PDE6ß, but alsoother gene mutations associated with IRDs, including RP. To date,RP and LCA. As a potent modifier gene, expression of NR2E3 within the retina may help reset retinal homeostasis, potentially stabilizing cells and rescuing photoreceptor degeneration. OCU400 has received ODDfour ODDs from the FDA for boththe treatment of the following disease genotypes: NR2E3, RHO, CEP290, and PDE6ß mutation-associated inherited retinal degenerations. OCU400 has additionally received OMPD from the EC, based on the recommendation of the EMA, for RP and LCA. We believe OCU400 has the potential for broad-spectrum application to treat many IRDs.
As previously described, in five unique mouse models of IRDs, treatment with AAV8-Nr2e3 by subretinal injection rescued multiple genetically diverse IRDs by protecting photoreceptors from further damage after disease onset. This result demonstrates the potential potency of a novel modifier gene therapy to elicit broad-spectrum therapeutic benefits in early and advanced stages of IRDs. We completed pre-IND biodistribution and toxicology studies of OCU400 and submitted an IND application to the FDA for the treatment of the NR2E3and CEP290 RHOmutation-associated retinal disease indications.
We completed the preclinical studies in multiple animal models of RP using mouse NHR. Currently, human NHRs are being evaluated in these animal models representing various forms of human RP diseases using an adeno-associated viral vectors for subretinal delivery. In parallel, we have initiated the cGMP for production of drug product to commence Investigational New Drug Application ("IND") enabling non-clinical studies and clinical supplies to initiate a Phase1/2a clinical trial.
We had a pre-IND meeting withgenotypes, which was accepted by the FDA in February 2019 and received guidance on IND-enabling preclinical studies to support the Phase 1/2a study.December 2021. We plan to initiatehave initiated a Phase 1/2a2 clinical trial targetingin the United States for the treatment of these disease genotypes and the first patient is expected to be dosed in the first half of 2022. This Phase 1/2 clinical trial is a multicenter, open-label, dose ranging study to assess the safety of unilateral subretinal administration of OCU400 in subjects with NR2E3 NR2E3-mutation-associated retinal disease in 2021.related RP.
OCU410 for the Treatment of Dry Age-Related Macular DegenerationAMD
We are developing OCU410 is a modifier gene therapy product candidate being developed for the treatment of dry AMD, which is the second product candidate being developed with our modifier gene therapy platform using NHRs. This candidate is currently in preclinical development.
AMD. OCU410 utilizes an AAV vectordelivery platform for the retinal delivery of the RORA gene. Various genesgenetic factors associated with AMD are regulated by RORA., which plays a role in numerous indications including the pathology of dry AMD. The RORA protein plays an important role in lipid metabolism and demonstrates an anti-inflammatory role, which we believe could be a potential therapeutic candidate for dry AMD. Dry AMD affects approximately nineWe are currently executing pre-IND studies consistent with FDA discussions to ten million patients in the United States and there is currently no approved treatmentsupport a Phase 1/2 clinical trial for the disease.OCU410.
NOVEL BIOLOGIC PRODUCT CANDIDATE FOR RETINAL DISEASES
We have a biological preclinical program, OCU200 for the treatment of DME, DR and wet AMD. We have exclusively in-licensed a broad range of rights for this preclinical program.
OCU200 for the Treatment of Diabetic Macular Edema, Diabetic Retinopathy and Wet Age-Related Macular Degeneration
OCU200 is aour novel biologic product candidate in preclinical development for treating severely sight-threatening diseases like DME, DR and wet AMD. Patients affected by these diseases share common symptoms, such as blurriness in vision and progressive vision loss. The formation of fragile and leaky new blood vessels leads to fluid accumulation in and around the retina, causing damage to vision.development. OCU200 is a novel fusion protein consistingdesigned to treat severely sight-threatening diseases like DR, DME, and wet AMD. We are currently establishing a cGMP process for the production of two human proteins, tumstatinclinical trial materials and transferrin, that are already present normally in retinal tissues. OCU200 possesses unique featuresexecuting pre-IND studies consistent with FDA discussions to support a Phase 1/2a clinical trial.
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Overview of DR and DME
DR is a complication from diabetes arising from the over-accumulation of glucose, which enable it to (a) efficiently target leaky blood vessels, (b) regress the existing abnormal blood vessels, and (c) inhibit the growth of newcan block blood vessels in the retina and choroid. Tumstatin, which actscut off the blood supply, leading to damage to the blood vessels in the retina. DR is classified as an anti-vascular endothelial growth factor ("VEGF"), anti-inflammatorytwo subtypes: non-proliferative DR and anti-oxidative agent,proliferative DR. Non-proliferative DR is the active component of OCU200. It bindsearly-stage in which blood vessels are not able to integrin receptors, which play a crucial rolegrow, blood vessel walls weaken, and nerve fibers in disease pathogenesis. Transferrin facilitates the targeted delivery of tumstatin into the retina and choroid and potentially helps increasemay swell. Proliferative DR is the interaction between tumstatin and integrin receptors.
OCU200 demonstrated efficacyadvanced stage in an in-vitro cell culture model where it inhibited in new vessel formation. In an animal model for DME and DR (Oxygen-induced retinopathy in mice), OCU200 demonstrated comparable efficacy at a significantly lower dose (10 µg/eye) comparedwhich damaged blood vessels are closed off, leading to existing approved therapy (Evlea®,40 µg/eye) in preventing disease manifestation and progression (Figure 14). In animal models for wet AMD (laser induced CNV in mice and rats), OCU200 demonstrated comparable or slightly better activity compared to anti-VEGF control groups in preventing the formation and growth of new leakyabnormal blood vessels and subsequent disease symptoms (Figure 14).
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Figure 14OCU200 Demonstrated Efficacy in Animal Models for DME, DR, and Wet-AMD.
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OCU200 is currently in preclinical development for the treatment of DME, DR, and wet AMD and we plan to initiate a Phase 1/2 clinical trial within the next two years.
Overview of Diabetic Macular Edema, Diabetic Retinopathy, and Wet Age-Related Macular Degeneration, and Current Treatment Options
Diabetic macular edema and diabetic retinopathy are the most common vision threatening diseases occurring in diabetic patients. Excess blood sugar (glucose) in these patients causes damage tonew abnormal blood vessels in the retina and promotes the formation of leaky blood vessels. These leaky blood vessels secrete fluidscan lead to scar tissue, which can result in the detachment of the retina andfrom the back of the eye.
Complications from DR could lead to DME. In DME, bulges can cause retinal detachment, and vitreous hemorrhageprotrude from the vessel walls, leading to blindness. When thisthe leakage of fluid accumulatesand blood into the retina. This leakage results in swelling, or “edema,” in the macula, regionwhich is a part of the retina,retina. DME may occur at any stage of DR, but is more likely to occur later as the region primarily responsibledisease progresses. DME is the most common reason for centralvision loss for patients with DR.
DR and color vision, it can cause DME.DME are the most common vision-threatening diseases occurring in diabetic patients. Approximately 7.7 million people are affected with DR and approximately 0.7 million with DME in the United States. These numbers areThe number of people affected by DR and DME is expected to further increase as the number of diabetic patients increases, due to poor disease management and lifestyle-related changes.
Currently there are limited treatment options available for DR and DME patients and a significant unmet need for the development of safe and effective therapies. Current first-line treatments for DR and DME include laser photocoagulation, use of anti-VEGFs,anti-vascular endothelial growth factor ("VEGF") therapy, and steroidscorticosteroids, which are sub-optimally active in these patients. Anti-VEGF therapy does not work effectively in approximately 50% of DME patients. Current
Additionally, current therapies target only one pathway associated with DR and DME, either angiogenesis (development of new blood vessels) with anti-VEGF therapy or inflammation in case of steroidcorticosteroid therapy. The development of a therapeutic which targets multiple causative pathways of DR and DME, such as angiogenesis, oxidation, and inflammation, would offer the besta potential treatment option for all of these patients. We believe that OCU200 possesspossesses unique characteristics to target these pathways and has the potential to offer better treatment options for all patients.
Overview of Wet AMD
OCU200 also has the potential to represent a superior treatment option for patients suffering from wet-AMD.wet AMD. Most AMD cases begin as dry AMD and may progress towards the advanced “wet” form, which is a degeneration of the macula of the retina that leads to impairment and loss of central vision. Wet AMD involves the growthcharacterized by penetration of abnormal blood vessels underin the retina and macula, resulting in edema, tissuethat leak fluid or blood into the macula. The result can be irreversible damage to photoreceptor cells and rapid, severe vision loss, particularly in the center of central vision.the field of vision, causing significant functional impairment. If left untreated, neovascularization in wet AMD patients typically results in significant vision loss and the formation of a scar under the macular regionmacula. Wet AMD affects approximately 10-15% of the retina. Most cases begin as dry AMD patients, but progresses more rapidly and may progressis known to wet AMD.be responsible for approximately 90% of acute blindness.
Wet AMD is a leading cause of blindness in people over the age of 5565 in the United States and the European Union. The incidence of wet AMD increases substantially with age, and we expect that the number of cases of wet AMD will increase with the growth of the elderly population in the United States. It has been estimated that approximately 11.011 million patients in the United States have some form of AMD of which, approximately 1.1 million, or 10 percent,10%, suffer from wet AMD. Approximately 200,0000.2 million new cases of wet AMD are diagnosed each year in the United States.
Current therapies for wet AMD focus on reducing new blood vessel formation (neovascularization) through the inhibition of a single key regulator, VEGF. Current FDA-approvedFDA approved therapeutics for wet AMD include intravitreal injection of either Lucentis®ranibizumab or Eylea®,aflibercept, which target VEGF. Bevacizumab (Avastin™), the parent antibody from which ranibizumab was derived, is also used as an off-label treatment. Though these productstreatments have been effective in mitigating the disease symptoms, they haveclinical studies suggest substantial limitations as demonstrated in clinical studies.remain. For example, a significant percentage of patientspeople do not respond to
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therapy and experience continuous deterioration of vision; long-termtheir vision. Additionally, the repeated dosing resultsuse of anti-VEGF therapy becomes less effective over time. Between 30-50% of people affected by wet AMD continue to have fluid remain in reduced effectiveness; and there remains a persistencethe middle of fluid inthe eye, also called the subretinal space, of 30-50% patients even after 1-2one to two years of treatment.
Given the above limitations of these existing treatments, we believe that a substantial unmet medical need still exists for the treatment of DR, DME, and wet AMD.
OCU200 for the Treatment of DR, DME, and Wet AMD
OCU200 is being developed to treat severely sight-threatening diseases like DR, DME, and wet AMD. Patients affected by these diseases share common symptoms, such as blurriness in these areas.vision and continued vision loss through disease progression. The
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formation of fragile and leaky new abnormal blood vessels leads to fluid accumulation in and around the retina, causing vision damage.
OCU200 is a novel fusion protein consisting of two human proteins, tumstatin and transferrin, that are already present normally in retinal tissues. OCU200 possesses unique features and is designed to enable it to efficiently target leaky blood vessels, regress the existing abnormal blood vessels, and inhibit the growth of new blood vessels in the retina and choroid. Tumstatin, which acts as an anti-VEGF, anti-inflammatory, and anti-oxidative agent, is the active component of OCU200. It binds to integrin receptors, which play a crucial role in disease pathogenesis. Transferrin facilitates the targeted delivery of tumstatin into the retina and choroid and potentially helps increase the interaction between tumstatin and integrin receptors. OCU200 is designed to address the limitations of current therapies by targeting multiple mechanisms associated with ocular neovascularization and inflammation.inflammation specifically focusing on non-responders to currently available treatment options.
We may expand theOCU200 demonstrated potential therapeutic applicationsbenefit in different animal models of neovascularization. In an animal model for DME and DR (oxygen-induced retinopathy in mice), OCU200, beyond DME, DR,at a significantly lower dose (10 micrograms per eye), was comparable to existing approved anti-VEGF therapy (Eylea, 20 micrograms per eye) in preventing disease manifestation and progression (Figure 12). In animal models for wet AMD potentially(laser induced choroidal neovascularization in mice and rats), OCU200 demonstrated comparable or slightly better activity compared to include macular edema following RVOanti-VEGF control groups in preventing the formation and mCNV. These patients suffer from retinal/choroidal complicationsgrowth of new leaky blood vessels and subsequent disease symptoms (Figure 12).
Figure 12:OCU200 demonstrated efficacy in the back of the eye which may have a suddenanimal models for DR, DME, and debilitating impact on visual acuity, eventually leading to blindness. Although anti-VEGF therapeutics have been recently approved for the treatment of these retinal disorders, we believe that, similar to its application to DME, DR, and wet AMD, OCU200 has the potential to fill a significant unmet need for the treatment of RVO and mCNV.Wet AMD.
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COMPETITION
The biopharmaceutical industry including gene therapy, is characterized by rapidly advancing technologies intense competition andas well as a strong emphasis on intellectual property.property leading to a highly competitive environment for the development and commercialization of vaccines and therapeutic products. We face competition with respect to our current product candidates and will face competition with respect to any product candidates that we may seek to develop or commercialize in the future. We face competition from many different sources, including large andfrom major pharmaceutical companies, specialty pharmaceutical andcompanies, biotechnology companies, academic institutions, governmentalgovernment agencies, and other public and private research institutions.organizations that conduct research, seek patent protection, and establish collaborative arrangements for research, development, manufacturing, and commercialization. We plan to compete in the segments of the pharmaceutical, biotechnological, and other related markets with vaccines and therapies that have an acceptable safety profile and target commercially attractive indications.
We face, and will continue to face, intense competition from companies as well as institutions pursuing research and development of vaccines, technologies, drugs, or other therapies that would compete with COVAXIN, if authorized or approved in the United States and Canada. Our competitors have and may continue to develop and commercialize vaccines or effective therapies or other treatments for COVID-19 more rapidly or more effectively than us. The competitive landscape of COVID-19 vaccines and therapies has been rapidly developing since the beginning of the COVID-19 pandemic and includes competitors such as Pfizer Inc./BioNTech SE, Moderna, Inc., Johnson & Johnson/Janssen Biotech, Inc., AstraZeneca PLC,
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Novavax, Inc., and Medicago Inc. The vaccine developed by Pfizer Inc./BioNTech SE has been granted BLA approval by the FDA for ages 16 years and older and has been granted EUA for ages five to 16 years. The vaccine developed by Moderna, Inc. has been granted BLA approval by the FDA for ages 18 years and older. The vaccine developed by Johnson & Johnson/Janssen Biotech has been granted EUA by the FDA for ages 18 years and older. Vaccines developed by Pfizer Inc./BioNTech SE, Moderna, Inc., Johnson & Johnson/Janssen Biotech, Inc., AstraZeneca PLC, Novavax, Inc., and Medicago Inc. have been authorized by Health Canada.
Competitors may include established, emerging,The development and growing companies.commercialization of gene therapy and biologic products is highly competitive. We are aware of several companies focusing on gene therapies for various ophthalmic indications including Applied Genetic Technologies Corporation, Editas Medicine, Allergan, Inc., Adverum Biotechnologies, MeiraGTx, IVERIC bio, Inc., Applied Genetic Technologies CorporationMeiraGTx Holdings plc, Nanoscope Therapeutics, Inc., ProQR Therapeutics N.V., REGENXBIO Inc., Novartis AG, and the Roche Group, which acquired Spark Therapeutics, Inc. Spark Therapeutics, Inc.'s product Luxturna, (Spark Therapeutics) which is currently the only gene therapy approved for an IRDto treat IRDs in the United States, addressingaddresses only one out of 150 known mutations of the RPE65 gene.gene mutations. The RPE65 gene mutation represents just one of more than 175 mutations linked to RP and LCA. Companies that may compete with our OCU200 product candidate include theF. Hoffmann-La Roche Group,AG (Roche), Regeneron Pharmaceuticals, Inc., Graybug Vision, Inc., Kodiak Sciences Inc., and Novartis AG. F. Hoffmann-La Roche AG, Regeneron Pharmaceuticals, Inc., and Novartis AG which have marketed anti-VEGF products. We are also aware of other companies that are working on therapies for the whole eye, including Santen, Inc. and Ocular Therapeutix.

Many of our competitors, either alone or with strategic partners, willmay have significantly greater financial resources to support research and development, manufacturing, preclinical testing,studies, and clinical trials, as well as regulatory, commercialization, and marketing efforts. These organizations also compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites, patient registration for clinical trials, and inlicensing or acquiring technologies necessary for our programs. Smallerprograms, and in our commercialization efforts if our product candidates are authorized or early stageapproved. Early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors.
We believe that the key competitive factors that will affect the development and commercial success of our product candidates are efficacy, safety and tolerability profile, convenience in dosing, product labeling, cost effectiveness, price, the level of generic competition and the availability of reimbursement from the government and other third-parties. Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we may develop. Our competitors may also obtain FDA or other regulatory approval for their products more rapidly than us. In addition, our ability to compete may be affected as insurers or other third-party payers seek to encourage the use of more cost-effective products.
MANUFACTURING AND RAW MATERIALS
We utilize our in-house expertise and know-how as well as the expertise and know-how of our industry leading manufacturing partners to develop and scale up itsour manufacturing processes before these processes are transferred to third-party contract manufacturersfor both the clinical and testing labscommercial supply of our product candidates. We collaborate with our manufacturing partners to understand and establish controls offor critical process parameters and critical quality attributes. We also haveOur in-house expertise includes personnel with deepextensive product development and commercialization experience who actively manage the third-party contract manufacturers producing OCU300, and otherour manufacturing partners that produce products that arein our product candidate pipeline, including active involvement in the development pipeline.technology transfer process to our manufacturing partners. Our manufacturing partners, including Bharat Biotech, Jubilant HollisterStier, and CanSinoBIO, have state-of-the-art facilities with significant expertise in biopharmaceutical manufacturing.
Our OCU300 product candidate (using our proprietary OcuNanoE™ nanoemulsion formulation) are currently manufactured atClinical and Commercial Supply of COVAXIN
Pursuant to the Covaxin Agreement with Bharat Biotech, we obtained an established contract manufacturing facility locatedexclusive right and license to develop, manufacture, and commercialize COVAXIN for the Ocugen Covaxin Territory. In accordance with the Covaxin Agreement, Bharat Biotech has agreed to provide us with preclinical and clinical data and is in the United States. The drug substance containing nanoemulsionprocess of transferring to us certain proprietary technology owned or controlled by Bharat Biotech that is sterilized by 0.2-micron filtrationnecessary for the commercial manufacture and is filled into sterile single-use vials. The final process has been successfully scaled upsupply of COVAXIN to support commercial sale in the Ocugen Covaxin Territory, if authorized or approved. In June 2021, we selected Jubilant HollisterStier as our commercial manufacturing partner for COVAXIN and initiated the technology transfer process from Bharat Biotech to Jubilant HollisterStier for drug product manufacturing. LabelingWe expect to complete qualification manufacturing runs at Jubilant HollisterStier by mid-2022. We also expect to enter into a master services agreement with Jubilant HollisterStier for the commercial manufacture of COVAXIN, if authorized or approved.
Additionally, we entered into the Development and packagingCommercial Supply Agreement ("Supply Agreement") with Bharat Biotech in September 2021, pursuant to which Bharat Biotech will supply our clinical trial materials as well as supply certain drug product components for commercial manufacturing and will continue to supply finished drug product as necessary for the commercial supply of vials also occurs atCOVAXIN subsequent to a regulatory authorization or approval.
For more information about our partnership with Bharat Biotech, see “—License and Development Agreements—Co-Development, Supply and Commercialization Agreement with Bharat Biotech” and see Note 3 in our notes to the same third-party manufacturer. Our third-party manufacturers and testing labs are subject to FDA inspections from time to time.consolidated financial statements included elsewhere in this Annual Report on Form 10-K.
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Clinical and Commercial Supply Agreements for OCU300of OCU400 and OCU410
We are currently working with third partiesparty to finalize our commercial supply agreements and have negotiated an arrangement with a third-party manufacturer to supply brimonidine tartrate (drug substance). We intend to use the current third-party contract manufacturing organization to supply the commercial drug products, and to perform labeling and packaging activities for us. Similarly, we will continue to use current third-party testing labs for release and stability testing of our commercial products.
Clinical Supply Agreement for OCU400
On September 27, 2019, we entered into a co-development and commercialization agreement (the “CanSinoBIO Agreement”) with CanSinoBIO with respect to the development and commercialization of the gene therapy product candidate, OCU400 and OCU410 (the "CanSinoBIO Agreement"). The CanSinoBIO Agreement was originally entered into in September 2019 with respect to certain disease indications (the “Field”). TheOCU400 and was subsequently amended in September 2021 to include OCU410. Pursuant to the CanSinoBIO Agreement, also grantswe and CanSinoBIO will collaborate on the development of OCU400 and OCU410 and CanSinoBIO will be responsible for the CMC development and manufacture of clinical supplies of such products and be responsible for the costs associated with such activities. CanSinoBIO has an exclusive option (the “Option”) to obtain a non-exclusive license from us to manufacture Products (defined below) in the Field for commercial sale by us, subject to the terms of a supply agreement to be negotiated by us and CanSinoBIO upon CanSinoBIO’s exercise of the Option.CanSinoBIO will have an exclusive license under our intellectual property and intellectual property jointly developed by CanSinoBIO and us (the “Joint IP”) to develop, manufacture, and commercialize products containing OCU400 (“Products”) in the Fieldand OCU410 in and for China, Hong Kong, Macau, and Taiwan (the “CanSinoBIO Territory”), and we will maintain exclusive development, manufacturing, and commercialization rights under our intellectual property and have an exclusive license under the Joint IP with respect to Products in the Field inOCU400 and for any global locationOCU410 outside the CanSinoBIO Territory (the “Ocugen“Company Territory”). CanSino will be responsible
We work with CanSinoBIO for all coststhe process development, manufacturing, testing, and release of drug products for chemistry, manufacturinguse in pre-IND studies and control developmentclinical trials. We perform discovery and manufacture of clinical supplies of OCU400 for all territories. CanSinoBIO will be solely responsible for all costs and expenses of itsanalytical development activities in our research and development lab. The partnership with CanSinoBIO enables us in completing manufacturing, with release of clinical trial materials in an expedited manner, and helps in mitigating the risk of delay that can be associated when working with highly competitive CDMOs that have long wait times with regard to gene therapy manufacturing. Although we rely on our partnership for manufacturing, we have personnel with extensive experience in cell and gene therapy manufacturing to oversee and guide the process and analytical development, scale-up, release, and stability testing at our partner site. We perform periodic audits of our manufacturing partner to confirm compliance with applicable regulation. We have successfully scaled-up production of OCU400 at 200L scale to manufacture and release clinical trial materials for use in our ongoing Phase 1/2 clinical trial.
For more information about our partnership with CanSinoBIO, Territorysee “—License and Development Agreements—Co-Development and Commercialization Agreement with CanSinoBIO" and see Note 3 in our notes to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K.
Clinical Supply of OCU200
In October 2020, we entered into a manufacturing agreement with a CDMO for the manufacture of OCU200. Under the manufacturing agreement, our CDMO will manage all CMC and clinical manufacturing activities for OCU200. Our CDMO is also providing supplies for the pre-IND studies we are currently executing for OCU200. We have completed the technology transfer of manufacturing processes to the CDMO.
Manufacturing Site Letter of Intent
In January 2022, we entered into a non-binding letter of intent ("LOI") with Liminal Biosciences Inc. ("Liminal") for the acquisition of Liminal's manufacturing site in Belleville, Ontario, which assuming the completion of the acquisition, we intend to further develop and upgrade. Completion of the proposed transaction is subject to the finalization of due diligence investigations by us and Liminal, the negotiation and execution of definitive transaction agreements, and other customary closing conditions including certain funding requirements. COVAXIN would be responsible for all costs and expenses of its development activitiesthe first product manufactured in the Ocugen Territory. CanSinoBIO will pay us an annual royalty between midmanufacturing site, if acquired. The manufacturing site also includes the potential for manufacturing of our modifier gene therapies. For more information about the non-binding LOI with Liminal, see Note 15 in our notes to high single digits basedthe consolidated financial statements included elsewhere in this Annual Report on net sales of Products in the CanSinoBIO Territory, and we will pay to CanSinoBIO an annual royalty between low to mid-single digits based on net sales of Products in the Ocugen Territory.Form 10-K.
LICENSE AND DEVELOPMENT AGREEMENTS
We are a party to license and development agreements under which we licenseslicense or co-own patents, patent applications, technical information, and other intellectual property for our product candidates: COVAXIN, OCU400, OCU410, OCU300 and OCU200. Certain diligence and financial obligations are tied to these agreements. We consider the following agreements to be material to our business.
Co-Development, Supply and Commercialization Agreement with Bharat Biotech
We entered into the Covaxin Agreement with Bharat Biotech to co-develop COVAXIN for the Ocugen Covaxin Territory. The Covaxin Agreement was originally entered into in February 2021 with respect to the U.S. market and was subsequently amended in June 2021 to add rights to the Canadian market. In consideration of the expansion of the Ocugen Covaxin Territory to include Canada, we paid Bharat Biotech a non-refundable, upfront payment of $15.0 million in June 2021. We additionally agreed to pay Bharat Biotech $10.0 million within 30 days after the first commercial sale of COVAXIN in Canada.
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Pursuant to the Covaxin Agreement, we obtained an exclusive right and license under certain of Bharat Biotech’s intellectual property rights, with the right to grant sublicenses, to develop, manufacture, and commercialize COVAXIN in the Ocugen Covaxin Territory. In consideration of the license and other rights granted to us by Bharat Biotech, we and Bharat Biotech agreed to share any Operating Profits (as defined in the Covaxin Agreement) generated from the commercialization of COVAXIN in the Ocugen Covaxin Territory, with us retaining 45% of such Operating Profits, and Bharat Biotech receiving the balance of such Operating Profits.
Under the Covaxin Agreement, we are collaborating with Bharat Biotech to develop COVAXIN for our respective territories. Except with respect to manufacturing rights under certain circumstances as described below, we have the exclusive right and are solely responsible for researching, developing, manufacturing, and commercializing COVAXIN for the Ocugen Covaxin Territory. Bharat Biotech is responsible for researching, developing, manufacturing, and commercializing COVAXIN outside of the Ocugen Covaxin Territory.
Bharat Biotech has agreed to provide us with preclinical and clinical data, and to transfer to us certain proprietary technology owned or controlled by Bharat Biotech, that is necessary for the successful commercial manufacture and supply of COVAXIN to support commercial sale in the Ocugen Covaxin Territory, if authorized or approved.
In September 2021, we entered into the Supply Agreement with Bharat Biotech, pursuant to which Bharat Biotech will supply us with clinical trial materials and commercial supplies of COVAXIN finished drug product prior to the completion of a technology transfer. Following the completion of a technology transfer, Bharat Biotech will supply COVAXIN drug product components and continue to supply finished drug product as necessary for commercial manufacture and supply of COVAXIN subsequent to a regulatory authorization or approval. The technology transfer process from Bharat Biotech to Jubilant HollisterStier for drug product manufacturing has been initiated.
The Covaxin Agreement continues in effect for the commercial life of COVAXIN, subject to the earlier termination of the Covaxin Agreement in accordance with its terms. The Covaxin Agreement also contains customary representations and warranties made by us and Bharat Biotech and customary provisions relating to indemnification, limitation of liability, confidentiality, information and data sharing, and other matters. The Supply Agreement expires upon expiration of the Covaxin Agreement and may be earlier terminated by us or Bharat Biotech in the event of an uncured material breach or bankruptcy of the other party.
License Agreement with The Schepens Eye Research Institute, Inc.
In December 2017, we entered into an exclusive license agreement with SERI, which was amended in January 2021 (as so amended, the "SERI Agreement"). The SERI Agreement gives us an exclusive, worldwide, sublicensable license to patent rights, biological materials, and technical information for NHR genes NR1D1, NR2E3 (OCU400), RORA (OCU410), Nuclear Protein 1, Transcriptional Regulator ("NUPR1"), and Nuclear Receptor Subfamily 2 Group C Member 1 ("NR2C1"). The January 2021 amendment to the SERI Agreement additionally granted us rights in co-owned intellectual property pursuant to certain patent applications and provisional patent applications at the time of the amendment. Under the SERI Agreement, we may make, have made, use, offer to sell, sell, and import licensed products, and must use commercially reasonable efforts to bring one or more licensed products to market as soon as reasonably practicable.
The SERI Agreement requires us to pay licensing fees for patent rights granted, an annual license maintenance fee, payment of certain regulatory and commercial milestones in the aggregate amount of $16.1 million, and low single-digit percentage royalties on annual net sales of products that fall under the licensed patent rights.
SERI maintains control of patent preparation, filing, prosecution, and maintenance. We are responsible for SERI’s out-of-pocket expenses related to the filing, prosecution, and maintenance of the licensed patent rights. In the event that SERI decides to discontinue the prosecution or maintenance of the licensed patent rights, we have the right, but not the obligation, to file for, or continue to prosecute, maintain, or enforce such licensed patent rights. We have assumed prosecution of certain licensed patent rights under the SERI Agreement.
The SERI Agreement will expire on the expiration date of the last to expire licensed patent rights, subject to the earlier termination of the SERI Agreement in accordance with its terms. We may terminate the license upon 180 days’ prior written notice. SERI may immediately terminate the SERI Agreement if we cease to carry on our business with respect to the licensed patent rights, fail to make payments within thirty days of receiving a written notice of missed payment, fail to comply with our diligence obligations, default on our obligation to procure and maintain insurance, one of our officers is convicted of a felony related to the licensed products, we breach any material obligation of the agreement and do not cure such breach within 90 days, or if we become bankrupt or insolvent.
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License Agreement with CanSinoBIO
We entered into the CanSinoBIO Agreement with CanSinoBIO with respect to the development and commercialization of our modifier gene therapy product candidates, OCU400 and OCU410. The CanSinoBIO Agreement was originally entered into in September 2019 with regards to OCU400, and was subsequently amended in September 2021 to include OCU410 in our existing collaboration with CanSinoBIO. Pursuant to the CanSinoBIO Agreement, we and CanSinoBIO will collaborate on the development of OCU400 and OCU410. CanSinoBIO will be responsible for the CMC development and manufacture of clinical supplies of such products and be responsible for the costs associated with such activities. CanSinoBIO has an exclusive license to develop, manufacture, and commercialize OCU400 and OCU410 in and for the CanSino Territory, and we maintain exclusive development, manufacturing, and commercialization rights with respect to OCU400 and OCU410 in the Company Territory.
CanSinoBIO will pay us an annual royalty between mid- and high-single digits based on Net Sales (as defined in the CanSinoBIO Agreement) of OCU400 and OCU410 in the CanSinoBIO Territory. We will pay to CanSinoBIO an annual royalty between low- and mid-single digits based on Net Sales of OCU400 and OCU410 in the Company Territory.
Unless earlier terminated, the CanSinoBIO Agreement will continue in force on a country-by-country and product-by-product basis until the later of (a) the expiration of the last valid claim of our patent rights covering OCU400 and OCU410 and (b) the tenth (10th) anniversary of the first commercial sale of OCU410 in such country. The CanSinoBIO Agreement will also terminate contemporaneously upon the termination of the SERI Agreement, provided that CanSinoBIO is not in breach or default of the CanSinoBIO Agreement. The CanSinoBIO Agreement may be terminated by either party in its entirety upon (a) a material or persistent breach of the CanSinoBIO Agreement by the other party, (b) a challenge by the other party or any of its affiliates of any intellectual property controlled by the terminating party, or (c) bankruptcy or insolvency of the other party.
License Agreement with University of Colorado
In March 2014, Former Ocugenwe entered into an exclusive license agreement with CU, which was amended in January 2017 and clarified by a letter of understanding in November 2017 (as so amended and clarified, the “CU Agreement”). The CU Agreement gives us an exclusive, worldwide, sublicensable license to patents for OCU200 to make, have made, use, import, offer to sell, sell, have sold, and practice the licensed products in all therapeutic applications. Under the CU Agreement, we must use commercially reasonable efforts to develop, manufacture, sublicense, market, and sell the licensed products.
Pursuant toproducts and have assumed primary responsibility for preparing, filing, and prosecuting broad patent claims for OCU200 for CU's benefit. Further, we have assumed primary responsibility for all patent activities, including all costs associated with the termsperfection and maintenance of the CU Agreement, we paid CU an initial fee of $26,179 and issued 0.1 million shares of common stock. Commencing in 2017, we pay CU an annual royalty payment. patents for OCU200.
The CU Agreement also requires the payment offor certain regulatory milestones aggregating to $1.5 million, andan annual minimum payment that began the third year after the effective date, low single-digit percentage earned royalties on net sales, and royalties in the mid-teens on sublicense income of OCU200.
The CU Agreement will expire on the later of the expiration date of the last to expire licensed patent or the end of any relevant statutory or regulatory exclusivity period. We may terminate the CU Agreement upon 60 days’ prior written notice. CU may terminate the CU Agreement upon 60 days’ notice if we fail to make payments within 60 days of such payment’s due date, breach and do not cure any diligence obligation, provide any materially false report, or otherwise materially breach and do not cure any material provision of the CU Agreement.
License Agreement with University of Illinois at Chicago
In February 2016, Former Ocugen entered into an exclusive license agreement (the “UIC Agreement”) with UIC. This agreement gives us an exclusive, worldwide, non-transferable, sublicensable license to patents and patent rights for OCU300 to make, have made, use, import, sell, and offer for sale products claimed by and/or incorporating or derived from the licensed patents. Under this agreement, we must use commercially reasonable efforts to develop and bring products to market. Pursuant to the terms of the UIC Agreement, we paid UIC a signing fee of $15,000. Commencing in 2019, we also pay UIC an annual
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minimum payment and reimburses UIC for reasonable documented patent costs and expenses. The UIC Agreement also requires the payment of certain regulatory and commercial milestones, aggregating $1.3 million and low single digits to low teens percentage royalties on annual net sales and sublicense revenues from products that fall under the licensed patent rights.
The UIC Agreement will expire on the later of the expiration date of the last to expire licensed patents, when we provide notice to UIC that use of the technical information has ceased or the end of any relevant statutory or regulatory exclusivity period. We may terminate the license upon 90 days’ prior written notice. UIC may terminate the UIC Agreement if we fail to make payments within thirty days of receiving a written notice of missed payment, breach any provision of the UIC Agreement and do not cure such breach within 30 days, breach any obligation under any other agreement between us and UIC and do not cure such breach within 45 days, make any materially false report, become bankrupt or insolvent, or take any action that causes a lien or encumbrance to be placed on the licensed patent rights or technical information.
License Agreement with The Schepens Eye Research Institute, Inc.
In December 2017, Former Ocugen entered into an exclusive license agreement (the “SERI Agreement”) with SERI. The SERI Agreement gives us an exclusive, worldwide, sublicensable license to patent rights, biological materials and technical information for nuclear hormone receptor genes NR1D1, NR2E3 (OCU400), RORA (OCU410), NUPR1, and NR2C1. Under the SERI Agreement, we may make, have made, use, offer to sell, sell and import licensed products.
Under this agreement, we must use commercially reasonable efforts to bring one or more licensed products to market as soon as reasonably practicable.
Pursuant to the terms of the SERI Agreement, we paid SERI an upfront fee of $39,681 to reimburse SERI for patent expenses prior to the effective date of the SERI Agreement and an initial license fee of $0.1 million. The SERI Agreement requires us to pay an annual license maintenance fee. The SERI Agreement also requires the payment of certain regulatory and commercial milestones, aggregating $16.1 million and low single-digit percentage royalties on annual net sales of products that fall under the licensed patent rights.
SERI maintains control of patent preparation, filing, prosecution and maintenance. After the first anniversary of the execution date of the SERI Agreement, we have the right, but not the obligation, to assume responsibility for and control of the prosecution and maintenance of the licensed patent rights, at our sole cost and expense. If we do not exercise this option, we must pay SERI’s out-of-pocket expenses related to the filing, prosecution and maintenance of the licensed patent rights. In the event that SERI decides to discontinue the prosecution or maintenance of the licensed patent rights, we have the right, but not the obligation, to file for, or continue to prosecute, maintain or enforce such licensed patent rights.
The SERI Agreement will expire on the expiration date of the last to expire licensed patents right. We may terminate the license upon 180 days’ prior written notice. SERI may immediately terminate the SERI Agreement if we cease to carry on our business with respect to the licensed patent rights, fail to make payments within thirty days of receiving a written notice of missed payment, fail to comply with our diligence obligations, default on our obligation to procure and maintain insurance, one of our officers is convicted of felony related to the licensed products, we breach any material obligation of the agreement and do not cure such breach within 90 days or if we become bankrupt or insolvent.
INTELLECTUAL PROPERTY
Our success depends in part upon our ability to protect our core technologies and intellectual products. We have applied, obtained, and licensed patent protection for all of our product candidates. We intend to maintain and defend our patentintellectual property rights to protect our technology, inventions, processes, and improvements that are commercially important to the development of our business. We cannot be sureThere is no guarantee that any of our existing patentscurrent or patents that we obtain infuture intellectual property will advance the future will be commercially useful in protectingcommercial success of our technology, or thatproduct candidates. There is also no guarantee patents will be issued or registered for any pending patent applications or patent applications that we may file in the future. Our commercial success also depends in part on our non-infringement of the patents and proprietary rights of third parties.
As of March 2020,February 15, 2022, our patent portfolio included 34 U.S. or foreigna total of eight issued patents and 30in the United States, 38 issued or registered patents in foreign countries, three pending patent applications including those licensed from CU, UICin the United States, and SERI.seven pending patent applications in foreign countries. Our intellectual property consists of issued or registered patents and pending patent applications forinclude those licensed from SERI and CU. Certain pending patent applications cover multiple of our product candidates. Our intellectual property includes compositions of
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matter, and methods of use, as well as for product candidates, and other proprietary technology, including our OcuNanoEtechnology. As of March 2020,February 15, 2022, we had exclusive rights or owned rights to: (i) threeone issued patents and 11U.S. patent, two pending U.S. patent applications, and three pending foreign patent applications related to OCU300;OCU400; (ii) one issuedtwo pending U.S. patent and four pending applications related to OCU400; and (iii) 25 issued U.S. and foreign patents and three pending foreign patent applications related to OCU410; and (iii) one issued U.S. patent, 25 issued or registered foreign patents, one pending U.S. patent application, and four pending foreign patent applications related to OCU200.
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issued patents in the U.S. and issued or registered patents in foreign countries related to OCU400 and OCU200 expire between 2032 and 2034. In February 2021, we entered into the Covaxin Agreement with Bharat Biotech, pursuant to which we obtained an exclusive right and license under certain of Bharat Biotech’s intellectual property rights, with the right to grant sublicenses, to develop, manufacture, and commercialize COVAXIN in the United States. In June 2021, the Covaxin Agreement was subsequently amended to include rights to Canada. In some instances, we may need to license additional patents and trade secrets to commercialize our product candidates in certain territories.
In addition to patents, we may rely, in some circumstances, on trade secrets to protect our technology. However, trade secrets can be difficult to protect. We seek to protect our proprietary technology and processes, and obtain and maintain ownership of certain technologies, in part, by confidentiality and invention assignment agreements with itsour employees, consultants, scientific advisors, and contractors. We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems.
HISTORICAL HISTOGENICS ASSETS (NEOCART®)
Histogenics historically focused on the development of restorative cell therapies (“RCTs”), which term referred to a new class of products designed to offer patients rapid-onset pain relief and restored function through the repair of damaged or worn tissue. Histogenics’ product, NeoCart®, is an innovative cell therapy that utilizes various aspects of its RCT platform to treat tissue injury in the field of orthopedics, specifically cartilage damage in the knee. In December 2018, after receiving feedback from the FDA regarding the need for an additional clinical trial prior to submission of a Biologic License Application (“BLA”), Histogenics discontinued the development of NeoCart®.
License and Commercialization Agreement with MEDINET Co., Ltd.
In December 2017, Histogenics entered into the License and Commercialization Agreement with MEDINET Co., Ltd. (“MEDINET”) to grant MEDINET a license under certain patents, patent applications, know-how, and technology to develop and commercialize certain therapeutic products related to the NeoCart® program. As consideration for the granting of the license, MEDINET agreed to pay Histogenics a non-refundable upfront cash payment of $10.0 million which was received in January 2018. Based on the results of the NeoCart® research, Histogenics suspended the NeoCart® program. Subsequently, since MEDINET relied on the NeoCart® product to supply clinical trial patients, MEDINET suspended the development of its clinical trial. As of December 31, 2019, the contract with MEDINET was wholly unperformed. As a result of the expected sale of the NeoCart® asset, we do not expect to retain any future obligations related to the MEDINET agreement.
Medavate Asset Purchase Agreement
In connection with the Merger, on May 8, 2019, Histogenics entered into an asset purchase agreement (the “Asset Purchase Agreement”) with Medavate Corp., a Colorado corporation (“Medavate”), pursuant to which Histogenics agreed to sell substantially all of its assets relating to its NeoCart® program, including, without limitation, intellectual property, business and license agreements and clinical trial data in return for a cash payment of $6.5 million. On September 26, 2019, the parties entered into an amendment to the Asset Purchase Agreement whereby the closing date was amended to October 4, 2019. On October 4, 2019, the parties entered into a second amendment (the “Second Amendment”) to the Asset Purchase Agreement whereby the purchase price was increased to $7.0 million under the Asset Purchase Agreement and the closing date of the Asset Purchase Agreement was revised from October 4, 2019 to two business days after Medavate obtains financing in an amount no less than the purchase price (the “Closing Date”). The Second Amendment further provides that if the Closing Date does not occur on or prior to October 31, 2019, we may choose to terminate the Asset Purchase Agreement without recourse and, if we do not terminate the Asset Purchase Agreement, the purchase price shall increase 10% per month (or any portion thereof) between October 31, 2019 and the Closing Date. The Closing Date did not occur as of October 31, 2019 and we did not terminate the agreement. As of March 1, 2020, the purchase price has increased to $11.3 million.
NeoCart® Intellectual Property
As of March 2020, our intellectual property portfolio related to NeoCart® was composed of 18 issued patents and six patent applications in the United States that we own, and eight issued patents and one patent application in the United States that we license from academic institutions and business entities. We also have approximately 70 counterpart patent and patent applications owned or licensed in certain foreign jurisdictions.
GOVERNMENT REGULATION AND PRODUCT APPROVAL
Government authorities in the United States, at the federal, state, and local level, and in other countries including Canada, extensively regulate, among other things, the research, development, testing, approval, manufacture, packaging, storage, recordkeeping, monitoring and reporting, labeling, advertising, promotion, distribution, marketing, sales, import, and export of biopharmaceutical and drug products such as those we are developing. In addition, labelers of biopharmaceutical and drug products (the entity owning the National Drug Code listed for a product) participating in Medicaid and Medicare are required to comply with mandatory price reporting, discount, rebatediscounts, rebates, and other requirements. The processes for obtaining regulatory approvals in the United States and in foreign countries including Canada, along with compliance with applicable statutes and regulations, require the expenditure of substantial time and financial resources.
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FDA Regulation
In the United States, the FDA regulates biologics and drug products under the Federal Food, Drug, and Cosmetic Act (“FDCA”("FDCA") and its implementing regulations. In addition to the FDCA and its implementing regulations, biologicbiological products are regulated under the Public Health Service Act (“PHSA”("PHSA") and its implementing regulations. The process required by the FDA before product candidates may be marketed in the United States generally involves the following:
completion of preclinical laboratory tests, animal studies, and formulation studies in compliance with the FDA’s Good Laboratory Practice (“GLP”("GLP") regulations, applicable requirements for the human use of laboratory animals, such as the Animal Welfare Act ("AWA"), or other applicable regulations;
submission to the FDA of an IND, which must become effective before human clinical trials may begin at United StatesU.S. clinical trial sites;
approval by an Institutional Review Board (“IRB”("IRB") for each clinical site, or centrally, before eacha clinical trial may be initiated;initiated at that site;
adequate and well-controlled human clinical trials to establish the safety and efficacy, in the case of a drug product candidate, or safety, purity, and potency, in the case of a biologicbiological product candidate for its intended use, performed in accordance with Good Clinical Practices (“GCPs”("GCPs"); and additional requirements for the protection of human research subjects and their health information;
development of manufacturing processes to ensure the product candidate’s identity, strength, quality, purity, and potency;potency in compliance with cGMP;
submission to the FDA of a NDA,New Drug Application ("NDA"), in the case of a drug product candidate, or a BLA, in the case of a biologicbiological product candidate, including results of preclinical testing, detailed information about the CMC, and proposed labeling and packaging for the product candidate;
satisfactory completion of an FDA advisory committee review, if applicable;
satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the products are produced to assess compliance with cGMPs,cGMP, and to assure that the facilities, methods, and controls are adequate to preserve the therapeutics’ identity, strength, quality, purity, and potency as well as satisfactory completion of an FDA
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inspection of selected clinical sites, selected clinical investigators to determine GCP compliance;compliance, and payment of user feesfees; and
FDA review and approval of the NDA, or licensure of a BLA to permit commercial marketing for particular indications for use.use, including agreement on post-marketing commitments, if applicable.
Preclinical Studies and IND Submission
The testing and approval process of product candidates requires substantial time, effort, and financial resources. Satisfaction of FDA pre-market approval requirements typically takes many years and the actual time required may vary substantially based upon the type, complexity, and novelty of the product or disease. Preclinical studies include laboratory evaluation of chemistry, pharmacology, toxicity, and product formulation, as well as animal studies to assess potential safety and efficacy. Such studies must generally be conducted in accordance with GLP, the FDA’s GLPs.AWA, and other federal regulations and requirements. Prior to commencing the first clinical trial at a United StatesU.S. investigational site with a product candidate, an IND sponsor must submit the results of the preclinical tests and preclinical literature, together with manufacturing information, analytical data, any available clinical data or literature, and proposed clinical study protocols, among other things, to the FDA as part of an IND. InSome preclinical studies may continue even after the case of drug product candidates for which the sponsor will seek marketing approval via a 505(b)(2) NDA application, some of the above information may be abbreviated or omitted.IND is in effect.
An IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, notifies the applicant of safety concerns or questions related to one or more proposed clinical trials and places the trial on a clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial canmay begin. Even after the IND has gone into effect and clinical testing has begun, the FDA may impose clinical holds on clinical trials due to safety concerns or non-compliance. If the FDA imposes a clinical hold, studies may not recommence without FDA authorization and then only under terms authorized by the FDA. As a result, submission of an IND may not result in FDA authorization to commence a clinical trial.trial, and we cannot be sure that once the trials have begun, issues will not arise that will suspend or terminate such studies. A separate submission to an existing IND must also be made for each successive clinical trial conducted during product development.
Clinical Trials
Clinical trials involve the administration of the investigational product to human subjects (healthy volunteers or patients) under the supervision of qualified investigatorsinvestigators. Clinical trials must be conducted in accordance with federal regulations and GCP requirements, which include the requirements that all research subjects provide their informed consent in writing for their participation in any clinical trial, as well as review and approval of the study by an IRB. Investigators must also provide certain information to the clinical trial sponsors to allow the sponsors to make certain financial disclosures to the FDA. Clinical trials are conducted under protocols detailing, among other things, the objectives of the trial, the trial procedures, the parameters to be used in monitoring safety, the effectiveness criteria to be
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evaluated, and a statistical analysis plan. A protocol for each clinical trial, and any subsequent protocol amendments, must be submitted to the FDA as part of the IND. If a product candidate is being investigated for multiple intended indications, separate INDs may also be required. In addition, an IRB at each study site participating in the clinical trial and/or a central IRB must review and approve the plan for any clinical trial, informed consent forms, and communications to study subjects before a study commences at that site. An IRB is charged with protecting the welfare and rights of trial participants, and considers, among other things, whether the risks to individuals participating in the trials are minimized and are reasonable in relation to anticipated benefits, and whether the planned human subject protections are adequate. The IRB must continue to oversee the clinical trial while it is being conducted. Progress reports detailing the results of the clinical trials must also be submitted at least annually to the FDA and the IRB and more frequently if serious adverse events or other significant safety information is found.
During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical data, and clinical trial investigators. Annual progress reports detailing the results of the clinical trials must be submitted to the FDA. Written IND safety reports must be promptly submitted to the FDA and the investigators for serious and unexpected adverse events, any findings from other studies, tests in laboratory animals or in-vitro testing and other sources that suggest a significant risk for human subjects, or any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The sponsor must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for reporting. The sponsor also must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the information. Phase 1, Phase 2, and Phase 3 clinical trials may not be completed successfully within any specified period, if at all. The FDA may order the temporary, or permanent, discontinuation of a clinical trial at any time or impose other sanctions, if it believes that the clinical trial either is not being conducted in accordance with FDA requirements or presents an unacceptable risk to the clinical trial patients. If the FDA issues a clinical hold halting a clinical trial, the agency must notify the
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IND sponsor of the grounds for the hold. Any identified deficiencies must be resolved before the FDA will lift the hold and allow the clinical trial to begin or resume. There is no guarantee the FDA will ever lift a clinical hold once put in place. An IRB may also require the clinical trial at the site to be halted, either temporarily or permanently, for failure to comply with the IRB’s requirements or if the trial poses an unexpected serious harm to subjects. The FDA or an IRB may also impose conditions on the conduct of a clinical trial. Clinical trial sponsors may also choose to discontinue clinical trials as a result of risks to subjects, a lack of favorable results, or changing business priorities.
Information about certain clinical trials, including a description of the study and study results, must be submitted within specific timeframes to the NIH for public dissemination on theirits clinicaltrials.gov website. Sponsors or distributors of investigational products for the diagnosis, monitoring, or treatment of one or more serious diseases or conditions must also have a publicly available policy on evaluating and responding to requests for expanded access requests. This requirement applies on the earlier of the first initiation of a Phase 2 or Phase 3 trial of the investigational drug or, as applicable, 15 days after the drug receives a designation as a breakthrough therapy, fast track product, or regenerative medicine advanced therapy.
The manufacture of investigational drugs and biologics for the conduct of human clinical trials is subject to cGMP requirements. Investigational drugs and biologics and active ingredients and therapeutic substances imported into the United States are also subject to regulation by the FDA. Further, the export of investigational products outside of the United States is subject to regulatory requirements of the receiving country, as well as U.S. export requirements under the FDCA.
In general, for purposes of NDA and BLA approval, human clinical trials are typically conducted in three sequential phases, which may overlap or be combined.
Phase 1—Studies are initially conducted in a small group of healthy human volunteers or subjects (e.g., 10 to 20 subjects) with the target disease or condition to test the product candidate for safety, dosage tolerance, structure-activity relationships, mechanism of action, absorption, metabolism, distribution, and excretion. If possible, Phase 1 trials may also be used to gain an initial indication of product effectiveness.
Phase 2—Controlled studies are conducted in larger but still limited subject populations (e.g., a few hundred patients) with a specified disease or condition to evaluate preliminary efficacy, identify optimal dosages, dosage tolerance and schedule, possible adverse effects and safety risks, and expanded evidence of safety.
Phase 3—These adequate and well-controlled clinical trials are undertaken in expanded subject populations (e.g., several hundred to several thousand patients), generally at geographically dispersed clinical trial sites, to generate enough data to provide statistically significant evidence of clinical efficacy and safety of the product candidate for approval, to establish the overall risk-benefit profile of the product candidate, and to provide adequate information for the labeling of the product candidate. Typically, two Phase 3 trials are required by the FDA for product approval. Under some limited circumstances, however, the FDA may approve an NDA or BLA based upon a single Phase 3 clinical study.
Moreover, in the case of 505(b)(2) NDAs, the above studies may be abbreviated. Additional kinds of data may also help to support a BLA or NDA, such as patient experience data and real world evidence. Real world evidence may also be used to assist in clinical trial design or to support an NDA for already approved products. For genetically targeted products and variant protein targeted products intended to address an unmet medical need in one or more patient subgroups with a serious or life threatening rare disease or condition, the FDA may allow a sponsor to rely upon data and information previously developed by the sponsor or for which the sponsor has a right of reference, that was previously submitted to support an approved application for a product that incorporates or utilizes the same or similar genetically targeted technology or a product that is the same or utilizes the same variant protein targeted drug as the product that is the subject of the application.
The FDA may also require, or companies may conduct, additional clinical trials for the same indication after a product is approved. These so-calledare referred to as Phase 4 studies and may be made a condition to be satisfied after approval. The results of Phase 4 studies can confirm or refute the effectiveness of a product candidate, and can provide important long-term safety information.
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Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the product candidate as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, manufacturers must develop methods for testing the identity, strength, quality, potency, and purity of the final product. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.
There are also various laws and regulations regarding laboratory practices, the experimental use of animals, and the use and disposal of hazardous or potentially hazardous substances in connection with our research. In each of these areas, the FDA and other regulatory authorities have broad regulatory and enforcement powers, including the ability to levy fines and civil penalties, suspend or delay issuance of approvals, seize or recall products, and withdraw approvals.
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Marketing Application Submission, Review by the FDA, and Marketing Approval
Assuming successful completion of the required clinical and preclinical testing, the results of product development, including chemistry, manufacture, and controls,CMC, non-clinical studies, and clinical trial results, including negative or ambiguous results, as well as positive findings, are all submitted to the FDA, along with the proposed labeling, as part of an NDA, in the case of a drug, or BLA, in the case of a biologic, requesting approval to market the product for one or more indications. In most cases, the submission of a marketing application is subject to a substantial application user fee. These user fees must be paid at the time of the first submission of the application, even if the application is being submitted on a rolling basis. Fee waivers or reductions are available in certain circumstances. One basis for a waiver of the application user fee is if the applicant employs fewer than 500 employees, including employees of affiliates, the applicant does not have an approved marketing application for a product that has been introduced or delivered for introduction into interstate commerce, and the applicant, including its affiliates, is submitting its first marketing application. Product candidates that are designated as orphan products, which are further described below, are also not subject to application user fees unless the application includes an indication other than the orphan indication. The testing and approval processes require substantial time and effort and there can be no assurance that the FDA will accept the BLA or NDA for filing and, even if filed, that any approval will be granted on a timely basis, if at all.
In addition, under the Pediatric Research Equity Act ("PREA"), a BLA or NDA or supplement to a BLA or NDA for a new active ingredient, indication, dosage form, dosage regimen, or route of administration, must contain data that areis adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after the approval of the product for use in adults, or full or partial waivers from the pediatric data requirements. Orphan products are also exempt from the PREA requirements.
The FDA also may require submission of a risk evaluation and mitigation strategy (“REMS”("REMS") to ensure that the benefits of the product candidate outweigh the risks. The REMS plan could include medication guides, physician communication plans, and elements to assure safe use, such as restricted distribution methods, patient registries, or other risk minimization tools. An assessment of the REMS must also be conducted at set intervals. Following product approval, a REMS may also be required by the FDA if new safety information is discovered and the FDA determines that a REMS is necessary to ensure that the benefits of the product continue to outweigh the risks. Any of these limitations on approval or marketing could restrict the commercial promotion, distribution, prescription, or dispensing of products.
Once the FDA receives an application, it hasgenerally takes 60 days to review the NDA or BLA to determine if it is substantially complete to permit a substantive review, before it accepts the application for filing. The FDA may refuse to review any application that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the application must be resubmitted with the additional information. The resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review.
Under the goals and policies agreed to by the FDA under the Prescription Drug User Fee Act (“PDUFA”("PDUFA"), the FDA has set the review goal of completing its review of 90% of all applications for new molecular entities within ten10 months of the 60-day filing date. The FDA also has the review goal of completing its review of 90% of non-new molecular entity marketing applications within ten10 months of the agency’s receipt of the application. These review goals are referred to as the PDUFA date. The PDUFA date is only a goal, thus, the FDA does not always meet its PDUFA dates. The review process and the PDUFA date may also be extended if the FDA requests or the sponsor otherwise provides substantial additional information or clarification regarding the submission.
The FDA may also refer certain applications to an advisory committee. Before approving a product candidate for which no active ingredient (including any ester or salt of an active ingredients)ingredient) has previously been approved by the FDA, the FDA must either refer that product candidate to an external advisory committee or provide in an action letter a summary of the reasons
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why the FDA did not refer the product candidate to an advisory committee. The FDA may also refer other product candidates to an advisory committee if the FDA believes that the advisory committee’s expertise would be beneficial. An advisory committee is typically a panel that includes clinicians and other experts, which review, evaluate, and make a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
The FDA reviews applications to determine, among other things, whether a product candidate meets the agency’s approval standards and whether the manufacturing methods and controls are adequate to assure and preserve the product’s identity, strength, quality, potency, and purity. Before approving a marketing application, the FDA typically will inspect the facility or
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facilities where the product is manufactured, referred to as a Pre-Approval Inspection. The FDA will not approve an application unless it determines that the manufacturing processes and facilities, including contract manufacturers and subcontractors, are in compliance with cGMP requirements and are adequate to assure consistent production of the product within required specifications. Additionally, before approving a marketing application, the FDA will inspect one or more clinical trial sites to assure compliance with GCPs. To assure cGMP and GCP compliance, an applicant will incur significant expenditure of time, money, and effort in the areas of training, recordkeeping, production, and quality control.
After evaluating the marketing application and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter, or, in some cases, a Complete Response Letter (“CRL”("CRL"). A CRL indicates that the review cycle for the application is complete and the application is not ready for approval. It also describes all of the specific deficiencies that the FDA identified. A CRL generally contains a statement of specific conditions that must be met in order to secure final approval of the marketing application, and may require additional clinical or preclinical testing in order for the FDA to reconsider the application. The deficiencies identified may be minor, for example, requiring labeling changes; or major, for example, requiring additional clinical trials. If a CRL is issued, the applicant may either: resubmit the marketing application addressing all of the deficiencies identified in the letter; withdraw the application; or request an opportunity for a hearing. The FDA has the goal of reviewing 90% of application resubmissions following a CRL in either two or six months of the resubmission date, depending on the kind of resubmission. Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval. If and when those conditions have been met to the FDA’s satisfaction, the FDA may issue an approval letter. An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.
Even if the FDA approves a product, it may limit the approved indications or populations for use of the product, require that contraindications, warnings, or precautions be included in the product labeling, including a boxed warning, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a product’s safety and efficacy after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product. The FDA may also not approve label statements that are necessary for successful commercialization and marketing.
After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes, and additional labeling claims, are subject to further testing requirements and FDA review and approval. The FDA may also withdraw the product approval if compliance with the pre- and post-marketing regulatory standards are not maintained or if problems occur after the product reaches the marketplace. Further, should new safety information arise, additional testing, product labeling changes, or FDA notification may be required.
505(b)(2) New Drug ApplicationsFor example, as a condition of approval of an NDA or BLA, the FDA may require post-marketing testing and surveillance to monitor the Hatch-Waxman Act
Section 505product’s safety or efficacy. In addition, holders of the FDCA describes three types of marketing applications that may be submittedan approved NDA or BLA are required to submit annual reports and keep extensive records to report certain adverse reactions and issues related to production to the FDA, to request marketing authorization for a new drug. A Section 505(b)(1) NDA is an application that contains full reports of investigations of safety and efficacy. A 505(b)(2) NDA is an application that contains full reports of investigations ofprovide updated safety and efficacy but whereinformation, and to comply with requirements concerning advertising and promotional labeling for their products. Additionally, quality control and manufacturing procedures must continue to conform to cGMP regulations and practices, as well as the manufacturing conditions of approval set forth in the NDA or BLA. The FDA periodically inspects manufacturing facilities to assess compliance with cGMP, which imposes certain procedural, substantive, and recordkeeping requirements. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance. If, after receiving approval, a company makes a material change in manufacturing equipment, location, or process (all of which are, to some degree, incorporated in the BLA), additional regulatory review and approval may be required.
Future FDA inspections may identify cGMP compliance issues at least somemanufacturing facilities or at the facilities of the information required for approval comes from investigationsthird-party suppliers that were not conductedmay disrupt production or distribution or require substantial resources to correct and prevent recurrence of any deficiencies, and could result in fines or penalties by or for the applicant and for which the applicant has not obtainedregulatory authorities. In addition, discovery of problems with a right of reference or use. This regulatory pathway enables the applicant to rely, in part, on the FDA’s prior findings of safety and efficacy for an existing product or published literature,the failure to comply with applicable requirements may result in support of its application. Section 505(j) establishes an abbreviated approval process for a generic version of approved drug products through the submission of an Abbreviated New Drug Application (“ANDA”). An ANDA provides for marketing of a generic drug product that has the same active ingredients, dosage form, strength, route of administration, labeling, performance characteristics and intended use to a previously approved product. ANDAs are termed “abbreviated” because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and efficacy. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent to, or performs in the same manner as, the innovator drug through in vitro, in vivo, or other testing. The generic version must deliver the same amount of active ingredients to the site of
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action in the same amount of time as the innovator drug and can often be substituted by pharmacists under prescriptions written for the reference listed drug.
In seeking approval for a drug through an NDA, applicants are required to list with the FDA each patent with claims that cover the applicant’s drug or a method of using the drug, as reflected in the NDA. Upon approval of a drug, each of the patents listed in the application for the drug is published in the FDA’s list of Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book. Drugs listed in the Orange Book can, in turn, be cited by potential competitors in support of approval of an ANDA or 505(b)(2) NDA.
Upon submission of an ANDA or a 505(b)(2) NDA, an applicant must certify to the FDA that (1) no patent information has been submitted to the FDA; (2) such patent has expired; (3) the daterestrictions on which such patent expires; or (4) such patent is invalid or will not be infringed upon by the manufacture, use or sale of the drug product for which the application is submitted. Generally, the ANDA or 505(b)(2) NDA cannot be approved until all listed patents have expired, except where the ANDA or 505(b)(2) NDA applicant challenges a listed patent through the last type of certification, also known as a paragraph IV certification. If the applicant does not challenge the listed patents or does not indicate that it is not seeking approval of a patented method of use, the ANDA or 505(b)(2) NDA application approval will not be made effective until all of the listed patents claiming the referenced product have expired.
If the ANDA or 505(b)(2) NDA applicant has provided a paragraph IV certification to the FDA, the applicant must send notice of the certification to the NDA and patent holders. The NDA and patent holders may then initiate a patent infringement lawsuit in response to the notice of the paragraph IV certification, in which case the FDA may not make an approval effective until the earlier of 30 months from the patent or application owner’s receipt of the notice of the paragraph IV certification, the expiration of the patent, when the infringement case concerning each such patent is favorably decided in the applicant’s favor or settled, or such shorter or longer period as may be ordered by a court. This prohibition is generally referred to as the 30-month stay. In instances where an ANDA or 505(b)(2) NDA applicant files a paragraph IV certification, the NDA holder or patent owner(s) regularly take action to trigger the 30-month stay. Thus, approval of an ANDA or 505(b)(2) NDA could be delayed for a significant period of time depending on the patent certification the applicant makes and the reference drug sponsor’s decision to initiate patent litigation.
The Hatch-Waxman Act establishes periods of regulatory exclusivity for certain approved drug products, during which the FDA cannot accept an ANDA or 505(b)(2) application that relies on the branded reference drug or make an approval of such a product, effective. For example, themanufacturer, or holder of an NDA,approved BLA, including a 505(b)(2) NDA, may obtain five yearswithdrawal or recall of exclusivity upon approval of a new drug containing new chemical entities that have not been previously approved by the FDA. A drug is a new chemical entity ifproduct from the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion, excluding appended portions that cause the drug to be an ester, salt,market or other noncovalent derivative, responsible for the therapeutic activityvoluntary, FDA-initiated or judicial action, including warning letters, fines, injunctions, civil penalties, license revocations, seizure, total or partial suspension of the drug substance. During the exclusivity period, the FDAproduction or criminal penalties, any of which could delay or prohibit further marketing. Newly discovered or developed safety or efficacy data may not accept for review an ANDA or a 505(b)(2) NDA submitted by another company that contains the previously approved active moiety. However, an ANDA or 505(b)(2) NDA may be submitted after four years if it contains a certification of patent invalidity or non-infringement.
The Hatch-Waxman Act also provides three years of marketing exclusivity to the holder of an NDA (including a 505(b)(2) NDA) for a particular condition of approval, or changerequire changes to a marketed product, such as aproduct’s approved labeling, including the addition of new indication or formulation for a previously approved product, if one or more new clinical studies (other than bioavailability or bioequivalence studies) was essential to the approval of the applicationwarnings and was conducted/sponsored by the applicant. This three-year exclusivity period protects against the FDA making an ANDA and 505(b)(2) NDA approval effective for the condition of the new drug’s approval. As a general matter, the three-year exclusivity does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for generic or modified versions of the original, unmodified drug product. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA; however, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and efficacy.
Biosimilars and Exclusivity
The Biologics Price Competition and Innovation Act of 2009 creates an abbreviated approval pathway for biological products shown to be highly similar to or interchangeable with an FDA-licensed reference biological product. Biosimilarity sufficient to reference a prior FDA-approved product requires a high similarity to the reference product notwithstanding minor differences in clinically inactive components, and no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency. Biosimilarity must be shown through analytical studies, animal studies, and at least one clinical trial, absent a waiver by the FDA. There must be no difference between the reference product and a biosimilarcontraindications.
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Emergency Use Authorization
The FDA has the authority to grant an EUA to allow unapproved medical products, including vaccines, to be used in mechanism of action,a public health emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions when there are no adequate, approved, and available alternatives. When issuing an EUA, the FDA imposes conditions of authorization, with which we must comply. Such conditions include, but may not be limited to, compliance with labeling, distribution of materials designed to ensure proper use, route of administration, dosage form,reporting obligations, and strength. A biosimilar product may be deemed interchangeable with a prior approved product if it meetsrestrictions on advertising and promotion. The EUA is only effective for the higher hurdle of demonstrating that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive useduration of the reference biologic.
A reference biologic is granted 12 yearspublic health emergency. Although the criteria of exclusivityan EUA differ from the timecriteria for approval of first licensure,an NDA or BLA, EUAs nevertheless require the development and submission of data to satisfy the relevant FDA standards and a number of ongoing compliance obligations. In addition, the FDA expects EUA holders to work toward submission of a full application, such as a BLA, as soon as possible. The FDA may revoke or terminate the EUA sooner if, for example, the holder of the EUA fails to comply with the terms of the EUA or the product is determined to be less efficacious or safe than it was initially believed to be. The FDA may revoke an EUA if there is a failure to comply with the conditions of authorization. There is no applicationguarantee that our product candidates will meet the criteria for a biosimilar can be submitted for four years from the date of licensure. However, certain changes and supplements to an approved BLA, and subsequent applications filed by the same sponsor, manufacturer, licensor, predecessor in interest, or other related entity do not qualify for the twelve-year exclusivity period. The PHSA also includes provisions to protect reference products that have patent protection. The biosimilar product sponsor and reference product sponsor may exchange certain patent and product information for the purpose of determining whether there should be a legal patent challenge. Based on the outcome of negotiations surrounding the exchanged information, the reference product sponsor may bring a patent infringement suit and injunction proceedings against the biosimilar product sponsor. The biosimilar applicant may also be able to bring an action for declaratory judgment concerning the patent.EUA.
Pediatric Exclusivity
Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity periods for both drugs and biologics, and also Orange Book listed patents in the case of drugs. Conditions for exclusivity include the FDA's determination that information relating to the use of a new drug in the pediatric population may produce health benefits in that population, the FDA making a written request for pediatric studies, and the applicant agreeing to perform and reportingreport on the requested studies within the statutory timeframe.
Orphan Products
The Orphan Drug Act provides incentives for the development of products for rare diseases or conditions. Specifically, sponsors may apply for and receive ODD if a product candidate is intended to treat rare diseases or conditions, which generally are diseases or conditions affecting less than 200,0000.2 million individuals in the United States, or affecting more than 200,0000.2 million individuals in the United States and for which there is no reasonable expectation that the cost of developing and making the product available in the United States will be recovered from United StatesU.S. sales. ODD must be requested before submitting an NDA.NDA or BLA. Additionally, sponsors must present a plausible hypothesis for clinical superiority to obtain ODD if there is a product already approved by the FDA that that is considered by the FDA to be the same as the already approved product and is intended for the same indication. This hypothesis must be demonstrated to obtain orphanODD exclusivity. If granted, prior to product approval, ODD entitles a party to financial incentives such as opportunities for grant funding towards clinical study costs, tax advantages, and certain user-fee waivers. The tax advantages, however, were limited in the 2017 Tax Cuts and Jobs Act. In addition, if a product candidate receives FDA approval for the indication for which it has ODD, the product is generally entitled to orphan exclusivity, which means the FDA may not approve any other application to market the same product for the same indication for a period of seven years, except in limited circumstances, such as a showing of clinical superiority over the product with orphan exclusivity. After the FDA grants ODD, the generic identity of the drug and its potential orphan use are disclosed publicly by the FDA. ODD does not convey any advantage in, or shorten the duration of, the regulatory review and approval process. The first NDA or BLA applicant to receive FDA approval for a particular active moiety to treat a particular disease with FDA Orphan Drug designationODD generally is entitled to a seven-year exclusive marketing period in the U.S.United States for that product, for that indication. During the seven-year exclusivity period, the FDA may not approve any other applications to market the same drug for the same disease, except in limited circumstances, such as a showing of clinical superiority to the product with Orphan DrugODD exclusivity by means of greater effectiveness, greater safety, or providing a major contribution to patient care. Orphan drugODD exclusivity does not prevent the FDA from approving a different drug for the same disease or condition, or the same drug for a different disease or condition. Among the other benefits of ODD are tax credits for certain research and a waiver of the NDA application user fee.
Patent Term Restoration
If approved, drug and biologic products may also be eligible for periods of U.S. patent term restoration. If granted, patent term restoration extends the patent life of a single unexpired patent, that has not previously been extended, for a maximum of five years. The total patent life of the product with the extension also cannot exceed fourteen14 years from the product’product’s approval date. Subject to the prior limitations, the period of the extension is calculated by adding half of the time from the effective date of an IND to the initial submission of a marketing application, and all of the time between the submission of the marketing application and its approval. This period may also be reduced by any time that the applicant did not act with due diligence. Only one patent claiming each approved product is eligible for restoration and the patent holder must apply for restoration within 60 days of approval. The U.S. Patent and Trademark Office ("USPTO"), in consultation with the FDA, reviews and approves the application for patent term restoration.
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Special FDA Expedited Review and Approval Programs
The FDA has various programs that are intended to expedite or simplify the process for the development and FDA review of certain productsproduct candidates that are intended for the treatment of serious or life threatening diseases or conditions, and demonstrate the potential to address unmet medical needs or present a significant improvement over existing therapy. The purpose of these programs is to provide important new therapeutics to patients earlier than under standard FDA review procedures. These expedited programs include fast track designation, breakthrough therapy designation, priority review, accelerated approval, and regenerative medicine advanced therapy (“RMAT”) designation. Each of these programs has its own features and qualifying criteria. A sponsor must submit a request for fast track designation, breakthrough therapy designation, or priority review, which may or may not be granted by the FDA.
To be eligible for a Fast Trackfast track designation, the FDA must determine, based on the request of a sponsor, that a product candidate is intended to treat a serious or life threatening disease or condition and demonstrates the potential to address an unmet medical need. If Fast Trackfast track designation is obtained, sponsors may be eligible for more frequent development meetings and correspondence with the FDA. In addition, the FDA may initiate review of sections of an application before the application is complete. This “rolling review”"rolling review" is available if the applicant provides and the FDA approves a schedule for the remaining information. Whether the FDA is able to commence its review of portions of an application, however, before receipt of the complete submission, depends on a number of factors. In some cases, a Fast Trackfast track product may be eligible for accelerated approval or priority review.
The FDA may give a priority review designation to product candidates that are intended to treat serious conditions and, if approved, would provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of the serious condition. A priority review means that the goal for the FDA is to review an application within six months, rather than the standard review of ten10 months under current PDUFA guidelines.
Drug or biological products studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval, which means the FDA may approve the product based upon a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. A drug or biologic candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or post-approval clinical trials to confirm the effect of the product. Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies, will allow the FDA to withdraw the drug or biologic from the market on an expedited basis. All promotional materials for drug or biologic candidates approved under accelerated regulations are subject to prior review by the FDA.
Under the provisions of the Food and Drug Administration Safety and Innovation Act, enacted in 2012, a sponsor can request designation of a product candidate as a “breakthrough"breakthrough therapy." A breakthrough therapy is defined as a product that is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. Products designated as breakthrough therapies are eligible for intensive guidance on an efficient development program beginning as early as Phase 1 trials, a commitment from the FDA to involve senior managers and experienced review staff in a proactive collaborative and cross-disciplinary review, rolling review, and the facilitation of cross-disciplinary review.
Established under the 21st Century Cures Act, RMAT designation is a dedicated program designed to expedite the drug development and review processes for promising pipeline products, including genetic therapies. A regenerative medicine advanced therapy is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life threatening disease or condition, and preliminary clinical evidence indicates that the drug or therapy has the potential to address unmet medical needs for such disease or condition. Similar to breakthrough therapy designation, RMAT designation provides the benefits of intensive FDA guidance on efficient drug development, including the ability for early interactions with FDA to discuss surrogate or intermediate endpoints, potential ways to support accelerated approval and satisfy post-approval requirements, potential priority review of a BLA, and other opportunities to expedite development and review.
Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.
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Post-approval Requirements
Any products manufactured or distributed pursuant to FDA approvals are subject to pervasiveextensive and continuing regulation by the FDA, including, among other things, requirements related to manufacturing, recordkeeping, and reporting, including adverse experience reporting, deviation reporting, shortage reporting, and periodic reporting, product sampling and distribution, advertising, marketing, promotion, certain electronic records and signatures, and post-approval obligations imposed as a condition of approval, such as Phase 4 clinical trials, REMS, and surveillance to assess safety and effectiveness after commercialization.
After approval, most changes to the approved product, such as adding new indications or other labeling claims are subject to prior FDA review and approval. There also are continuing annual program user fee requirements for approved products, excluding orphan products. In addition, manufacturers and other entities involved in the manufacture and distribution of approved therapeutics are required to register their establishments with the FDA and certain state agencies, list their products, and are subject to periodic announced and unannounced inspections by the FDA and these state agencies for compliance with cGMP and other requirements. Manufacturers must continue to expend time, money, and effort in the areas of production and
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quality-control to maintain compliance with cGMPs.cGMP. Regulatory authorities may undertake regulatory enforcement action, withdraw product approvals, require label modifications, or request product recalls, among other actions, if a company fails to comply with regulatory standards, if it encounters problems following initial marketing, or if previously unrecognized problems are subsequently discovered.
Changes to the manufacturing process are strictly regulated and often require prior FDA approval or notification before being implemented. FDA regulations also require investigation and correction of any deviations from cGMP and specifications, and impose reporting and documentation requirements upon the sponsor and any third-party manufacturers that the sponsor may decide to use. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.
The FDA also strictly regulates marketing, labeling, advertising, and promotion of products that are placed on the market. A company can make only those claims relating to a product that are approved by the FDA. Physicians, in their independent professional medical judgment, may prescribe legally available products for unapproved indications that are not described in the product’s labeling and that differ from those tested and approved by the FDA. Biopharmaceutical companies, however, are required to promote their products only for the approved indications and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including, but not limited to, criminal and civil penalties under the FDCA and False Claims Act ("FCA"), exclusion from participation in federal healthcare programs, mandatory compliance programs under corporate integrity agreements, suspension and debarment from government contracts, and refusal of orders under existing government contracts. In addition, newly discovered or developed safety or efficacy data may require changes to a product's approved labeling, including the addition of new warnings and contraindications.
In addition, the distribution of prescription biopharmaceutical samples is subject to the Prescription Drug Marketing Act (“PDMA”("PDMA"), which regulates the distribution of samples at the federal level. Both the PDMA and state laws limit the distribution of prescription biopharmaceutical product samples and impose requirements to ensure accountability in distribution. Free trial or starter prescriptions provided through pharmacies are also subject to regulations under the Medicaid Drug Rebate Program ("MDRP") and potential liability under anti-kickback and false claims laws.
Moreover, the enacted Drug Quality and Security Act imposes obligations on sponsors of biopharmaceutical products related to product tracking and tracing. Among the requirements of this legislation, sponsors are required to provide certain information regarding the products to individuals and entities to which product ownership is transferred, are required to label products with a product identifier, and are required to keep certain records regarding the product. The transfer of information to subsequent product owners by sponsors is also required to be done electronically. Sponsors must also verify that purchasers of the sponsors’ products are appropriately licensed. Further, under this legislation, manufactures have product investigation, quarantine, disposition, and notification responsibilities related to counterfeit, diverted, stolen, and intentionally adulterated products that would result in serious adverse health consequences or death to humans, as well as products that are the subject of fraudulent transactions or which are otherwise unfit for distribution such that they would be reasonably likely to result in serious health consequences or death. Similar requirements additionally are and will be imposed through this legislation on other companies within the biopharmaceutical product supply chain, such as distributors and dispensers, as well as certain sponsor licensees and affiliates.
Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in significant
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regulatory actions. Such actions may include refusal to approve pending applications, license or approval suspension or revocation, imposition of a clinical hold or termination of clinical trials, warning letters, untitled letters, cyber letters, modification of promotional materials or labeling, provision of corrective information, imposition of post-market requirements including the need for additional testing, imposition of distribution or other restrictions under a REMS, product recalls, product seizures or detentions, refusal to allow imports or exports, total or partial suspension of production or distribution, FDA debarment, injunctions, fines, consent decrees, corporate integrity agreements, suspension and debarment from government contracts, and refusal of orders under existing government contracts, exclusion from participation in federal and state healthcare programs, restitution, disgorgement, or civil or criminal penalties including fines and imprisonment, and adverse publicity, among other adverse consequences.
Additional controls for biologics
To help reduce the increased risk of the introduction of adventitious agents, the PHSA emphasizes the importance of manufacturing controls for products whose attributes cannot be precisely defined. The PHSA also provides authority to the FDA to immediately suspend licenses in situations where there exists a danger to public health, to prepare or procure products
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in the event of shortages and critical public health needs, and to authorize the creation and enforcement of regulations to prevent the introduction or spread of communicable diseases in the United States and between states.
After a BLA is approved, the product may also be subject to official lot release as a condition of approval. As part of the manufacturing process, the manufacturer is required to perform certain tests on each lot of the product before it is released for distribution. If the product is subject to official release by the FDA, the manufacturer submits samples of each lot of the product to the FDA together with a release protocol showing the results of all of the manufacturer’s tests performed on the lot. The FDA may also perform certain confirmatory tests on lots of some products before releasing the lots for distribution by the manufacturer.
In addition, the FDA conducts laboratory research related to the regulatory standards on the safety, purity, potency, and effectiveness of biological products.
Gene therapy products are also subject to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, which require, among other things, that trials involving recombinant or synthetic nucleic acid molecules be reviewed by an Institutional Biosafety Committee (“IBC”("IBC"). The IBC reviews, approves, and supervises research involving recombinant or synthetic nucleic acid molecules.
In addition to the regulations discussed above, there are a number of additional standards that apply to clinical trials involving the use of gene therapy. The FDA has issued various guidance documents regarding gene therapies, which outline additional factors that the FDA will consider during product development. By example,development that relate to, among other things: the proper preclinical assessment of gene therapies; the CMC information that should be included in an IND application; the proper design of tests to measure product potency in support of an IND or BLA application; and measures to observe delayed adverse effects in subjects who have been exposed to investigational gene therapies when the risk of such effects is high. Further, the FDA recommends that sponsors observe subjects for potential gene therapy-related delayed adverse events for a prolonged period of time.
Fraud and Abuse, Data Privacy and Security, and Transparency Laws and Regulations
Our business activities, including but not limited to, research, marketing, sales, promotion, distribution, medical education, and other activities following product approval will be subject to regulation by numerous federal and state regulatory and law enforcement authorities in the United States in addition to the FDA, including potentially the Department of Justice, the Department of Health and Human Services and its various divisions, including the Centers for Medicare and Medicaid Services (“CMS”("CMS") and the Health Resources and Services Administration, the Department of Veterans Affairs, the Department of Defense, and state and local governments. Our business activities must comply with numerous healthcare laws, including but not limited to, anti-kickback and false claims laws and regulations as well as data privacy and security laws and regulations, which are described below, as well as state and federal consumer protection and unfair competition laws. Moreover, to the extent that we license the right to sell itsour product candidates, if approved, to another entity under that entity’s labeler code, the licensee would have regulatory responsibilities, including healthcare, reimbursement, pricing, and reporting regulatory responsibilities.
The federal Anti-Kickback Statute, which regulates, among other things, marketing practices, educational programs, pricing policies, and relationships with healthcare providers or other entities, prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting, or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering, or arranging for or recommending the purchase, lease,
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or order, or the referral to another for the furnishing or arranging for the furnishing of any item or service reimbursable under Medicare, Medicaid, or other federal healthcare programs, in whole or in part. The term “remuneration”"remuneration" has been interpreted broadly to include anything of value. The Anti-Kickback Statute has been interpreted to apply to arrangements between biopharmaceutical industry members on one hand and prescribers, purchasers, formulary managers, and beneficiaries on the other. There are certain statutory exceptions and regulatory safe harbors protecting some common activities from prosecution. The exceptions and safe harbors are drawn narrowly, and practices that involve remuneration that may be alleged to be intended to induce prescribing, purchases, or recommendations may be subject to scrutiny if they do not qualify for an exception or safe harbor. Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the Anti-Kickback Statute. Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all of its facts and circumstances. Several courts have interpreted the statute’s intent requirement to mean that if any one purpose of an arrangement involving remuneration is to induce referrals of a federal healthcare covered business, including purchases of products paid by federal healthcare programs, the statute has been violated. The Patient Protection and Affordable Care Act of 2010, as amended (the “ACA”"ACA"), modified the intent requirement under the Anti-Kickback Statute to a stricter standard, such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation. In addition, the ACA also provided that a violation of the federal Anti-Kickback Statute is grounds for the government or a whistleblower to assert that a claim for payment of items or services resulting from such violation constitutes a false or fraudulent claim for purposes of the federal civil FCA.
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The federal civil FCA prohibits, among other things, any person or entity from knowingly presenting, or causing to be presented, a false or fraudulent claim for payment to, or approval by, the federal government, knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government, or avoiding, decreasing, or concealing an obligation to pay money to the federal government. A claim includes “any request or demand” for money or property presented to the U.S. government. The civil FCA has been used to assert liability on the basis of kickbacks and other improper referrals, improperly reported government pricing metrics such as Best Price or Average Manufacturer Price, improper use of Medicare provider or supplier numbers when detailing a provider of services, improper promotion of off-label uses not expressly approved by the FDA in a product’s label, and allegations as to misrepresentations with respect to products, contract requirements, and services rendered. In addition, private payerspayors have been filing follow-on lawsuits alleging fraudulent misrepresentation, although establishing liability and damages in these cases is more difficult than under the FCA. Intent to deceive is not required to establish liability under the civil FCA. Civil FCA actions may be brought by the government or may be brought by private individuals on behalf of the government, called “qui tam”"qui tam" actions. If the government decides to intervene in a qui tam action and prevails in the lawsuit, the individual will share in the proceeds from any fines or settlement funds. If the government declines to intervene, the individual may pursue the case alone. The civil FCA provides for treble damages and a civil penalty for each false claim, such as an invoice or pharmacy claim for reimbursement, which can aggregate into millions of dollars. For these reasons, since 2004, FCA lawsuits against biopharmaceutical companies have increased significantly in volume and breadth, leading to several substantial civil and criminal settlements, as much as $3.0 billion, regarding certain sales practices and promoting off label uses. Civil FCA liability may further be imposed for known Medicare or Medicaid overpayments, for example, overpayments caused by understated rebate amounts, that are not refunded within 60 days of discovering the overpayment, even if the overpayment was not caused by a false or fraudulent act. In addition, conviction or civil judgment for violating the FCA may result in exclusion from federal health care programs, and suspension and debarment from government contracts, and refusal of orders under existing government contracts.
The government may further prosecute conduct constituting a false claim under the criminal FCA. The criminal FCA prohibits the making or presenting of a claim to the government knowing such claim to be false, fictitious, or fraudulent and, unlike the civil FCA, requires proof of intent to submit a false claim.
The civil monetary penalties statute is another potential statute under which biopharmaceutical companies may be subject to enforcement. Among other things, the civil monetary penalties statue imposes fines against any person who is determined to have knowingly presented, or caused to be presented, claims to a federal healthcare program that the person knows, or should know, is for an item or service that was not provided as claimed or is false or fraudulent.
Payment or reimbursement of prescription therapeutics by Medicaid or Medicare requires the product’s labeler to submit certified pricing information to CMS. The Medicaid Drug Rebate statute requires labelers, as a condition of payment by Medicaid, to calculate and report price points, which are used to determine Medicaid rebate payments shared between the states and the federal government and Medicaid payment rates for certain therapeutics, to pay quarterly rebates on prescriptions paid by Medicaid, and to provide a discount based on the Medicaid rebate percentage to certain hospitals and clinics under the 340B program. For most therapeutics paid under Medicare Part B, labelers must also calculate and report their Average Sales Price, ("ASP"), which is used to determine the Medicare Part B payment rate. In addition, therapeutics covered by Medicaid are subject to an additional inflation penalty which can substantially increase rebate payments. For products approved under a BLA (including
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biosimilars) or an NDA, the Veterans Health Care Act (“VHCA”("VHCA") requires labelers, as a condition of payment by Medicaid, to calculate and report to the Veterans Administration (“VA”("VA") a different price called the Non-Federal Average Manufacturing Price, which is used to determine the maximum price that can be charged to certain federal agencies, referred to as the Federal Ceiling Price ("FCP"). Like the Medicaid rebate amount, the FCP includes an inflation penalty. A Department of Defense statute and regulation requires labelers to provide this discount on therapeutics dispensed by retail pharmacies when paid by the TRICARE Program.Program, the health care program for military personnel, retirees, and related beneficiaries. All of these price reporting requirements create risk of submitting false information to the government, and potential FCA liability.
The VHCA also requires labelers of covered therapeutics participating in the Medicaid program to enter into Federal Supply Schedule contracts with the VA through which their covered therapeutics must be sold to certain federal agencies at FCP. This necessitates compliance with applicable federal procurement laws and regulations, including submission of commercial sales and pricing information, and subjects us to contractual remedies as well as administrative, civil, and criminal sanctions. In addition, the VHCA requires labelers participating in Medicaid to agree to provide different mandatory discounts to certain Public Health Service grantees and other safety net hospitals and clinics under the 340B program based on the labelers’slabelers’ reported Medicaid pricing information. The 340B program has its own regulatory authority to impose sanctions for non-compliance and adjudicate overcharge claims against labelers by the purchasing entities.
The federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”("HIPAA") also created federal criminal statutes that prohibit, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by
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means of false or fraudulent pretenses, representations or promises, any of the money or property owned by, or under the custody or control of, a healthcare benefit program, regardless of whether the payor is public or private, in connection with the delivery or payment for health care benefits, knowingly and willfully embezzling or stealing from a health care benefit program, willfully obstructing a criminal investigation of a health care offense and knowingly and willfully falsifying, concealing, or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items, or services relating to healthcare matters. Additionally, the ACA amended the intent requirement of certain of these criminal statutes under HIPAA so that a person or entity no longer needs to have actual knowledge of the statute, or the specific intent to violate it, to have committed a violation.
The ACA further created new federal requirements for reporting, by applicable drug manufacturers of covered therapeutics, payments and other transfers of value to physicians and teaching hospitals, and ownership and investment interests held by physicians and other healthcare providers and their immediate family members, including the Physician Payments Sunshine Act.
Further, we may be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business. HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (“HITECH”("HITECH") and its respective implementing regulations imposes certain requirements on covered entities relating to the privacy, security, and transmission of certain individually identifiable health information, known as protected health information. Among other things, HITECH, through its implementing regulations, makes HIPAA’s security standards and certain privacy standards directly applicable to business associates, defined as a person or organization, other than a member of a covered entity’s workforce, that creates, receives, maintains, or transmits protected health information on behalf of a covered entity for a function or activity regulated by HIPAA. HITECH also strengthened the civil and criminal penalties that may be imposed against covered entities, business associates, and individuals, and gave state attorneys generalattorney generals new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions. In addition, other federal and state laws may govern the privacy and security of health and other information in certain circumstances, many of which differ from each other in significant ways and may not be preempted by HIPAA, thus complicating compliance efforts.
Many states have also adopted laws similar to each of the above federal laws, which may be broader in scope and apply to items or services reimbursed by any third-party payor, including commercial insurers. Certain state laws also regulate sponsors’ use of prescriber-identifiable data. Certain states also require implementation of commercial compliance programs and compliance with the pharmaceutical industry’s voluntary compliance guidelines and the applicable compliance guidance promulgated by the federal government, or otherwise restrict payments or the provision of other items of value that may be made to healthcare providers and other potential referral sources; impose restrictions on marketing practices; or require drug companies to track and report information related to payments, gifts, and other items of value to physicians and other healthcare providers.
Recently, states have enacted or are considering legislation intended to make drug prices more transparent and deter significant price increases, typically as consumer protection laws. These laws may affect itsour future sales, marketing, and other promotional activities by imposing administrative and compliance burdens.
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If our operations are found to be in violation of any of the laws or regulations described above or any other applicable laws, we may be subject to penalties or other enforcement actions, including criminal and significant civil monetary penalties, damages, fines, disgorgement, imprisonment, exclusion from participation in government healthcare programs, corporate integrity agreements, suspension and debarment from government contracts, and refusal of orders under existing government contracts, reputational harm, diminished profits and future earnings, and the curtailment or restructuring of itsour operations, any of which could adversely affect our ability to operate our business and our results of operations. Enforcement actions can be brought by federal or state governments, or as “qui tam”"qui tam" actions brought by individual whistleblowers in the name of the government under the civil FCA if the violations are alleged to have caused the government to pay a false or fraudulent claim.
To the extent that any of our products are sold in a foreign country, we may be subject to similar foreign laws and regulations, which may include, for instance, applicable post-marketing requirements, including safety surveillance, anti-fraud and abuse laws, and implementation of corporate compliance programs and reporting of payments or transfers of value to healthcare professionals.
Coverage and Reimbursement
The commercial success of our product candidates and our ability to commercialize any approved product candidates successfully will depend in part on the extent to which governmental payor programs at the federal and state levels, including Medicare and Medicaid, private health insurers, and other third-party payors provide coverage for and establish adequate
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reimbursement levels for our product candidates. Government authorities, private health insurers, and other organizations generally decide which therapeutics they will pay for and establish reimbursement levels for healthcare. Medicare is a federally funded program managed by CMS through local fiscal intermediaries and carriers that administer coverage and reimbursement for certain healthcare items and services furnished to the elderly and disabled. Medicaid is an insurance program for certain categories of patients whose income and assets fall below state defined levels and who are otherwise uninsured that is both federally and state funded and managed by each state. The federal government sets general guidelines for Medicaid and each state creates specific regulations that govern its individual program, including supplemental rebate programs that restrict coverage to therapeutics on the state Preferred Drug List. Similarly, government laws and regulations establish the parameters for coverage of prescription therapeutics by health plans participating in state exchanges and Tricare, the health care program for military personnel, retirees, and related beneficiaries.TRICARE. Some states have also created pharmacy assistance programs for individuals who do not qualify for federal programs. In the United States, private health insurers and other third-party payors often provide reimbursement for products and services based on the level at which the government provides reimbursement through the Medicare or Medicaid programs for such products and services.
In the United States, the European Union,EU, and other potentially significant markets for our product candidates, government authorities and third-party payors are increasingly attempting to limit or regulate the price of medical products and services, particularly for new and innovative products and therapies, which often has resulted in average selling prices lower than they would otherwise be and sometimes at or below the provider’s acquisition cost. In the United States, it is also common for government and private health plans to use coverage determinations to leverage rebates from labelers in order to reduce the plans’ net costs. These restrictions and limitations influence the purchase of healthcare services and products and lower the realization on labelers’ sales of prescription therapeutics. Third-party payors are developing increasingly sophisticated methods of controlling healthcare costs. Third-party payors may limit coverage to specific therapeutic products on an approved list, or formulary, which might not include all of the FDA-approvedFDA approved products for a particular indication or might impose high copayment amounts to influence patient choice. Third-party payors also control costs by requiring prior authorization or imposing other dispensing restrictions before covering certain products and by broadening therapeutic classes to increase competition. Third-party payors are increasingly challenging the price and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy. Absent clinical differentiators, third-party payors may treat products as therapeutically equivalent and base formulary decisions on net cost. To lower the prescription cost, labelers frequently rebate a portion of the prescription price to the third-party payors. Recently, purchasers and third-party payors have begun to focus on value of new therapeutics and sought agreements in which price is based on achievement of performance metrics.
Federal programs also impose price controls through mandatory ceiling prices on purchases by federal agencies and federally funded hospitals and clinics and mandatory rebates on retail pharmacy prescriptions paid by Medicaid and Tricare.TRICARE. These restrictions and limitations influence the purchase of healthcare services and products. Legislative proposals to reform healthcare or reduce costs under government programs may result in lower reimbursement for itsour product candidates or exclusion of itsour product candidates from coverage. In addition, government programs like Medicaid include substantial penalties for increasing commercial prices over the rate of inflation which can affect realization and return on investment.
Private payors often rely on the lead of the governmental payors in rendering coverage and reimbursement determinations. Therefore, achieving favorable CMS coverage and reimbursement is usually a significant gating issue for successful introduction of a new product. In addition, many government programs as a condition of participation mandate fixed discounts
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or rebates from labelers regardless of formulary position or utilization, and then rely on competition in the market to attain further price reductions, which can greatly reduce realization on the sale.
Further, the increased emphasis on managed healthcare in the United States and on country and regional pricing and reimbursement controls in the European UnionEU will put additional pressure on product pricing, reimbursement, and utilization, which may adversely affect itsour future product sales and results of operations. These pressures can arise from rules and practices of managed care groups, competition within therapeutic classes, judicial decisions and governmental laws and regulations related to Medicare, Medicaid, and healthcare reform, biopharmaceutical coverage and reimbursement policies, and pricing in general. Patients who are prescribed treatments for their conditions and providers performing the prescribed services generally rely on third-party payors to reimburse all or part of the associated healthcare costs. Sales of our product candidates will therefore depend substantially, both domestically and abroad, on the extent to which the costs of our products will be paid by health maintenance, managed care, pharmacy benefit, and similar healthcare management organizations, or reimbursed by government health administration authorities, such as Medicare and Medicaid, private health insurers, and other third-party payors.
As a result of the above, we may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to obtain the FDA approvals. Our product
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candidates may not be considered medically necessary or cost-effective, or the rebate percentages required to secure coverage may not yield an adequate margin over cost. Additionally, companies are increasingly finding it necessary to establish bridge programs to assist patients with access to new therapies during protracted initial coverage determination periods.
Moreover, a payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved or that significant price concessions will not be required to avoid restrictive conditions. High health plan co-payment requirements may result in patients refusing prescriptions or seeking alternative therapies. Additionally, where a new indication has been approved for a drug or biologic previously approved under a different NDA or BLA, health plans may cover off-label use of the original drug, even if it cannot be marketed for the new indication. Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in therapeutic development. Legislative proposals to reform healthcare or reduce costs under government insurance programs may result in lower reimbursement for our products and product candidates or exclusion of our products and product candidates from coverage. The cost containment measures that healthcare payors and providers are instituting and any healthcare reform could significantly reduce our revenues from the sale of any approved product candidates. We cannot provide any assurances that we will be able to obtain and maintain third-party coverage or adequate reimbursement for our product candidates in whole or in part.
Healthcare Reform Measures
The United States and somemany foreign jurisdictions are considering or have enacted a number ofor proposed legislative and regulatory proposals designed to changechanges affecting the healthcare system in ways that could affect our ability to sell our products profitably. Among policy makerssystem. The U.S. government, state legislatures and payors in the United States and elsewhere, there isforeign governments also have shown significant interest in promotingimplementing cost-containment programs to limit the growth of government-paid healthcare costs, including price controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription drugs.
In recent years, Congress has considered reductions in Medicare reimbursement levels for drugs administered by physicians. CMS, the agency that administers the Medicare and Medicaid programs, also has authority to revise reimbursement rates and to implement coverage restrictions for some drugs. Cost reduction initiatives and changes in healthcare systems with the stated goalscoverage implemented through legislation or regulation could decrease utilization of containing healthcare costs, improving quality, and expanding access. In the United States, the biopharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives.
For example, the ACA created hybrid payment methodologyreimbursement for biosimilars underany approved products. While Medicare Part B, which covers products administered by physicians in an outpatient setting, intendedregulations apply only to neutralize the incentive to purchase higher priced biologics reimbursed at ASP plus 6% of ASP by paying providers ASP of a biosimilar but adding the margin based on ASP of the reference biologic. More recently, the Bipartisan Budget Act extended labeler responsibilitydrug benefits for prescription costs in the Medicare Part D coverage gap to biosimilars, which had previously been exempt.
Similarly, the American Recovery and Reinvestment Act of 2009 established funding for the federal government to compare the effectiveness of different treatments for the same illness. The Agency for Healthcare Research and Quality among other things, conducts patient-centered outcome research, develops evidence-based tools and resources on medication therapies, maintains databases of health care related data and standards, and issues periodic reports on specific studies. Although the results of the comparative effectiveness studies are not intended to mandate coverage policies for public orbeneficiaries, private payors itoften follow Medicare coverage policy and payment limitations in setting their own reimbursement rates. Therefore, any reduction in reimbursement that results from federal legislation or regulation may result in a similar reduction in payments from private payors.
The ACA, substantially changed the way healthcare is not clear what effect, if any,financed by both governmental and private insurers, and significantly impacts the organization’s research has had or will have on the sales of any product, if any such product or the condition that itpharmaceutical industry. The ACA is intended to treat is the subject of a study. It is also possible that comparative effectiveness research demonstrating benefits in a competitor’s product could adversely affect the sales of our product candidates. If third-party payors do not consider our product candidates to be cost-effective compared to other available therapies, they may not cover our product candidates or may severely restrict access, once approved, as a benefit under their plans or, if they do, the level of payment may not be sufficient to allow us to sell our products on a profitable basis.
Moreover, the ACA broadenedbroaden access to health insurance, attempts to reduce or constrain the growth of healthcare spending, enhancedenhance remedies against healthcare fraud and abuse, addedadd new transparency requirements for healthcare and health insurance industries, imposedimpose new taxes and fees on the health care industry,pharmaceutical and imposedmedical device manufacturers, and impose additional health policy reforms. The lawAmong other things, the ACA expanded manufacturers’ rebate liability under the eligibility criteria and mandatory eligibility categories for Medicaid programs, thereby potentiallyMDRP by increasing both the volume of sales and labelers’minimum Medicaid rebate liability. The law alsofor both branded and generic drugs, expanded the 340B discount program, that mandates discounts to certain hospitals, community centers, and other qualifying providers, by expanding the categories of entities eligible to purchase under the program, although, with the exception of children’s hospitals, these newly eligible entities are ineligible to receive discounted 340B pricing on orphan therapeutics used to treat an orphan disease or condition. The ACA revised the definition of “averageaverage manufacturer priceprices ("AMP")” for reporting purposes,, which generally increasedcould increase the amount of Medicaid drug rebates manufacturers are required to states and created a separate AMP for certain categoriespay to states. The legislation also extended Medicaid drug rebates, previously due only on fee-for-service Medicaid utilization, to include the utilization of therapeutics provided in non-retail outpatient settings. The law additionally extended labeler’s Medicaid rebate liability to covered therapeutics dispensed to patients enrolled in Medicaid managed care organizations as well and increasedcreated an alternative rebate formula for certain new formulations of certain existing products that is intended to increase the statutory minimumamount of rebates a labeler must paydue on those drugs. On February 1, 2016, CMS issued final regulations to implement the changes to the MDRP under the Medicaid Drug Rebate program. The revisions to the AMP definition and Medicaid rebate formula can have the further effect of increasing the required 340B discounts. Further, the ACA requires labelers of therapeutics, to pay 50% of the pharmacy charge to Medicare Part D patients while they are in the coverage gap, and this percentage was increased to 70% by the Bipartisan Budget Act of 2018. Finally, the ACA imposes a significant annual fee on companies that manufacture or import brandedACA. These
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prescription therapeutic products. Substantial new provisions affecting complianceregulations became effective on April 1, 2016. Since that time, there have also been enacted throughsignificant ongoing efforts to modify or eliminate the ACA.
The ACA has been subject to challenges in the courts. On December 14, 2018, a Texas U.S. District Court Judge ruled that the ACA is unconstitutional in its entirety because the "individual mandate" was repealed by Congress. On December 18, 2019, the Fifth Circuit U.S. Court of Appeals held that the individual mandate is unconstitutional and otherwise, includingremanded the reportingcase to the Texas District Court to reconsider its earlier invalidation of therapeutic sample distribution, which may require usthe entire ACA. An appeal was taken to modify our business practices with healthcare practitioners. Althoughthe U.S. Supreme Court. On June 17, 2021, the Supreme Court ruled that the plaintiffs lacked standing to challenge the law as they had not alleged personal injury traceable to the allegedly unlawful conduct. As a result, the Supreme Court did not rule on the constitutionality of the ACA was recently amended to repeal the individual insurance mandate, and efforts to repeal and replace portionsor any of the law may continue, it is likely that pressure on biopharmaceutical pricing, especially under the Medicare program, will continue, and may also increase our regulatory burdens and operating costs. Moreover, in the coming years, additional changes could be made to governmental healthcare programs that could significantly impact the success of our product candidates.its provisions.
The cost of biopharmaceuticals continues to generate substantial governmental and third-party payor interest. We expect that the biopharmaceutical industry will experience pricing pressures due to the trend toward managed healthcare, the increasing influence of managed care organizations and additionalOther legislative proposals. Our results of operations could be adversely affected by current and future healthcare reforms.
Some third-party payors also require pre-approval of coverage for new or innovative devices or therapies before they will reimburse healthcare providers that use such therapies. While we cannot predict whether any proposed cost-containment measures will be adopted or otherwise implemented in the future, the announcement or adoption of these proposals could have a material adverse effect on our ability to obtain adequate prices for our product candidates and operate profitably.
In addition, other legislative and regulatory changes have been proposed and adopted since passage of the ACA was enacted.ACA. The Budget Control Act of 2011, as amended,among other things, created the Joint Select Committee on Deficit Reduction to recommend proposals in spending reductions to Congress. The Joint Select Committee on Deficit Reduction did not achieve its targeted deficit reduction of at leastan amount greater than $1.2 trillion for the fiscal years 20132012 through 2021, triggering the legislation’s automatic reductions to several government programs. These reductions includeincluded aggregate reductions to Medicare payments to healthcare providers of up to 2%2.0% per fiscal year. The Bipartisan Budget Act of 2018 (the "BBA") retained the federal budget “sequestration”"sequestration" Medicare payment reductions of 2%, and extended it through 2027 unless congressional action is taken, and also increased labeler responsibility for prescription costs in the Medicare Part D coverage gap. TheOn January 2, 2013, the American Taxpayer Relief Act of 2012, furtherwas signed into law, which, among other things, reduced Medicare payments to several categoriestypes of healthcare providers, including hospitals, imaging centers, and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. These
Further legislative and regulatory changes under the ACA remain possible, although the Biden Administration has signaled that it plans to build on the ACA and expand the number of people who are eligible for subsidies under it. President Biden indicated that he intends to use executive orders to undo changes to the ACA made by the Trump administration and would advocate for legislation to build on the ACA. It is unknown what form any such changes or any law would take, and how or whether it may affect our business in the future. We expect that changes or additions to the ACA, the Medicare and Medicaid programs, changes allowing the federal government to directly negotiate drug prices and changes stemming from other healthcare reform initiatives may resultmeasures, especially with regard to healthcare access, financing or other legislation in additional reductions in Medicare and other healthcare funding, whichindividual states, could have a material adverse effect on our financial operations. business and other biopharmaceutical companies.
The ACA requires pharmaceutical manufacturers of branded prescription drugs to pay a branded prescription drug fee to the federal government. Each individual pharmaceutical manufacturer pays a prorated share of the branded prescription drug fee, based on the dollar value of its branded prescription drug sales to certain federal programs identified in the law. Furthermore, the law requires manufacturers to provide a 50% discount off the negotiated price of prescriptions filled by beneficiaries in the Medicare Part D coverage gap, referred to as the "donut hole." The BBA, among other things, amended the ACA, effective January 1, 2019, to close the donut hole by increasing from 50 percent to 70 percent the point-of-sale discount that is owed by pharmaceutical manufacturers who participate in Medicare Part D.
The ACA also expanded the Public Health Service’s 340B drug pricing program. As noted above, the 340B drug pricing program requires participating manufacturers to agree to charge statutorily-defined covered entities no more than the 340B "ceiling price" for the manufacturer’s covered outpatient drugs. The ACA expanded the 340B program to include additional types of covered entities: certain free-standing cancer hospitals, critical access hospitals, rural referral centers, and sole community hospitals, each as defined by the ACA. Because the 340B ceiling price is determined based on AMP and Medicaid drug rebate data, revisions to the Medicaid rebate formula and AMP definition could cause the required 340B discounts to increase.
Payment methodologies may be subject to changes in healthcare legislation and regulatory initiatives as well. For example, CMS may develop new payment and delivery models, such as bundled payment models. Recently, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products. Such scrutiny has resulted in several recent U.S. Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the cost of drugs under Medicare, and reform government program reimbursement methodologies for pharmaceutical products.
At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product
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access, and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
We expect that additional federal, state and federalforeign healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could further limit the prices we are able to charge, or the amounts ofresult in limited coverage and reimbursement available,and reduced demand for our product candidatesproducts, once they are approved.
In 2016, CMS issued a final rule regarding the Medicaid drug rebate program. The final rule, effective April 1, 2016, among other things, extended labeler rebate obligations to U.S. territories, revised the manner in which the AMP is calculated by labelers participating in the program, and implements certain amendments to the Medicaid rebate statute created under the ACA. At the state level, legislatures are increasingly passing legislation and implementing regulations designed to control pharmaceutical productapproved, or additional pricing including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. The full impact of these laws, as well as other new laws and reform measures that may be proposed and adopted in the future remains uncertain, but may result in additional reductions in Medicare and other health care funding, or higher production costs which could have a material adverse effect on our customers and, accordingly, our financial operations.
There have been several recent U.S. Congressional inquiries and proposed and adopted federal and state legislation designed to, among other things, bring more transparency to drug pricing and deter price increases, review the relationship between pricing and sponsor patient programs, and reform government program reimbursement methodologies for drugs. Further, the current U.S. Presidential administration’s budget proposal for fiscal year 2020 contained proposed policy changes and further drug price control measures that could be enacted in future legislation. While any proposed measures will require authorization through additional legislation to become effective, Congress and the current U.S. Presidential administration have each indicated that it will continue to seek new legislative and/or administrative measures to control drug costs.pressures.
The Foreign Corrupt Practices Act
The Foreign Corrupt Practices Act (“FCPA”("FCPA") prohibits any U.S. individual or business from paying, offering, or authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party, or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business. The FCPA also obligates companies whose securities are listed in the United States to comply with accounting provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of
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the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations. Activities that violate the FCPA, even if they occur wholly outside the United States, can result in criminal and civil fines, imprisonment, disgorgement, oversight, and suspension and debarment from government contracts, and refusal of orders under existing government contracts.
Health Canada
EMPLOYEESHealth Canada is the Canadian federal authority that regulates, evaluates, and monitors the safety, effectiveness, and quality of drugs, medical devices, and other therapeutic products available to Canadians. Health Canada’s regulatory process for review, approval, and regulatory oversight of products is similar to the regulatory process conducted by the FDA. To initiate clinical testing of a drug candidate in human subjects in Canada, a Clinical Trial Application ("CTA") must be filed with and approved by Health Canada. In addition, all federally regulated trials must be approved and monitored by research ethics boards ("REB"). The REB studies and approves study-related documents and monitors trial data.
Prior to being given market authorization for a drug product, a manufacturer must present substantive scientific evidence of a product’s safety, efficacy, and quality as required by the Food and Drugs Act and its associated regulations, including the Food and Drug Regulations ("FDR"). This information is usually submitted in the form of an NDS. Health Canada reviews the submitted information, sometimes using external consultants and advisory committees, to evaluate the potential benefits and risks of a drug. If after the review, the conclusion is that the patient benefits outweigh the risks associated with the drug, the drug is issued a Drug Identification Number (“DIN”), followed by a Notice of Compliance (“NOC"), which permits the market authorization holder (i.e., the NOC and DIN holder) to market the drug in Canada. Drugs granted an NOC may be subject to additional post-market surveillance and reporting requirements.
All establishments engaged in the fabrication, packaging/labeling, importation, distribution, and wholesale of drugs and operation of a testing laboratory relating to drugs are required to hold a Drug Establishment License ("DEL") to conduct one or more of the licensed activities unless expressly exempted under the FDR. The basis for the issuance of a DEL is to ensure the facility complies with cGMP as stipulated in the FDR and as determined by cGMP inspection conducted by Health Canada. An importer of pharmaceutical products manufactured at foreign sites must also be able to demonstrate that the foreign sites comply with cGMP, and such foreign sites are included on the importer’s DEL.
Regulatory obligations and oversight will continue to follow after the initial market approval of a pharmaceutical product. For example, every market authorization holder must report any new information received concerning adverse drug reactions, including timely reporting of serious adverse drug reactions that occur in Canada and any serious unexpected adverse drug reactions that occur outside of Canada. The market authorization holder must also notify Health Canada of any new safety and efficacy issues that it becomes aware of after the launch of a product.
The Canadian regulatory approval requirements for new drugs outlined above are similar to those of other major pharmaceutical markets. While the testing carried out in Canada is often acceptable for the purposes of regulatory submissions in other countries, individual regulatory authorities may request supplementary testing during their assessment of any submission. Therefore, the clinical testing conducted under Health Canada's regulation may not be accepted by regulatory authorities outside Canada.
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Regulation Outside of the United States and Canada
In addition to regulations in the U.S. and Canada, we may be subject to a variety of regulations in foreign jurisdictions that govern, among other things, clinical trials and any commercial sales and distribution of our products, if approved, either directly or through our distribution partners. Whether or not we obtain FDA or Health Canada approval for a product candidate, we must obtain the requisite approvals from regulatory authorities in foreign jurisdictions prior to the commencement of clinical trials or marketing and sale of the product in those countries. The foreign regulatory approval process includes all of the risks associated with the FDA and Health Canada approval processes described above, and the time required to obtain approval in other countries and jurisdictions might differ from and be longer than that required to obtain FDA or Health Canada approval. Some foreign jurisdictions have a drug product approval process similar to that in the U.S. or Canada, which requires the submission of a CTA much like the IND prior to the commencement of clinical studies. In Europe, for example, a CTA must be submitted to each country’s national health authority and an independent ethics committee, much like the FDA and IRB, respectively. Once the CTA is approved in accordance with a country’s requirements, clinical trial development may proceed. To obtain regulatory approval of a therapeutic product candidate under EU regulatory systems, we would be required to submit a Marketing Authorisation Application, which is similar to the NDA, except that, among other things, there are country-specific documentation requirements. For countries outside of the EU, such as countries in Eastern Europe, Latin America or Asia, and recently the United Kingdom, the requirements governing the conduct of clinical trials, product approval, pricing, and reimbursement vary from country to country. Regulatory approval in one country or jurisdiction does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in other countries. Moreover, some nations may not accept clinical studies performed for U.S. approval to support approval in their countries or require that additional studies be performed on natives of their countries. In addition, in certain foreign markets, the pricing of drug products is subject to government control and reimbursement may in some cases be unavailable or insufficient. Resulting prices could be insufficient to generate an acceptable return to us or any future partner of ours. If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions, and criminal prosecution.
HUMAN CAPITAL
As of February 15, 2022, we had 56 employees, all of which were full-time employees. None of our employees are represented by a labor union or covered by a collective bargaining agreement, and we consider our relationship with our employees to be good.
Investing in, developing, and maintaining human capital is critical to our success. We emphasize a number of measures and objectives in managing our human capital assets, including, among others, employee safety and wellness, including COVID-19 safety protocols, talent acquisition and retention, employee engagement, development and training, diversity and inclusion, and compensation and pay equity, as further detailed below.
Compensation, Benefits, and Development
We have 16 full-timeprovide our employees aswith competitive salaries and bonuses, opportunities for equity ownership, and a robust employment package that promotes well-being across all aspects of March 1, 2020.our employees’ lives, including health care, retirement planning, and paid time off. As part of our promotion and retention efforts, we also invest in the ongoing development of our employees through our internal training programs and individualized performance plans, including yearly goals and objectives and other developmental milestones.
Diversity and Inclusion
We value the diversity of our employees and take pride in our commitment to diversity and inclusion across all levels of our organizational structure and with respect to our board of directors. We continue to focus on expanding our commitment to diversity and inclusion across our entire workforce, including working with managers to develop strategies for building diverse teams and promoting the advancement of employees from diverse backgrounds.
CORPORATE INFORMATION
Histogenics wasWe were originally incorporated as a Massachusetts corporation in 2000. In 2006,2000 under the name Histogenics Corporation ("Histogenics") and underwent a corporate reorganization in 2006, pursuant to which it was incorporatedwe were reincorporated as a Delaware corporation. On September 27, 2019, Histogenicswe completed itsa reverse merger (the "Merger") with Former Ocugen OpCo, Inc. ("OpCo") in accordance with the terms of the Agreement and Plan of Merger Agreementand Reorganization, dated as of April 5, 2019, by and among Histogenics, Former Ocugen
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OpCo, Restore Merger Sub, Inc., our wholly owned subsidiary ("Merger Sub"), and Merger Sub,us, as amended, pursuant to which Merger Sub merged with and into Former Ocugen,OpCo, with Former OcugenOpCo surviving as aour wholly owned subsidiary of Histogenics. Followingsubsidiary. Immediately after the completion of the Merger, Histogenicswe changed itsour name to Ocugen, Inc. and the business previously conducted by OpCo became the business conducted by us. Our common stock trades on The Nasdaq Capital Market ("Nasdaq") under the symbol "OCGN."
Our principal offices areoffice is located at 5263 Great Valley Parkway, Suite 160, Malvern, Pennsylvania 19355, and our telephone number is (484) 328-4701. Our website address is www.ocugen.com.www.ocugen.com. Our website and the information contained on, or that can be accessed through, our website shall not be deemed to be incorporated by reference in, and areis not considered part of this Annual Report. You should not rely on any such information in making your decision whether to purchase our common stock.
AVAILABLE INFORMATION
We file annual, quarterly, and current reports, proxy statements, and other documents with the Securities and Exchange Commission ("SEC") under the Securities Exchange Act of 1934, as amended (the "Exchange Act"). The SEC maintains an internet website, www.sec.gov, that contains reports, proxy and information statements, and other information regarding issuers, including us, that file electronically with the SEC.
Copies of each of our filings with the SEC on Form 10-K, Form 10-Q, and Form 8-K and all amendments to those reports, can be viewed and downloaded free of charge at our website, www.ocugen.com, as soon as reasonably practicable after the reports and amendments are electronically filed with or furnished to the SEC.
Our code of ethics, other corporate policies and procedures, and the charters of our Audit Committee, Compensation Committee, and Nominating/Corporate Governance Committee are available through our website at www.ocugen.com.
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Item 1A.    Risk Factors.
Risk Factors Summary
Investing in our securities involves a high degree of risk. Before deciding whether to invest in our securities, you should consider carefully the risks and uncertainties described in “Part I, Item 1A. Risk Factors” of this Annual Report on Form 10-K. These risks and uncertainties include, but are not limited to, the following:
We have incurred significant losses from operations and negative cash flows from operations since our inception. We may incur losses over the next several years and may never achieve or maintain profitability. These factors raise substantial doubt about our ability to continue as a going concern absent obtaining significant additional funding.
We will need substantial additional funding. If we are unable to raise capital when needed, we could be forced to delay, reduce, or eliminate our product development programs or commercialization efforts.
Raising additional capital may cause dilution to stockholders, restrict our operations, or require us to relinquish rights to our technologies or product candidates.
We are substantially dependent on the success of our product candidates, and in particular, COVAXIN, which is in a later stage of development than our other product candidates. We cannot guarantee that our product candidates will successfully complete development, receive regulatory authorization or approval, or be successfully commercialized.
COVAXIN has been evaluated by Bharat Biotech in a Phase 3 clinical trial in India in adults, who were healthy or had stable chronic medical conditions ages 18 and older, and approved for EUL by the WHO. We will need to conduct a Phase 2/3 immuno-bridging and broadening clinical trial and a safety-bridging clinical trial to support a BLA submission for COVAXIN for adult use in the United States. We may be unable to successfully produce and commercialize a vaccine that effectively and safely treats the virus in a timely manner, if at all, and ultimately may be unable to obtain regulatory approval for adult use in the United States.
We have obtained the rights to develop and commercialize COVAXIN in Canada and we have completed a rolling submission to Health Canada for COVAXIN. We have been provided with a NOD from Health Canada regarding our NDS submission. We have responded to and provided proposed resolutions for the deficiencies included in the NOD but there is no guarantee that Health Canada will accept our proposed resolutions. We have no experience in obtaining marketing approval for, or commercializing products in Canada.
We have submitted an EUA application to the FDA for COVAXIN for pediatric use. The FDA may not grant us the EUA for pediatric use, and, even if they do, absent supplemental BLA approval for that indication, such EUA would be revoked when the COVID-19 emergency terminates, and, prior to that time, we would face significant competition from other pharmaceutical and biotechnology companies, and may not be able to compete effectively.
The ongoing COVID-19 pandemic and actions taken in response to it may result in disruptions to our business operations, which would have a materially adverse effect on our business, financial position, operating results, and cash flows.
Our product candidates generated from our modifier gene therapy platform are based on a novel technology and face an uncertain regulatory environment, which makes it difficult to predict the time and cost of product candidate development and subsequently obtaining regulatory approval.
If we experience delays or difficulties in the enrollment of patients in clinical trials, our completion of clinical trials and receipt of necessary regulatory approvals could be delayed or prevented.
We may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success.
We have no prior experience in the marketing, sale, and distribution of pharmaceutical or biologic products and there can be no assurance that our products, if authorized or approved, will be successfully commercialized.
We face significant competition from other pharmaceutical and biotechnology companies, academic institutions, government agencies, and other research organizations. Our operating results will suffer if we fail to compete effectively.
We have selected a manufacturing partner for COVAXIN, if authorized or approved, to provide commercial supply for the United States and Canada. We may still encounter difficulties with respect to the manufacturing of COVAXIN, including with respect to our third-party manufacturers, which could impair our ability to commercialize COVAXIN, if authorized or approved. Further, if we encounter difficulties in negotiating commercial manufacturing and supply
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agreements with third-party manufacturers and suppliers of our other product candidates or any product components, our ability to commercialize our other product candidates, if approved, would be impaired.
We rely, and expect to continue to rely, on third parties to conduct, supervise, and monitor our preclinical studies and clinical trials we may initiate, and those third parties may not perform satisfactorily, including failing to meet deadlines for the completion of such trials or failing to comply with regulatory requirements.
If the manufacturers upon whom we rely fail to produce our product candidates or components pursuant to the terms of contractual arrangements with us or fail to comply with stringent regulations applicable to biologic and pharmaceutical manufacturers, we may face delays in the development and commercialization of, or be unable to meet demand for, our product candidates and may lose potential revenues.
We may seek to collaborate with third parties for the development or commercialization of our product candidates. We may not be successful in establishing or maintaining collaborative relationships, any of which could adversely affect our ability to develop and commercialize our product candidates.
We may be unable to obtain and maintain patent protection for our technology and product candidates, or the scope of the patent protection obtained may not be sufficiently broad or enforceable, such that our competitors could develop and commercialize technology and products similar or identical to ours, and our ability to successfully commercialize our technology and product candidates may be impaired.
We may become involved in lawsuits to protect or enforce our patents or other intellectual property, which could be expensive, time-consuming, and unsuccessful.
Certain aspects of our product candidates are protected by patents exclusively licensed from other companies or institutions. If these third parties terminate their agreements with us or fail to maintain or enforce the underlying patents or licenses thereto, or we otherwise lose our rights to these patents, our competitive position and our market share in the markets for any of our approved products will be harmed.
Provisions in our charter documents and under Delaware law could discourage a takeover that stockholders may consider favorable and may lead to entrenchment of management.
The trading price of the shares of our Common Stock could be highly volatile, and purchasers of the Common Stock could incur substantial losses.
If we fail to maintain proper and effective internal control over financial reporting, our ability to produce accurate and timely financial statements could be impaired, investors may lose confidence in our financial reporting, and the trading price of our common stock may decline.
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Risks Related to Our Financial Position and Capital Requirements
We have incurred significant losses from operations and negative cash flows from operations since our inception. We expect tomay incur losses over the next several years and may never achieve or maintain profitability. These factors raise substantial doubt about our ability to continue as a going concern absent obtaining significant additional funding.
Since inception, we have incurred significant net losses and expects tomay continue to incur net losses in the future. Our recurring losses from operations raise substantial doubt about our ability to continue as a going concern for the foreseeable future. next 12 months from the date of the consolidated financial statements included in this Annual Report on Form 10-K. As a result, our independent public accounting firm included an explanatory paragraph regarding the same in its report to this Annual Report on Form 10-K. Substantial doubt about our ability to continue as a going concern may create negative reactions to the price of our common stock and we may have a more difficult time obtaining financing in the future as a result.
We have not generated anysignificant revenue to date and have funded our operations to date through the sale of common stock, warrants to purchase common stock, the issuance of convertible notes, debt, and borrowings under credit facilities.grant proceeds. We incurred net losses of approximately $58.4 million, $21.8 million, and $20.2 million for the yearyears ended December 31, 2021, 2020, and 2019, and $18.2 million for the year ended December 31, 2018.respectively. As of December 31, 2019,2021, we had an accumulated deficit of $51.5$131.7 million and a cash, cash equivalents, and restricted cash balance of $7.6$95.1 million. This amount will not meet our capital requirements over the next 12 months. Based on this estimate, we will need to raise significant additional capital in order to fund our future operations. We have based this estimate on assumptions that may prove to be wrong, and our operating and capital requirements may change as a result of many factors currently unknown to us.
There can be no assurance that we will be able to raise sufficient additional capital on acceptable terms or at all. If such additional financing is not available on satisfactory terms, or is not available in sufficient amounts, or we do not have sufficient authorized shares, we may be required to delay, limit, or eliminate the development of business opportunities and our ability to achieve our business objectives, our competitiveness, and our business, financial condition, and results of operations will be materially adversely affected. In addition, the impact of the COVID-19 pandemic on the global financial markets may reduce our ability to access capital, which could negatively affect our liquidity and ability to continue as a going concern. Further, the perception that we may not be able to continue as a going concern may cause others to choose not to do business with us due to concerns about our ability to meet our contractual obligations.
To date, we have not commercialized any products or generated any revenues from the sale of products, and absent the realization of sufficient revenues from product sales, if any, of our current or future product candidates, if authorized or approved, we may never attain profitability in the future. To date, we have devoted substantially all of itsour financial resources and efforts to research and development, including preclinical studies and clinical trials.studies. We expect that over the next several years we willmay continue to incur losses from operations in the next several years as we increase our expenditures in research and development in connection with clinical trials and other development and commercialization activities. Even if we obtain an EUA or regulatory approval to market a product candidate, our future revenues will depend upon the size of any markets in which our product candidates have received such authorization or approval, and our ability to
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achieve sufficient market acceptance, reimbursement from third-party payors, and adequate market share for our products in those markets.
We anticipate that our expenses will increase substantially in 2022 as compared to prior periods2021 as we completeprepare for the potential commercialization of COVAXIN in the U.S. and Canada, conduct a Phase 2/3 immuno-bridging and broadening clinical trial and a safety-bridging clinical trial evaluating COVAXIN for ages 18 years and older, continue our Phase 3 trial with respect to OCU300, prepare to commence Phase 1/2ahuman clinical trials with respect to OCU400, and OCU200,continue development of OCU410 and otherwise develop and prepare for commercialization of our product candidates,OCU200. Our expenses will increase as a result of increased headcount, including management personnel to support our clinical, manufacturingresearch and commercializationdevelopment and clinical activities, expanded infrastructure, increased legal, compliance, accounting and investor and public relations expenses associated with being a public company, and increased insurance premiums, among other factors.
Due to the inherently unpredictable nature of preclinical and clinical development and the numerous risks and uncertainties associated with such activities, we are unable to predict with any certainty the nature or amounts of the costs we will incur, the timelines we will require in our continued development efforts or the timing, or if, we will be able to achieve profitability.
Additionally, our expenses will also increase if, and, as we:
continue to pursue the clinical development of OCU300, through Phase 3 clinical development, particularly if we are required by the FDA, European Medicines Agency ("EMA") or other foreign regulatory agencies to perform trials or studies in addition to those currently expected;
initiate preclinical studies and clinical trials for any additional product candidates that we may pursue in the future, particularly if there are any delays in enrollment of patients in or completing our clinical trials or the development of our product candidates;
seek marketing approvals for product candidates that successfully complete clinical development;
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establish sales, marketing, and distribution capabilities for our product candidates for which we obtain an EUA or marketing approval;
scale up our manufacturing processes and capabilities to support our clinical trials of our product candidates and commercialization of any of our product candidates for which we obtain an EUA or marketing approval;
expand our operational, financial, and management systems and increase personnel, including personnel to support our clinical development, manufacturing, and commercialization efforts, and our operations as a public company;
hire additional clinical, quality control, scientific and managementscientific personnel;
in-licenseacquire other companies, products, product candidates, or acquiretechnologies, or in-license the rights to other products, product candidates, or technologies; and
develop, maintain, expand, and protect our intellectual property portfolio; and
increase our product liability insurance coverage as we expand our commercialization efforts.portfolio.
Our ability to become and remain profitable depends on our ability to generate revenue. We do not expect to generate revenue that is sufficient to achieve profitability unless and until we obtain an EUA or marketing approval for and commercializescommercialize one of our product candidates. We do not expect to commercialize any of ourOur product candidates are in various stages of preclinical and clinical development and it is unknown whether our near-term efforts to obtain an EUA in the United States or NDS approval in Canada may be successful or whether additional preclinical, clinical, or manufacturing data may be needed before 2021,we obtain regulatory authorization or approval for any candidate, if ever. Even if we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis. Our failure to become profitable or inability to remain profitable would decrease the value of theour company and could impair our ability to raise capital, expand our business, maintain our research and development efforts, continue or undertake commercialization efforts, diversify our product offerings, or even continue our operations. A decline in the value of theour company could also cause you to lose all or part of your investment.
Our recurring operating losses have raised substantial doubt regarding our ability to continue as a going concern.
Our recurring operating losses raise substantial doubt about our ability to continue as a going concern. For the year ended December 31, 2019, we had a net loss of $20.2 million and net cash used in operating activities of $16.9 million. We have no current source of revenue to sustain our present activities, and we do not expect to generate revenue until and unless we receive regulatory approval of and successfully commercialize our product candidates. These circumstances raise substantial doubt about our ability to continue as a going concern. As a result of this uncertainty and the substantial doubt about our ability to continue as a going concern as of December 31, 2019, the report of our independent registered public accounting firm in this Annual Report on Form 10-K for the years ended December 31, 2019 and 2018 includes a going concern explanatory paragraph. Our ability to continue as a going concern is dependent upon our ability to obtain additional equity or debt financing, attain further operating efficiencies, reduce expenditures and ultimately, to generate revenue by obtaining approval of our product candidates and successfully commercializing such product candidates. The perception of our ability to continue as a
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going concern may make it more difficult for us to obtain financing for the continuation of our operations and could result in the loss of confidence by investors, suppliers and employees.
We have a limited operating history and no history of commercializing pharmaceutical products, which may make it difficult for you to evaluate the success of our business to date and to assess our future viability.
We are a clinical-stage biopharmaceutical company with a limited operating history. Investmentand investment in biopharmaceutical product development is a highly speculative endeavor. Biopharmaceutical product development entails substantial upfront capital expenditures and there is significant risk that any potential product candidate will fail to demonstrate adequate efficacy or an acceptable safety profile, to gain any required regulatory authorizations or approvals or to become commercially viable. To date, our operations have been limited to organizing and staffing theour company, acquiring rights to intellectual property, business planning, raising capital, and developing OCU300 and otherour product candidates. We have not yet demonstrated an ability to obtain marketing approvals, manufacture a commercial-scale product, or arrange for a third party to do so on its behalf, or conduct sales and marketing activities necessary for successful product commercialization. Consequently, any predictions you make about our future success or viability may not be as accurate as they could be if we had a longer operating history.
We have encountered, and will continue to encounter, risks and difficulties frequently experienced by growing companies in a rapidly developing and changing industry, such as the biopharmaceutical industry, including challenges in forecasting accuracy, determining appropriate investments of our limited resources, gaining market acceptance of our products, if authorized or approved, including those created using our modifier gene therapy platform, managing a complex regulatory landscape, and developing new product candidates. Our current operating model may require changes in order for us to scale our operations efficiently. We will need to transition from a company with a research and development focus to a company capable of supporting commercial activities. We may not be successful in such a transition. You should consider our business and prospects in light of the risks and difficulties we face as an early-stagea company focused on developing products in the fields of biopharmaceuticals and biotechnology.
We expect our financial condition and operating results to fluctuate significantly from quarter-to-quarter and year-to-year due to a variety of factors, many of which are beyond our control. Accordingly, you should not rely upon the results of any quarterly or annual periods as indications of future operating performance.
We will need substantial additional funding. If we are unable to raise capital when needed, we could be forced to delay, reduce, or eliminate our product development programs or commercialization efforts.
We expect to devote substantial financial resources to our ongoing and planned product development activities, particularly as we conduct multiple clinical trials and, assuming positive results from these trials, seek marketing approval for OCU300 and continue the development of and potentially seek EUA or marketing approval for other clinical and preclinicalour product candidates, including COVAXIN in the United States (including the clinical trials necessary to support a BLA submission for the adult population) and Canada (subject to the deficiencies included in the NOD being resolved), as well as OCU400, OCU410, OCU200, and OCU200.any potential future product candidates. As of December 31, 2019,2021, we had cash, cash equivalents, and restricted cash of approximately $7.6 $95.1
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million. We believe thatThis amount will not meet our cash and cash equivalentscapital requirements over the next 12 months. Based on this estimate, we will enable usneed to raise significant additional capital in order to fund our operating expenses and capital expenditure requirements through mid-2020. However, wefuture operations. We have based this estimate on assumptions that may prove to be wrong, and our operating planand capital requirements may change as a result of many factors currently unknown to us.
Conducting preclinical testing and clinical trials is a time-consuming, expensive, and uncertain process that takes years to complete. We may nevercannot predict when we will be able to generate the necessary data or results required to obtain regulatory authorization or approval of products with the market potential sufficient to enable us to achieve profitability. We do not expect to generate revenue from sales of any product candidates until at least 2021,profitability, if at all.ever. Accordingly, we may need to obtain substantial additional funding in connection with our continuing operations. Our future capital requirements will depend on many factors, including:
the progress, costs, and results of our Phase 3 clinical trial for OCU300, any clinical trials for our preclinical product candidates, and any clinical activities for the regulatory review of OCU300 or our other product candidates outsidecandidates;
the costs, timing, and outcome of the United States;regulatory review of our preclinical product candidates;
the costs and timing of process development and manufacturing scale-up activities associated with OCU300 and its preclinicalour product candidates;
the costs, timing and outcome of regulatory review of OCU300 and our preclinical product candidates;candidates, if we receive, or expect to receive, an EUA or marketing approval;
the costs of commercialization activities for OCU300 or our preclinical product candidates if we receive, or expect to receive, an EUA or marketing approval, including the costs and timing of establishing product sales, marketing, distribution, and outsourced manufacturing capabilities;
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subject to receipt of an EUA or marketing approval, revenue received from commercial sales of OCU300 or our preclinical product candidates;
our ability to establish and maintain strategic collaborations, licensing, or other agreements and the financial terms of such agreements;
the scope, progress, results, and costs of any additional product candidates that we may derive from its OcuNanoE™ programour modifier gene therapy platform or any other product candidates that we may develop;
the extent to which we in-license or acquire rights to other products, product candidates, or technologies; and
the costs and timing of preparing, filing, and prosecuting patent applications, maintaining and protecting our intellectual property rights, and defending against any intellectual property-related claims.
Any additional fundraising efforts may divert our management from their day-to-day activities, which may adversely affect our ability to develop and commercialize our product candidates. Moreover, adequate additional financing may not be available to us on acceptable terms, or at all. If adequate funds are not available to us on a timely basis, we may be required to delay, limit, reduce, or terminate preclinical studies, clinical trials, or other development activities for one or more of our product candidates or delay, limit, reduce, or terminate our establishment of sales and marketing capabilities or other activities that may be necessary to commercialize our product candidates.
We will need additional funding in order to enable us to successfully develop COVAXIN, and such funding may not be available on acceptable terms, or at all. The commitment of substantial resources to this program entails additional risks.
We will need additional funding in order to enable us to successfully develop and obtain authorization or approval for COVAXIN in the United States (including the clinical trials necessary to support a BLA submission for the adult population) and Canada (subject to the deficiencies included in the NOD being resolved), and have sufficient capacity to manufacture, commercialize, and distribute COVAXIN, if the clinical trials are successful and COVAXIN is authorized for pediatric use by the FDA or approved for adult use by the FDA or Health Canada. Such funding may not be available on acceptable terms, or at all. Moreover, our commitment of substantial financial resources and personnel to the joint development of a vaccine candidate entails additional risks. In particular, this commitment may cause delays in or otherwise negatively impact our other development programs, despite uncertainties surrounding the longevity and extent of COVID-19 as a global health concern. Our business could be negatively impacted by our allocation of significant resources to a global health threat that is unpredictable and could rapidly dissipate. The U.S. or Canadian markets may also become saturated by authorized or approved COVID-19 vaccines before we are able to receive approval in Canada or, with respect to the U.S. market, conduct our BLA submission supporting clinical trials and and obtain authorization or approval for COVAXIN, which could limit or altogether eliminate the potential for revenues from the sales of COVAXIN in the United States or Canada. In addition, there is no guarantee that our clinical trials will be successful or that our vaccine candidate will be authorized or approved by the FDA or Health Canada.
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Raising additional capital may cause dilution to stockholders, restrict our operations, or require us to relinquish rights to our technologies or product candidates.
Until such time, if ever, as we can generate substantial product revenues, weWe expect to finance our cash needsraise additional capital through a combinationpublic and private placements of equity offerings,and/or debt, financings, collaborations,payments from potential strategic alliances,research and development, sale of assets, government grants, licensing and/or collaboration arrangements with pharmaceutical companies or other institutions, and marketing and distribution arrangements.other funding from the government. To the extent that we raise additional capital through the sale of equity or convertible debt securities, your ownership interest will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect the rights of our stockholders. Debt financing and preferred equity financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures, or declaring dividends.
If we raise additional funds through collaborations, strategic alliances, licensing arrangements, or marketing and distribution arrangements, we may have to relinquish valuable rights to our technologies, future revenue streams, research programs or product candidates, or grant licenses on terms that may not be favorable to us. Such arrangements may require us to grant rights to develop and market products or product candidates that we would otherwise prefer to develop and market on our own.
Our management will have broad discretion in the use of the net proceeds from our capital raises, including our February 2022 public offering, and may not use them effectively.
Our management will have broad discretion in the application of the net proceeds from our capital raises (our “Capital Raises”), including our February 2022 public offering, and our stockholders will not have the opportunity as part of their investment decision to assess whether the net proceeds from our Capital Raises are being used appropriately. Our stockholders may not agree with our decisions, and our use of the proceeds may not yield any return on investment for our stockholders. Because of the number and variability of factors that will determine our use of the net proceeds from our Capital Raises their ultimate use may vary substantially from their currently intended use. Our failure to apply the net proceeds of our Capital Raises effectively could compromise our ability to pursue our growth strategy and we might not be able to yield a significant return, if any, on our investment of those net proceeds. Our stockholders will not have the opportunity to influence our decisions on how to use our net proceeds from our Capital Raises. Pending their use, we may invest the net proceeds from our Capital Raises in short-term, investment-grade, interest-bearing instruments and U.S. government securities. These temporary investments are not likely to yield a significant return.
Our existing and future indebtedness may limit cash flow available to invest in the ongoing needs of our business.
As of December 31, 2019,2021, we had $1.0$1.5 million of outstanding principal borrowings under a Loan Agreement (the "EB-5 Loan Agreement") with EB5 Life Sciences, L.P. (the "Lender"("EB-5 Life Sciences"), which we are required to repay on the seventh anniversary of the date of the last disbursement under the EB-5 Loan Agreement (unless terminated earlier pursuant to the terms of the EB-5 Loan Agreement). On March 26, 2020, we borrowed an additional $0.5 million under the terms and conditions of the EB-5 Loan Agreement. We are also eligible to borrow an additional $9.0 millionOur obligations under the EB-5 Loan Agreement limited by the amount of funds raised by the Lender and subject to availability under the program and certain job creation requirements by it. Our obligations under this agreement are secured by substantially all of our assets other than our intellectual property. We could in the future incur additional indebtedness beyond our borrowings under the EB-5 Loan Agreement.
Our existing or future debt could have significant adverse consequences, including:
requiring us to dedicate a substantial portion of cash flow from operations or cash on hand to the payment of interest on, and principal of, our debt, which will reduce the amounts available to fund working capital, capital expenditures, product development efforts, and other general corporate purposes;
increasing our vulnerability to adverse changes in general economic, industry, and market conditions;
subjecting us to restrictive covenants that may reduce our ability to take certain corporate actions or obtain further debt or equity financing (for instance, the EB-5 Loan Agreement includes restrictive covenants related to, among other things, the disposition of our property, the incurrence by us of any additional indebtedness, and the creation by us of any liens or other encumbrances); and
limiting our flexibility in planning for, or reacting to, changes in our business and our industry; and
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placing us at a competitive disadvantage compared to our competitors that have less debt or better debt servicing options.
We intend to satisfy our current and future debt service obligations with our existing cash and funds from external sources. Nonetheless, we may not have sufficient funds or may be unable to arrange for additional financing to pay the amounts due under our existing debt. Funds from external sources may not be available on acceptable terms, if at all. In addition, aA failure to comply with the covenants under the EB-5 Loan Agreement, including covenants to take or avoid specific actions as set forth above, could result in an event of default and acceleration of amounts due. If an event of default occurs and the LenderEB-5 Life Sciences accelerates the amounts due under the EB-5 Loan Agreement, we may not be able to make accelerated payments, and the LenderEB-5 Life Sciences could seek to enforce security interests in the collateral securing such indebtedness.
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In order to satisfy our current and future debt service obligations, we will be required to raise funds from external sources. We may be unable to arrange for additional financing to pay the amounts due under our existing debt. Funds from external sources may not be available on acceptable terms, if at all. Our failure to satisfy our current and future debt obligations could adversely affect our financial condition and results of operations.
If we are unable to use carryforward tax losses or benefit from favorable tax legislation to reduce our taxes, our business, results of operations, and financial condition may be adversely affected.
We have incurred significant net operating losses since our inception. As of December 31, 2019,2021, we had U.S. federal and U.S. state net operating loss carryforwards of approximately $113.6$184.4 million and $112.4$183.1 million, respectively. If we are unable to use carryforward tax losses to reduce our future taxable income and liabilities in our business, our results of operations and financial condition may be adversely affected.
Under Section 382 of the Internal Revenue Code of 1986, as amended, if a corporation undergoes an “ownership change,” which will occur if there is a cumulative change in ownership by “5-percent shareholders” that exceeds 50 percentage points over a rolling three-year period, the corporation’s ability to use its pre-change net operating loss carryforwards and other pre-change tax attributes to offset its post-change income may be limited. A corporation that experiences an ownership change will generally be subject to an annual limitation on the use of its pre-ownership change net operating losses equal to the value of the corporation immediately before the ownership change, multiplied by the long-term tax-exempt rate (subject to certain adjustments). The annual limitation for a taxable year generally is increased by the amount of any “recognized built-in gains” for such year and the amount of any unused annual limitation in a prior year. This could limit the amount of tax attributes that can be utilized annually to offset future taxable income or tax liabilities.
Recent and any potential future U.S. tax legislation may materially adversely affect our financial condition, results of operations, and cash flows.
Recently-enactedRecently enacted U.S. tax legislation has significantly changed the U.S. federal income taxation of U.S. corporations, including by reducing the U.S. corporate income tax rate, limiting interest deductions, modifying or repealing many business deductions and credits (including reducing the business tax credit for certain clinical testing expenses incurred in the testing of certain drugs for rare diseases or conditions generally referred to as “orphan drugs”), adopting elements of a territorial tax system, imposing a one-time transition tax, or repatriation tax, on all undistributed earnings and profits of certain U.S.-owned foreign corporations, revising the rules governing net operating losses and the rules governing foreign tax credits, and introducing new anti-base erosion provisions. Many of these changes are effective immediately, without any transition periods or grandfathering for existing transactions. The legislation is unclear in many respects and could be subject to potential amendments and technical corrections, as well as interpretations and implementing regulations by the Treasury and Internal Revenue Service, any of which could lessen or increase certain adverse impacts of the legislation. In addition, it is unclear how these U.S. federal income tax changes will affect state and local taxation, which often uses federal taxable income as a starting point for computing state and local tax liabilities. Furthermore, it is also possible that there will be technical corrections or other legislation proposed with respect to the tax reform legislation, the effect of which cannot be predicted and may be adverse to us or our stockholders.
While some of the changes made by the tax legislation may adversely affect us in one or more reporting periods and prospectively, other changes may be beneficial on a going forward basis. We continue to work with our tax advisors and auditors to determine the full impact that the recent tax legislation as a whole will have on us. We urge our investors to consult with their legal and tax advisors with respect to such legislation.
Risks Related to Our Business and the Development of Our Product Candidates
We are substantially dependent on the success of our product candidates, and in particular, COVAXIN, which is in a later stage of development than our leadother product candidate, OCU300.candidates. We cannot guarantee that our product candidates will successfully complete development, receive regulatory authorization or approval, or be successfully commercialized.
We have invested a significant portion of our efforts and financial resources in the development of our product candidates.candidates, and in particular, COVAXIN. We believe our prospects are highly dependent on, and a significant portion of the value of our company relates to, our ability to successfully obtain regulatory authorization or approval for, and successfully commercialize, COVAXIN. Notwithstanding such investment, we currently have no products approved for commercial distribution and we generate no revenues from sales of any products. Our business and our ability to generate revenues in the near term depends entirely on the successful development and commercialization of our product candidates, and in particular, COVAXIN, which may never occur. Our product candidates areIf the results or timing of regulatory filings, the regulatory process, regulatory developments, clinical trials or
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preclinical studies, or other activities, actions, or decisions related to COVAXIN do not meet our or others’ expectations, the market price of our common stock could decline significantly.
Our product candidates are susceptible to the risks of failure inherent at any stage of product development, including the appearance of unexpected or unacceptable adverse events or failure to demonstrate efficacy in clinical trials. Further, our product candidates may not receive regulatory authorization or approval even if they are successful in clinical trials, and our product candidates may not be successfully commercialized even if they receive regulatory authorization or approval.
We currently have limited experience with our product candidates. We have advanced only one product candidate, OCU300, a small molecule therapeutic currently in Phase 3 clinical development for patients with oGVHD, beyond the preclinical development stage. All of our otherOur product candidates are in earlyvarious stages of development. Accordingly, our abilitydevelopment ranging from preclinical development to generate product revenues in the near term will depend almost entirely on our ability to successfully obtain marketing approval for and commercialize OCU300. As of March 20, 2020, the ongoing Phase 3 trials for OCU300, in which we anticipate 60 patients will be randomized in a 2:1 ratio to receive either OCU300 (brimonidine 0.18% nanoemulsion) or a placebo, has completed over 95% of our planned enrollment. We cannot assure you that we will meet our timelines for the Phase 3late-stage clinical trials for OCU300 or for any of our other anticipated clinical trials, which may be delayed or not completed for a number of reasons.development.
The success of our product candidates and our ability to generate revenues from our product candidates will depend on many factors including our ability to:
complete and obtain favorable results from our clinical trials and preclinical trialsstudies with respect to our product candidates;
apply for and receive authorization or marketing approval from the applicable regulatory authorities;
receive regulatory approval for claims that are necessary or desirable for successful marketing;
receive approval for our manufacturing processes and third-party manufacturing facilities from the applicable regulatory authorities;
recruit and enroll qualified patients for clinical trials with respect to our product candidates in a timely manner;
expand and maintain a workforce of experienced scientists and others with experience in the relevant technologytechnologies to continue to develop our product candidates;
hire, train, and deploy marketing and sales representatives or contract with a third-party for marketing and sales representatives to commercialize product candidates in the United States;States and Canada;
launch and create market demand for our product candidates through marketing and sales activities, and any other arrangements to promote these product candidates that we may otherwise establish;
achieve market acceptance of our product candidates by patients, the medical community, and third-party payors;
effectively compete with other therapies and establish a market share;
maintain a continued acceptable safety and efficacy profile of our product candidates following commercial launch;
achieve appropriate reimbursement, pricing, and payment coverage for our product candidates;
manufacture product candidates in sufficient quantities and at acceptable quality and manufacturing cost to meet commercial demand at launch and thereafter;
establish and maintain agreements with wholesalers, distributors, and group purchasing organizations on commercially reasonable terms;
pursue partnerships with, or offer licenses to, qualified third parties to promote and sell product candidates in domestic and key foreign markets where we receive authorization or marketing approval;
develop our product candidates for additional indications or for use in broader patient populations;
maintain patent and trade secret protection and regulatory exclusivity for our product candidates;
qualify for, identify, register, maintain, enforce, and defend intellectual property rights and claims covering our products and intellectual property portfolio; and
not infringe on others’ intellectual property rights.
To the extent we are not able to do any of the foregoing, our business may be materially harmed. If we do not receive FDA or Health Canada authorization or approval for, and successfully commercialize our product candidates, we will not be able to generate revenue from these product candidates in the United States or Canada in the foreseeable future or at all.
COVAXIN has been evaluated by Bharat Biotech in a Phase 3 clinical trial in India in adults, who were healthy or had stable chronic medical conditions ages 18 and older, and approved for EUL by the WHO. We will need to conduct a Phase 2/3 immuno-bridging and broadening clinical trial and a safety-bridging clinical trial to support a BLA submission for COVAXIN for adult use in the United States. We may be unable to successfully produce and commercialize a vaccine that
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effectively and safely treats the virus in a timely manner, if at all, and ultimately may be unable to obtain regulatory approval for adult use in the United States.
COVAXIN has moved rapidly through the regulatory review process for emergency use in India. However, we cannot predict the speed at which we will be able to obtain regulatory marketing approval for adult use for COVAXIN in the United States, if at all. In February 2021, we entered into the Covaxin Agreement with Bharat Biotech, pursuant to which we obtained an exclusive right and license under certain of Bharat Biotech’s intellectual property rights, with the right to grant sublicenses, to develop, manufacture, and commercialize COVAXIN, a whole-virion inactivated COVID-19 vaccine candidate, in the United States, its territories and possessions. Our development efforts with respect to the U.S. market are in their initial stages and uncertain. The FDA indicated that it did not anticipate reviewing and processing an EUA application for the adult population for COVAXIN, and recommended that we consider submitting a BLA for COVAXIN, rather than seeking an EUA. Subsequently, we submitted an IND application to initiate a Phase 2/3 immuno-bridging and broadening clinical trial for COVAXIN to support a BLA submission, which was placed on clinical hold. The clinical hold on our IND application was lifted in February 2022, which allows us to initiate our Phase 2/3 immuno-bridging and broadening clinical trial for COVAXIN when we are able to. Subject to discussions with the FDA, we plan to initiate a safety-bridging clinical trial in the first half of 2022. Subject to the foregoing, we anticipate submitting a BLA with the FDA near the end of 2022.
These additional clinical trials will need to be conducted in the United States to support the BLA submission. There can be no assurances that the results of any clinical trials we may conduct will resemble the results obtained by Bharat Biotech in their Phase 3 clinical trial in India. In addition, it is unclear whether and to what extent the FDA will allow us to rely on clinical trial data generated by Bharat Biotech in India. Any results from further clinical testing by Bharat Biotech or by us may raise new questions and require us to redesign planned clinical trials, including revising proposed endpoints or adding new clinical trial sites or cohorts of subjects. In addition, the FDA’s analysis of any clinical data may differ from our interpretation and the FDA may require that we conduct additional analysis or trials. Further, ongoing clinical testing by Bharat Biotech and administration by Bharat Biotech under emergency use authorization in India may demonstrate that the vaccine candidate is less effective than currently believed, including against new or emerging variants, or has an unacceptable safety profile, which would have a negative impact on our development efforts in the United States.
The clinical trials to be used as the basis for a BLA submission must meet certain criteria related to trial participant demographics and manufacturing standards. We are currently evaluating the nature of the activities we will have to undertake in order to develop and commercialize COVAXIN. BLA approval will entail a lengthier development process than an EUA pathway for COVAXIN. Moreover, evolving or changing plans or priorities at the FDA, including changes based on new knowledge of COVID-19, the effectiveness of other available vaccines for COVID-19, the extent to which the U.S. population has been vaccinated or obtained natural immunity, emerging variants of SARS-CoV-2, and how the new variants of the disease affect the human body, may significantly affect the regulatory development and timeline for COVAXIN in the United States.
We have obtained the rights to develop and commercialize COVAXIN in Canada and we have completed a rolling submission to Health Canada for COVAXIN. We have been provided with a NOD from Health Canada regarding our NDS submission. We have responded to and provided proposed resolutions for the deficiencies included in the NOD but there is no guarantee that Health Canada will accept our proposed resolutions. We have no experience in obtaining marketing approval for, or commercializing products in Canada.
In June 2021, we entered into an amendment to the Covaxin Agreement with Bharat Biotech that provided us with the rights to develop and commercialize COVAXIN in Canada. In order to market and sell COVAXIN in Canada, we must obtain marketing approval for COVAXIN from Health Canada and must comply with that agency’s regulatory requirements. Health Canada regulates the testing, manufacture, labeling, marketing, and sale of pharmaceutical products in Canada. Effective September 16, 2020, COVID-19 vaccine products in Canada were being evaluated for approval under the Interim Order. The Interim Order provided temporary regulatory tools to expedite the approval of drugs and vaccines developed for the treatment of COVID-19. In July 2021, we announced we had completed our rolling submission to Health Canada for COVAXIN. The rolling submission process, which permits companies to submit safety and efficacy data and information as they become available, was recommended and accepted under the Interim Order and transitioned to an NDS for COVID-19. We are in discussions with Health Canada regarding our NDS submission for COVAXIN. In December 2021, we were provided with a NOD from Health Canada regarding our NDS submission. Health Canada requested further analyses of the COVAXIN preclinical and clinical data, as well as additional information regarding CMC. We have responded to and provided proposed resolutions for the deficiencies included in the NOD. Our responses are currently under review by Health Canada. While we believe that we provided sufficient resolution for the deficiencies raised by the NOD, there can be no guarantee that Health Canada will accept our proposed resolutions.
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Generally, the approval process under an NDS in Canada includes all of the risks associated with obtaining BLA approval from the FDA. The clinical trials of COVAXIN conducted by Bharat Biotech in India may not be sufficient to support an application for marketing approval in Canada. Accordingly, seeking Canadian regulatory approval could result in difficulties and costs for us and require additional preclinical studies or clinical trials which could be costly and time-consuming. We do not have any product candidates approved for sale in any jurisdiction, including in Canada, and we do not have experience in obtaining regulatory approval in Canada. We, or any collaborators, may not obtain approval for COVAXIN from Health Canada on a timely basis, if at all. Even if we obtain approval from the FDA for COVAXIN, approval by the FDA does not ensure approval by regulatory authorities in other countries or jurisdictions, including in Canada, or vice versa. Ultimately, we may not receive the necessary approval to commercialize COVAXIN in Canada.
We have submitted an EUA application to the FDA for COVAXIN for pediatric use. The FDA may not grant us the EUA for pediatric use, and, even if they do, absent supplemental BLA approval for that indication, such EUA would be revoked when the COVID-19 emergency terminates, and, prior to that time, we would face significant competition from other pharmaceutical and biotechnology companies, and may not be able to compete effectively.
In November 2021, we submitted a request to the FDA for EUA for COVAXIN for pediatric use in children ages two to 18 years in the United States. The EUA submission was based on the results of the Phase 2/3 immuno-bridging pediatric clinical trial conducted by Bharat Biotech in India.
The FDA has the authority to grant an EUA to allow unapproved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions when there are no adequate, approved, and available alternatives. Generally, EUAs for unapproved products require that manufacturers distribute factsheets for healthcare providers, which addresses significant known and potential benefits and risks, and the extent to which benefits and risks are unknown, and the fact that the FDA has authorized emergency use; and, distribution of factsheets for recipients of the product, which addresses significant known and potential benefits and risks, and the extent to which benefits and risks are unknown, the option to accept or refuse the product, the consequences of refusing, available alternatives, and the fact that FDA has authorized emergency use.
EUAs for unapproved products also include requirements for adverse event monitoring and reporting, and other recordkeeping and reporting requirements. In addition, the FDA may include various requirements in an EUA as a matter of discretion as deemed necessary to protect the public health, including restrictions on which entities may distribute the product, and how to perform distribution (including requiring that distribution be limited to government entities), restrictions on who may administer the product, requirements for collection and analysis of safety and effectiveness data, waivers of cGMP, and restrictions applicable to prescription drugs or restricted devices (including advertising and promotion restrictions).
Our EUA submission is currently under review by the FDA. In February 2022, Delta and Omicron neutralization results along with a safety database of more than 36 million teenagers who had been vaccinated with COVAXIN were submitted to the FDA to support our EUA submission. There can be no guarantee that the data and results from the preclinical studies and clinical trials of COVAXIN, which have been conducted by Bharat Biotech in India, or the additional data provided to the FDA to support our EUA submission, will be accepted by the FDA or be otherwise sufficient to support our EUA submission.
If we are granted an EUA by the FDA for COVAXIN for pediatric use, we would be able to commercialize it for that use without FDA approval. However, the FDA may revoke the EUA where it is determined that the COVID-19 public health emergency no longer exists or warrants such authorization, and we cannot predict how long, if ever, an EUA would remain in place. Such revocation could adversely impact our business in a variety of ways including if we, Bharat Biotech, and our manufacturing partners have invested in the supply chain to provide COVAXIN for pediatric use under an EUA in the United States. In addition, the FDA may revoke or terminate the EUA sooner if, for example, we fail to comply with the conditions of authorization or other terms of the EUA or if COVAXIN is determined to be less effective or safe than it was initially believed to be. We cannot predict how long, if ever, an EUA for the pediatric use of COVAXIN would remain in place.
Furthermore, many biotechnology and pharmaceutical companies are developing treatments for COVID-19 or vaccines against SARS-CoV-2, the virus that causes COVID-19. Many of these companies, which include large pharmaceutical companies, have greater resources for development and established commercialization capabilities than us. In addition, some of these companies have already received regulatory approval or a grant of EUA for their respective products, some of which include authorization for the administration of COVID-19 vaccines in certain pediatric patient populations. Given the products currently approved or authorized for use, as well as those in development by others, even if our EUA is approved for pediatric use, we will face significant competition. If existing vaccines in the market or if competitors develop and commercialize additional COVID-19 vaccines before we can complete regulatory review and obtain an EUA for pediatric use or regulatory approval for COVAXIN, or if they develop and commercialize one or more COVID-19 vaccines that are safer, more effective, have fewer or less severe
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side effects, have broader market acceptance, are more convenient, or are less expensive than COVAXIN, our business, financial condition, and results of operations would be materially adversely affected.
Newly emerging SARS-CoV-2 variants could reduce the immunogenicity and effectiveness of COVAXIN as a potential COVID-19 vaccine.
Multiple variants of the virus that causes COVID-19 have been documented in the United States and globally over the course of the pandemic. New and emerging SARS-CoV-2 variants could be less affected by the immune responses generated by COVAXIN in the vaccine recipients and therefore could reduce the overall efficacy of our vaccine candidate in controlling COVID-19 infection.
The regulatory approval processes of the FDA and comparable foreign authorities are lengthy, time consuming, and inherently unpredictable. If we are not able to obtain, or if there are delays in obtaining required regulatory approvals, we will not be able to commercialize our product candidates as expected, and our ability to generate revenue will be materially impaired.
The research, testing, manufacturing, labeling, approval, selling, marketing, and distribution of pharmaceutical products are subject to extensive regulationregulations by the FDA and other regulatory authorities, which regulations differ from country to country. The time required to obtain approval by the FDA and comparable foreign authorities is unpredictable but typically takes many years following the commencement of clinical trials. The outcome of the approval process is inherently uncertain and depends upon numerous factors, including the substantial discretion of the regulatory authorities. This is especially true for rare and/or complicated diseases. Failure can occur at any time during the clinical trial process. We cannot predict if or when we might receive regulatory approvals for any of our product candidates currently under development. Any delay in our obtaining or our failure to obtain required approvals could materially adversely affect our ability to generate revenue from the particular product candidate, which likely would result in significant harm to our financial position and adversely impact our stock price.
Securing marketing approval requires the submission of extensive preclinical and clinical data and supporting information to regulatory authorities for each therapeutic indication to establish the product candidate’s safety and efficacy for that indication. We have limited experience in designing clinical trials and may be unable to design and execute a clinical trial to support marketing approval. Securing marketing approval also requires the submission of information about the product manufacturing process to, and inspection of manufacturing facilities and clinical trial sites by the regulatory authorities. Regulatory authorities have substantial discretion in the approval process and may refuse to accept any application or may decide that our data is insufficient for approval and require additional preclinical, clinical, or other studies. The number and types of preclinical studies and clinical trials that will be required for regulatory approval also varies depending on the product candidate, the disease or condition that the product candidate is designed to address, and the regulations applicable to any particular product candidate. The FDA or other similar regulatory authorities may determine that our product candidates are not effective or only moderately effective (e.g., studies may not produce the necessary result on all study endpoints), that our studies failed to reach the necessary level of statistical significance, or that our product candidates have undesirable or unintended side effects, toxicities, or other characteristics that preclude us from obtaining marketing approval or prevent or limit commercial use.
Our Phase 3 clinical program for OCU300 consists of two clinical trials evaluating OCU300. As of March 20, 2020, we achieved over 95% of planned enrollment of 60 patients in the first trial. We expect that we will be required to demonstrate effectiveness of both of the co-primary endpoints for marketing approval of OCU300 for the indication of treatment of ocular redness and discomfort in patients with oGVHD. However, the timing of the completion of the Phase 3 clinical trials for OCU300 is dependent, in part, on our ability to locate and enroll a sufficient number of eligible patients on a timely basis, as well as a sample size re-estimation based on data from the first approximately 50% of the planned sample size of 60 patients. If, moreover, OCU300 does not achieve statistical significance in both primary endpoints in our Phase 3 clinical trials, the FDA may require us to conduct additional clinical trials to support the approval of our proposed indications.
Approval policies, regulations, or the type and amount of clinical data necessary to gain approval may change during the course of a product candidate’s clinical development and may vary among jurisdictions. If such changes occur, we may be required to amend our clinical trial protocols, conduct additional studies that require regulatory or IRB approval, or such changes may otherwise cause delays in the approval of an application. If we are required to conduct additional clinical trials or other testing of our product candidates that we develop beyond those that we currently expect, we may be delayed in obtaining marketing approval for our product candidates, or not obtain marketing approval at all.
We may also experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent our ability to receive marketing approval or commercialize our product candidates, including:
regulators, including the FDA and the NIH, or IRBs or IBCs may not authorize us or our investigators to commence or continue a clinical trial, conduct a clinical trial at a prospective trial site, or amend trial protocols, or regulators, IRBs, or IBCs may require that we modify or amend our clinical trial protocols;
we may experience delays in reaching, or fail to reach, agreement on acceptable clinical trial contracts or clinical trial protocols with prospective trial sites and our CROs;CDMOs;
the number of patients required for clinical trials of our product candidates may be larger than we anticipate, enrollment in these clinical trials may be slower than we anticipate, or participants may drop out of these clinical trials, or be lost to follow-up at a higher rate than we anticipate. By example, the Phase 1/2 clinical study of brimonidine tartrate in patients with oGVHD was discontinued early due to slow enrollment;anticipate;
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our third-party contractors may fail to comply with regulatory requirements or the clinical trial protocol, or meet their contractual obligations to us in a timely manner, or at all, or we may be required to engage in additional clinical trial site monitoring;
us, the regulators, IRBs, or IBCs may require the suspension or termination of clinical research for various reasons, including noncompliance with regulatory requirements or a finding that the participants are being exposed to unacceptable health risks, undesirable side effects, or other unexpected characteristics (alone or in combination with
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other products) of the product candidate, or due to findings of undesirable effects caused by a chemically or mechanistically similar therapeutic or therapeutic candidate;
changes in marketing approval policies or regulations, or changes in or the enactment of additional statutes or regulations, during the development period rendering our data insufficient to obtain marketing approval;
changes in or the enactment ofapproval and requiring us to conduct additional statutes or regulations;studies;
the cost of clinical trials of our product candidates may be greater than we anticipate or we may have insufficient funds for a clinical trial or to pay the substantial user fees required by the FDA upon the filing of a marketing application;
the supply or quality of our product candidates or other materials necessary to conduct clinical trials of our product candidates may be insufficient or inadequate;
we may fail to reach an agreement with regulators, IRBs or IBCs regarding the scope, design, or implementation of our clinical trials. For instance, the FDA or comparable foreign regulatory authorities may require changes to our study design that make further study impractical or not financially prudent;
we may have delays in adding new investigators or clinical trial sites, or we may experience a withdrawal of clinical trial sites;
patients that enroll in our studies may misrepresent their eligibility or may otherwise not comply with the clinical trial protocol, resulting in the need to drop the patients from the study, increase the needed enrollment size for the study, or extend the study’s duration;
there may be regulatory questions or disagreements regarding interpretations of data and results, or new information may emerge regarding our product candidates;
the FDA or comparable foreign regulatory authorities may disagree with our study design, including endpoints, or our interpretation of data from preclinical studies and clinical trials or find that a product candidate’s benefits do not outweigh its safety risks;
the FDA or comparable foreign regulatory authorities may not accept data from studies with clinical trial sites in foreign countries;
the FDA or comparable foreign regulatory authorities may disagree with our intended indications;
the FDA or comparable foreign regulatory authorities may fail to approve or subsequently find fault with the manufacturing processes or our contract manufacturer’s manufacturing facility for clinical and future commercial supplies;
the data collected from clinical trials of our product candidates may not be sufficient to the satisfaction of the FDA or comparable foreign regulatory authorities to support the submission of a marketing application, or other comparable submissions in foreign jurisdictions, or to obtain regulatory approval in the United States or elsewhere;
the FDA or comparable foreign regulatory authorities may take longer than we anticipate to make a decision on its product candidates; and
we may not be able to demonstrate that a product candidate provides an advantage over current standards of care or current or future competitive therapies in development.
Significant delays relating to any preclinical or clinical trials also could shorten any periods during which we may have the exclusive right to commercialize our product candidates or allow our competitors to bring products to market before we do. This may prevent us from receiving marketing approvals and impair our ability to successfully commercialize our product candidates and may harm our business and results of operations. In addition, many of the factors that cause, or lead to, delays in clinical trials may ultimately lead to the denial of marketing approval of any of our product candidates. If any of this occurs, our business, financial condition, results of operations, and prospects will be materially harmed.
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The failure to comply with FDA and comparable foreign regulatory requirements may, either before or after product approval, if any, subject us to administrative or judicially imposed sanctions, including:
restrictions on our ability to conduct clinical trials, including full or partial clinical holds on ongoing or planned trials;
restrictions on our products, manufacturers, or manufacturing process;
warning letters, Form 483s, or untitled letters alleging violations;
civil and criminal penalties;
injunctions;
suspension or withdrawal of regulatory approvals;
product seizures, detentions, or import bans;
voluntary or mandatory product recalls and publicity requirements;
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total or partial suspension of production;
imposition of restrictions on operations, including costly new manufacturing requirements; and
refusal to approve pending marketing applications or supplements to approved marketing applications.
Even if we were to obtain regulatory approval of a product candidate, the FDA or comparable foreign regulatory authorities may grant approval for fewer or more limited indications, populations, or uses than we request, may require significant safety warnings, including black box warnings, contraindications, and precautions, may grant approval contingent on the performance of costly post-marketing clinical trials, surveillance, restrictions on use or other requirements, including a REMS to monitor the safety or efficacy of the product, or may approve a product candidate with a label that does not include the labeling claims necessary or desirable for the successful commercialization of that product candidate. Any of these scenarios could compromise the commercial prospects for our product candidates.
If we experience delaysThe ongoing COVID-19 pandemic and actions taken in obtaining approval,response to it may result in disruptions to our ability to generate revenues from that product candidate will bebusiness operations, which would have a materially impaired. If we fail to obtain marketing approval for a product candidate, we will be prevented from commercializing the product candidate.
Ouradverse effect on our business, may be adversely affected by the Coronavirus pandemic.financial position, operating results, and cash flows.
In December 2019, a novelthe strain of coronavirus, orSARS-CoV-2, causing the disease known as COVID-19, was reported to have surfaced in Wuhan, China. As ofIn March 2020, the WHO declared the COVID-19 hasoutbreak a global pandemic. Since being discovered, new variants of SARS-CoV-2 have emerged.
We are pursuing development of COVAXIN, the COVID-19 vaccine candidate developed by Bharat Biotech in India, for the U.S. and Canadian markets pursuant to the Covaxin Agreement. We submitted an IND to the FDA to begin a Phase 2/3 immuno-bridging and broadening clinical trial to evaluate COVAXIN in adults ages 18 years and older in the United States, which was placed on a clinical hold by the FDA. The FDA lifted its clinical hold in February 2022 and we plan to initiate the Phase 2/3 immuno-bridging and broadening clinical trial for COVAXIN as soon as we are able to. We have also submitted an EUA application to the FDA for pediatric use. Any significant delays in our planned COVAXIN clinical trials or otherwise could adversely affect our business, results of operations, or financial condition. We have also filed an NDS with Health Canada, for which we received a NOD in December 2021. Health Canada requested further analyses of the COVAXIN preclinical and clinical data, as well as additional information regarding CMC. We have responded to and provided proposed resolutions for the deficiencies included in the NOD. Our responses are currently under review by Health Canada. While we believe that we provided sufficient resolution for the deficiencies raised by the NOD, there can be no guarantee that Health Canada will accept our proposed resolutions. It is also uncertain whether, or if, the FDA or Health Canada will allow us to rely on clinical trial data generated by Bharat Biotech or commercialize COVAXIN manufactured by Bharat Biotech in India.
With respect to our gene therapy product candidates, we initiated a Phase 1/2 clinical trial for OCU400, for the treatment of the NR2E3 and RHO disease genotypes, in the United States earlier this year and the first patient is expected to be dosed in the first half of 2022. If COVID-19 continues to spread to other countries, includingin the United States and has been declared to be a pandemic by the World Health Organization. The United States has declared a National Emergency and efforts to contain the spread of COVID-19 have intensified, including severe travel restrictions imposed by the U.S. government related to China and Europe. The outbreak and any preventative or protective actions that we, our suppliers, our licensors and other collaborators or governments may take in respect of this coronavirus may disrupt our business. We are diligently working to ensure that we can operate with minimal disruption, and to mitigate the impact of the outbreak on our employees’ health and safety. However, given the interconnectivity of the global economy and the possible rate of future global transmission, the full extent to which the coronavirus pandemic could affect the global economy is unknown and its impact may extend beyond the areas which are currently known to be impacted. Any resulting financial impact will depend on future developments and cannot be reasonably estimated at this time, but may materially affect our business, financial condition and results of operations.
COVID-19 has and may continue to have an impact on ports and trade into and out of China and Hong Kong, as well as travel in the region and globally. We currently rely on CanSinoBIO, which is headquartered in Tianjin, China, for CMC development and manufacturing of clinical supplies for our gene therapy candidate, OCU400. Accordingly, there is a risk that supplies of OCU400 may be significantly delayed or may become unavailable as a result of COVID-19 and the resulting impact on CanSinoBIO’s labor force and operations and its ability to obtain the materials required for the manufacture of our clinical supplies, including impacts resulting from the Chinese government’s imposition of certain restrictions on business operations and the movement of people and goods in an effort to curtail the spread of the virus. There can be no assurance that we would be able to timely locate an alternative supplier or otherwise successfully implement any mitigation plans. Disruptions in our operations or supply chain, whether as a result of restricted travel, quarantine requirements or otherwise, could negatively impact our ability to proceed with our clinical trials, preclinical development and other activities and delay our ability to receive product approval and generate revenue.
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In addition, our ongoing clinical trials for OCU300 may be affected by the COVID-19 outbreak. Clinical site initiation, patient enrollment and recruitment of clinical site investigators and staff at hospitals and medical institutions may be delayed due to prioritization of healthcare resources, such as physicians and staff, toward the COVID-19 outbreak. As COVID-19 has become a worldwide pandemic,elsewhere, it may delay enrollment and ultimately completion of this clinical trial and delay enrollment in ourany clinical trials and somethat we have planned or otherwise may initiate for our other product candidates in 2022. Some patients may not be able to comply with clinical trial protocols if any future quarantines impede patient movement or interrupt healthcare services. Moreover, limitations on global international travel may interruptdelay key trial activities, including necessary interactions with regulators, ethics committees, and other important agencies and contractors. We may be faced with limitations in employee resources that would otherwise be focused on the conduct of clinical trials, including because of sickness of employees or their families or the desire of employees to avoid contact with large groups of people. Any of the above could delay our planned clinical trials for OCU300any of our product candidates or prevent us from completing thesethe clinical trialstrial at all, and harm our ability to obtain approval for OCU300.OCU400 or our other product candidates.
Moreover, we may experience additional disruptions that could severely impact our business and development activities, including, but not limited to, strain on our suppliers and other third parties, possibly resulting in supply disruptions of our product candidates for preclinical development and potential future clinical trials we expect to initiate, decrease in clinical enrollment in any clinical trials we initiate, and the ability to raise capital when needed on acceptable terms, if at all. The COVID-19 pandemic continues to impact the global supply chain, causing disruptions to service providers, logistics, and the flow and availability of supplies and products. Disruptions in our operations or supply chain, whether as a result of government intervention, restricted travel, quarantine requirements, or otherwise, could negatively impact our ability to proceed with our clinical trials, preclinical development, and other activities and delay our ability to receive product approval and generate revenue.
In addition, the continued spread of COVID-19 has ledmay lead to severe disruption and volatility in the global capital markets, which could increase our cost of capital and adversely affect our ability to access the capital markets. It is possible that the continued
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spread of COVID-19 could cause an economic slowdown or recession or cause other unpredictable events, each of which could adversely affect our business, results of operations, or financial condition.
The ultimate impact of the COVID-19 pandemic is highly uncertain and subject to change. The extent to which the coronavirusCOVID-19 impacts our results will depend on future developments, which are highly uncertain and cannot be predicted, including new information which may emerge concerning the severity of COVID-19, the coronavirus, the ultimate geographic spreademergence of any new mutations or variants of the coronavirus,virus, the duration of the outbreak, travel restrictions imposed by the United States, Canada, India, and other countries, business closures or business disruption in the United States, Canada, India, and other countries, a reduction in time spent out of home and the actions taken throughout the world, including in our markets, to contain the coronavirusCOVID-19 or treat its impact. We do not yet know the full extent of potential delays or impacts on our business, our clinical trials, our preclinical development efforts, healthcare systems, or the global economy as a whole. However, these effects could have a material impact on our operations, and we will continue to monitor the COVID-19 situation closely.
Data from preclinical studies and early stage clinical trials may not be predictive of success in later clinical trials.
The results of preclinical studies, preliminary study results, and early clinical trials of our product candidates may not be predictive of the results of later-stage clinical trials or the ultimately completed trial. Preliminary and final results from such studies may not be representative of study results that are found in larger, controlled, blinded, and more long-term studies. Product candidates in later stages of clinical trials may fail to show the desired safety and efficacy traits despite having progressed through preclinical studies and initial clinical trials. A number of companies have suffered significant setbacks in advanced clinical trials, notwithstanding promising results in earlier trials. In some instances, there can be significant variability in safety or efficacy results between different clinical trials of the same product candidate due to numerous factors, including changes in trial procedures set forth in protocols, differences in the size and type of the patient populations, changes in and adherence to the clinical trial protocols and the rate of dropout among clinical trial participants.
In addition, from time to time, we may publish interim, “top-line,” initial, or preliminary data from our clinical studies. Interim data from clinical trials are subject to the risk that one or more of the clinical outcomes may materially change as patient enrollment continues and more patient data becomes available. Preliminary, initial, or “top-line” data also remain subject to audit and verification procedures that may result in the final data being materially different from the preliminary data previously published. As a result, interim, “top-line”, initial, and preliminary data should be viewed with caution until the final data are available. Adverse changes between preliminary, initial, “top-line” or interim data and final data could significantly harm our business prospects.
With respect to OCU300, we have not conducted any clinical studies specifically with our proprietary nanoemulsion technology in patients with oGVHD. The formulation used in previous clinical studies conducted in patients with oGVHD is different from our proposed OCU300 nanoemulsion. The different formulation may impact the final Phase 3 clinical study results for OCU300. We have evaluated results from an investigator-led retrospective analyses of the use of brimonidine tartrate 0.15% eye drops in patients with oGVHD and an investigator-led prospective Phase 1/2 clinical trial assessing the use of 0.15% and 0.075% brimonidine tartrate eye drops in patients with oGVHD. The formulations used in these studies are different than our proposed OCU300 formulation. These studies and results are not sufficient to establish the safety and efficacy of OCU300 and the results from these studies should be viewed with caution. Additionally, these clinical studies were not powered for statistical significance due to their small sample size and the Phase 1/2 clinical study was discontinued early due to slow enrollment. These studies may not be predictive of the results of later studies conducted with the OCU300 formulation for which we intend to seek marketing approval. Moreover, although a dose ranging study was recommended but not required by FDA, we do not intend to conduct such a study and have proceeded directly into Phase 3 clinical trials. We cannot provide any assurance that
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the results of our ongoing and future clinical trials will reflect favorable results obtained in prior preclinical studies or clinical trials.
The development and manufacture of biologics is a complex process and entails particular risks.
OCU200, our product candidate currently in preclinical development, is a novel biologic designed to treat retinal diseases. The process of developing and manufacturing biologics is complex, highly regulated and subject to multiple risks, andorganization, we have no experience in successfully developing,the development, manufacturing, distribution, or commercializingcommercialization of a biologics product. Thevaccine candidate.
We have never undertaken the development, manufacturing, distribution, or commercialization of biologics is highly susceptiblea vaccine candidate, and we may be unable to obtain regulatory authorization or approval in the United States or Canada. Additionally, development of an effective vaccine candidate depends on the success of our and our partner’s manufacturing capabilities. We have not previously ramped our organization for a commercial launch of any product, loss dueand doing so in a pandemic environment with an urgent, critical global need creates additional challenges such as clinical trials, licensing, distribution channels, intellectual property disputes or challenges, and the need to contamination, equipment failure, improper installation or operationestablish teams of equipment, vendor or operator error, inconsistency in yields, variability in product characteristics and difficulties in scalingpeople with the production process. Even minor deviations from normal manufacturing processes could result in reduced production yields, product defects and other supply disruptions and higher costs.
Therelevant skills. We may also face challenges with sourcing a sufficient amount of raw materials required in our third-party vendors’ manufacturing processesto support the demand for a vaccine, including any potential import issues. We may be unable to effectively create a supply chain for COVAXIN that will adequately support demand. Furthermore, there are derived from biological sources. We cannot assure youno assurances that our third-party vendors have,any vaccine candidate would be approved or will be able to obtain on commercially reasonable terms,authorized by the FDA or Health Canada at all sufficient rightsor for inclusion in government stockpile programs, which may be material to these materials derived from biological sources. Such raw materials are difficult to procure and may also be subject to contamination or recall. If microbial, viral or other contaminations are discovered at the facilitiescommercial success of our manufacturer, such facilities may need to be closed for an extended period of time to investigate and remedy the contamination, which could delay clinical trials, result in higher costs of druga vaccine product and adversely harm our business. A material shortage, recall, or restriction on the use of biologically derived substancescandidate, in the manufacture of our product candidates could adverselyUnited States and Canada.
Our ability to produce a successful vaccine may be curtailed by one or more government actions or interventions, which may be more likely during a global health crisis such as COVID-19.
Given the significant global impact or disrupt the clinical and commercial manufacturing of our product candidates, which could materially and adversely affect our operating results and development timelines.
In addition, our biologics product candidates may expose us to additional potential product liability claims. The development of biologics products entails a risk of additional product liability claims because of the riskCOVID-19 pandemic, it is possible that the U.S. government may take actions that directly or indirectly have the effect of transmitting disease to human recipients, and substantial product liability claims may be asserted against us as a result.
We may not be successful in our efforts to develop product candidates based on our OcuNanoE nanoemulsion formulation or expand the use of our OcuNanoE nanoemulsion formulation for treating additional diseases and conditions.
We are currently directingdiminishing some of our development efforts towards developing product candidates, includingrights or opportunities with respect to COVAXIN and the economic value of a COVID-19 vaccine to us could be limited. In the United States, the Defense Production Act of 1950, as amended, or the Defense Production Act ("DPA"), gives the U.S. government rights and authorities that may directly or indirectly diminish our lead product candidate, OCU300, basedown rights or opportunities with respect to COVAXIN, if approved for adult use or authorized for pediatric use, and the economic value of a COVID-19 vaccine to us could be limited. Our potential third-party service providers may be impacted by government entities regarding potentially invoking the DPA or other potential restrictions to all or a portion of services they might otherwise offer. Government entities imposing restrictions or limitations on our proprietary OcuNanoE™ nanoemulsion formulation. Wethird-party service providers may require us to obtain alternative service sources for our vaccine candidate. If we are the first companyunable to use nanoemulsion technologytimely enter into alternative arrangements, or if such alternative arrangements are not available on satisfactory terms, we will experience delays in the ophthalmology space.
We expect to apply its OcuNanoE™ nanoemulsion formulation to support therapeutic interventions of other ocular diseases with the potential of improving the tear film stability and targeting of drug molecules to the specialized tissues. We have product candidates at various stages of development for treatment of eye diseases and are exploring the potential useor production of our OcuNanoE™ nanoemulsion formulationvaccine candidate, increased expenses, and delays in other diseases. Our existing product candidates and any other potential product candidates that we identify may not be suitable for continued preclinicaldistribution or clinical development, including as a resultcommercialization of being shown to have harmful side effects, a lack of efficacyour vaccine candidate, if authorized or other characteristics that indicate that such product candidates are unlikely to be products that will receive marketing approval and achieve market acceptance.
If we do not successfully develop and commercialize our product candidates based upon our OcuNanoE™ nanoemulsion formulation, we may not be able to obtain substantial product revenues in future periods.approved.
Our product candidates generated from our modifier gene therapy platform are based on a novel technology and face an uncertain regulatory environment, which makes it difficult to predict the time and cost of product candidate development and subsequently obtaining regulatory approval.
We anticipate that someA substantial portion of our product research and development efforts will beis centered around our modifier gene therapy platform. The regulatory approval and successful commercialization of product candidates such as OCU400, a gene therapy designed to treat NR2E3 mutation-associated retinal degenerative diseaseRP, LCA, and other IRDs, and OCU410, a gene therapy designed to treat dry AMD, depend on the successful development of this platform. There can be no assurance that any development problems we experience in the future related to our modifier gene therapy platform will not cause significant delays or unanticipated costs, or that such development problems can be solved. The clinical trial requirements of the FDA, the EMA, and other regulatory agencies, and the criteria used by these regulators use to determine the safety and efficacy of a product candidate vary substantially according to the type, complexity, novelty, and intended use and market of such product candidates. The regulatory approval process for novel product candidates
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such as OCU400 and OCU410 can be more expensive and take longer than for other, better known or extensively studied pharmaceutical or other product candidates.
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Regulatory requirements governing gene and cell therapy products have changed frequently and may continue to change in the future. For example, the FDA established the Office of Tissues and Advanced Therapies within its Center for Biologics Evaluation and Research (“CBER”("CBER") to consolidate the review of gene therapy and related products, and the Cellular, Tissue and Gene Therapies Advisory Committee to advise CBER on its review. Gene therapy clinical trials conducted at institutions that receive funding for recombinant DNA research from the United States NIH are also subject to review by the NIH Novel and Exceptional Technology and Research Advisory Committee (“NExTRAC”("NExTRAC"), formerly the Recombinant DNA Advisory Committee, which now focuses on emerging areas of research including, but not restricted to, technologies surrounding advances in recombinant or synthetic nucleic acid research. Although the FDA decides whether individual gene therapy protocols may proceed, it is possible the NExTRAC review process, which is still being implemented, could delay the initiation of a clinical trial, even if the FDA has reviewed the trial design and details and approved its initiation. Before a clinical trial can begin at a study site, that the institution’s IRB, and its IBC, have to review the proposed clinical trial to assess the safety of the trial. In addition, adverse developments in clinical trials of gene therapy products conducted by others may cause the FDA or other regulatory bodies to change the requirements for approval of any of our product candidates.
These regulatory review committees and advisory groups and the new guidelines they promulgate may lengthen the regulatory review process, require us to perform additional studies, increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of our product candidates, or lead to significant post-approval limitations or restrictions. As we advance our gene therapy product candidates, we will be required to consult with these regulatory and advisory groups, and comply with applicable guidelines. If we fail to do so, we may be required to delay or discontinue development of our gene therapy product candidates. These additional processes may result in a review and approval process that is longer than we otherwise would have expected for orphan ophthalmology product candidates. Delay or failure to obtain, or unexpected costs in obtaining the regulatory approval necessary to bring a potential product to market could decrease our ability to generate sufficient product revenue to maintain our business.
Existing data on the safety and efficacy of gene therapy is very limited and sometimes include historically poor clinical efficacy of previous non-replicating gene therapy products. In addition, there have been publicized safety issues associated with previous gene therapy products in third-party clinical trials, including patient deaths. The results of preclinical and clinical trials performed for our product candidates will not definitively predict safety or efficacy in humans. OCU400 usesand OCU410 use an adeno-associated virusAAV vector. Possible serious side effects of other viral vector-based gene therapies in general include uncontrolled viral infections and the development of cancer, particularly lymphoma or leukemia. The risk of insertional mutagenesis or oncogenesis remains a significant concern for gene therapy, and we cannot provide any assurance that it will not occur in any of our planned or future clinical trials with respect to our product candidates based on our modifier gene therapy platform. There is also the potential risk of delayed adverse events following exposure to gene therapy products due to persistent biological activity of the genetic material or other components of products used to carry the genetic material. Potential procedure-related adverse reactions, including inflammation, can also occur. If any such adverse events occur during clinical trials, further advancement of such clinical trials could be halted or delayed, which would have a material adverse effect on our business and operations.
Finally, the public's attitude may be influenced by claims that gene therapy technology is unsafe, unethical, or immoral. If we are unable to convincingly demonstrate the safety and efficacy of our product candidates arising from our gene modifier platform, our product candidates, even if approved by the FDA or foreign regulatory authorities, may not gain the acceptance of the public or the medical community.
The development and manufacture of biologics is a complex process and entails particular risks.
OCU200, our product candidate currently in preclinical development, is a novel biologic designed to treat retinal diseases. The process of developing and manufacturing biologics is complex, highly regulated, and subject to multiple risks, and we have no experience in successfully developing, manufacturing, or commercializing a biologics product. The manufacturing of biologics is highly susceptible to product loss due to contamination, equipment failure, improper installation or operation of equipment, vendor or operator error, inconsistency in yields, variability in product characteristics, and difficulties in scaling the production process. Even minor deviations from normal manufacturing processes could result in reduced production yields, product defects and other supply disruptions, and higher costs.
The raw materials required in our third-party vendors’ manufacturing processes are derived from biological sources. We cannot assure you that our third-party vendors have, or will be able to obtain on commercially reasonable terms, or at all, sufficient rights to these materials derived from biological sources. Such raw materials are difficult to procure and may also be subject to contamination or recall. If microbial, viral, or other contaminations are discovered at the facilities of our manufacturer, such facilities may need to be closed for an extended period of time to investigate and remedy the contamination, which could delay clinical trials, result in higher costs of drug product, and adversely harm our business. A material shortage, recall, or restriction
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on the use of biologically derived substances in the manufacture of our product candidates could adversely impact or disrupt the clinical and commercial manufacturing of our product candidates, which could materially and adversely affect our operating results and development timelines. In addition, the U.S. government may impose restrictions on goods, including biologically derived substances, manufactured in or imported from China. This could have a material adverse effect on our business and operations.
In addition, our biologic product candidates may expose us to additional potential product liability claims. The development of biologic products entails a risk of additional product liability claims because of the risk of transmitting disease to human recipients, and substantial product liability claims may be asserted against us as a result.
OCU400 has received four ODDs from the FDA and two OMPDs from the EC. However, there is no guarantee that we will be able to maintain these designations, receive this designation for any of our other product candidates, or receive or maintain any corresponding benefits, including periods of exclusivity.
We have obtained from the FDA Office of Orphan Products, ODDs for OCU400 for NR2E3, CEP290, RHO, and PDE6ß mutation-associated inherited retinal degenerations. OCU400 additionally received OMPD from the EC, based on the recommendation of the EMA, for RP and LCA in February 2021. We may also seek ODD or OMPD for our other product candidates, as appropriate. While these ODDs and OMPDs provide us with certain advantages, they neither shorten the development time or regulatory review time of a product candidate nor give the product candidate any advantage in the regulatory review or approval process.
Generally, if a product candidate with ODD subsequently receives marketing approval before another product considered by the FDA or EMA to be the same, for the same orphan indication, the product is entitled to a period of marketing exclusivity, which precludes the FDA or EMA from approving another marketing application for the same drug or biologic for the same indication for a specified time period. The applicable period is seven years in the United States and 10 years in Europe. The European exclusivity period can be reduced to six years if a product no longer meets the criteria for OMPD or if the product is sufficiently profitable so that market exclusivity is no longer justified.
We may not be able to obtain any future ODDs or OMPDs that we apply for, ODDs or OMPDs do not guarantee that we will be able to successfully develop our product candidates, and there is no guarantee that we will be able to maintain any ODDs or OMPDs that we receive. For instance, ODDs may be revoked if the FDA finds that the request for designation contained an untrue statement of a material fact or omitted material information, or if the FDA finds that the product candidate was not eligible for designation at the time of the submission of the request.
Moreover, even if we are able to receive and maintain ODDs or OMPDs, we may ultimately not receive any period of regulatory exclusivity if our product candidates are approved. For instance, we may not receive orphan product regulatory exclusivity if the indication for which we receive FDA or EMA regulatory approval is different than the ODD or OMPD. Orphan exclusivity may also be lost for the same reasons that ODD or OMPD may be lost. Orphan exclusivity may further be lost if we are unable to assure a sufficient quantity of the product to meet the needs of patients with the rare disease or condition.
Even if we obtain orphan exclusivity for any of our current or future product candidates, that exclusivity may not effectively protect the product from competition as different products can be approved for the same condition or products that are the same as ours can be approved for different conditions. Even after an orphan product is approved, the FDA or EMA can also subsequently approve a product containing the same principal molecular features for the same condition if the regulatory authority concludes that the latter product is clinically superior by means of greater effectiveness, greater safety, or providing a major contribution to patient care.
If another sponsor receives approval for such product before we do, we would be prevented from launching our product for the orphan indication during the period of marketing exclusivity unless we can demonstrate clinical superiority.
In the future, we may seek FDA designations to facilitate product candidate development, such as fast track or breakthrough therapy designation. We may not receive any such designations or if we receive such designations they may not lead to faster development or regulatory review or approval and it does not increase the likelihood that our product candidates will receive marketing approval.
In the future, we may seek product designations, such as fast track or breakthrough therapy designation, which are intended to facilitate the development or regulatory review or approval process for product candidates. Receipt of such a designation is within the discretion of the FDA. Accordingly, even if we believe one of our product candidates meets the criteria for a
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designation, the FDA may disagree. In any event, the receipt of such a designation for a product candidate may not result in a faster development process, review, or approval compared to product candidates considered for approval under conventional FDA procedures and does not assure ultimate marketing approval by the FDA. In addition, the FDA may later decide that the product candidates no longer meet the designation conditions, in which case any granted designations may be revoked.
The FDA may determine that our product candidates have undesirable side effects that could delay or prevent their regulatory authorization or approval or commercialization. If such side effects are identified during the development of our product candidates, we may need to abandon our development of such product candidates.
Undesirable side effects caused by our product candidates could cause us, IRBs, and other reviewing entities or regulatory authorities to interrupt, delay, or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA or other comparable foreign authorities. For example, if concerns are raised regarding the safety of one of our product candidates as a result of undesirable side effects identified during clinicalpreclinical or preclinicalclinical testing, the FDA may order us to cease further development or issue a letter requesting additional data or information prior to making a final decision regarding whether or not to approve the product candidate. FDA requests for additional data or information can result in substantial delays in the approval of a new product candidate.
Undesirable side effects caused by or any unexpected characteristics (alone or in combination with other products) for any of our product candidates could also result in denial of regulatory approval by the FDA or other comparable foreign authorities for any or all targeted indications or the inclusion of unfavorable information in our product labeling, such as limitations on the indicated uses or populations for which the products may be marketed or distributed, a label with significant safety warnings, including boxed warnings, contraindications, and precautions, a label without statements necessary or desirable for successful commercialization, or may result in requirements for costly post-marketing testing and surveillance, or other requirements,
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including REMS, to monitor the safety or efficacy of the products. These could prevent us from commercializing and generating revenues from the sale of our product candidates.
Many compounds that initially showed promise in clinical or earlier stage testing have later been found to cause side effects that prevented further development of the compound. In addition, adverse events which had initially been considered unrelated to the study treatment may later be found to be caused by the study treatment. Moreover, incorrect or improper use of our product candidates (including use more frequently than is prescribed) by patients could cause unexpected side effects or adverse events. There can be no assurance that our product candidates will be used correctly, and if used incorrectly, such misuse could prevent itsour receipt or maintenance of marketing authorization, resulting in label changes or regulatory authority safety communications or warnings, or hamper commercial adoption of our product candidate, if authorized or approved, at the rate we currently expect.
While there have been a few adverse events that have occurred in the investigator-led clinical studies of brimonidine tartrate for the treatment of ocular redness and discomfort in patients with oGVHD, overall brimonidine tartrate was well-tolerated. We do not have any studies exploring long term exposure in these patient populations to brimonidine tartrate or our product candidates. Our understanding of the relationship between our product candidates and any adverse effects may change as we gather more information, and unexpected adverse effects, including serious adverse effects, may occur. We also do not have any studies demonstrating the safety profile of our other planned product candidates, which are currently in preclinical development.
If any of our product candidates are associated with serious adverse events, or undesirable side effects, or have properties that are unexpected, we may need to abandon development or limit development of that product candidate to certain uses or subpopulations in which the undesirable side effects or other characteristics are less prevalent, less severe, or more acceptable from a risk-benefit perspective. The therapeutic-related side effects could affect patient recruitment or the ability of enrolled patients to complete the trial or result in potential product liability claims. We may also be held liable for harm caused to patients and our reputation may suffer. Any of these occurrences may significantly harm our business, financial condition, results of operations, and prospects.
If we experiencesexperience delays or difficulties in the enrollment of patients in clinical trials, our completion of clinical trials and receipt of necessary regulatory approvals could be delayed or prevented.
Identifying and qualifying patients to participate in clinical trials of our product candidates is critical to our success. The timing of our clinical trials depends on the speed at which we can recruit patients to participate in testing our product candidates. Our planned Phase 2/3 immuno-bridging and broadening clinical trial for COVAXIN and our ongoing Phase 1/2 clinical study examining the use of brimonidine tartrate eye drops in patients with oGVHD wastrial for OCU400, could be discontinued early due toif they experience slow enrollment, and we may also experience similar difficulties in the future.future clinical trials for our other product candidates currently in preclinical development. If patients are unwilling to participate in our clinical trials because of negative publicity from adverse events related to vaccines, gene therapy, or in the industry ormore broadly, in the clinical trials for otherrelated third party product candidates, or for other reasons, including competitive clinical trials for similar patient populations, the timeline for recruiting patients, conducting studies, and obtaining regulatory approval of potential products may be delayed. These delays could result in increased costs, delays in advancing our product development, delays in testing the effectiveness of our product candidates, or termination of the clinical trials altogether.
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We or our clinical trial sites may not be able to identify, recruit, and enroll a sufficient number of patients, or those with the required or desired characteristics in a clinical trial, to complete our clinical trials in a timely manner. Patient enrollment is affected by other factors including:
the size and nature of the patient population (for instance, we are pursuing clinical trials for certain orphan indications, for which the size of the patient population is limited);
the severity of the disease under investigation;
the existence of current treatments for the indications for which we are conducting clinical trials;
the eligibility criteria for and design of the clinical trial in question, including factors such as frequency of required assessments, length of the study, and ongoing monitoring requirements;
the perceived risks and benefits of the product candidate, including the potential advantages or disadvantages of the product candidate being studied in relation to other available therapies (for instance, novel therapies such as those involving our modifier gene therapy platform may suffer from negative publicity due to adverse events or other reasons);therapies;
competition in recruiting and enrolling patients in clinical trials;
efforts to facilitate timely enrollment in clinical trials;
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patient referral practices of physicians;
effectiveness of publicity created by clinical trial sites regarding the trial;
patients’ ability to comply with the specific instructions related to the trial protocol, proper documentation, and use of the product candidate;
an inability to obtain or maintain patientpatients' informed consents;
the risk that enrolled patients will drop out before completion or not return for post-treatment follow-up;
the ability to monitor patients adequately during and after treatment;
the ability to compensate patients for their time and effort; and
the proximity and availability of clinical trial sites for prospective patients.
We may not be able to initiate or continue conducting clinical trials for our product candidates if we are unable to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA or similar regulatory authorities outside the United States. Our inability to enroll a sufficient number of patients for our clinical trials would result in significant delays and could require us to abandon one or more clinical trials altogether. In particular, there may be low or slow enrollment, and the studies may enroll subjects that do not meet the inclusion criteria, requiring the erroneously enrolled subjects to be excluded and the trial population to be increased. Moreover, patients in our clinical trials, especially patients in our control groups, may be at risk for dropping out of our studies if they are not experiencing relief of their disease. A significant number of withdrawn patients would compromise the quality of a study's data.
Enrollment difficulties or delays in our clinical trials may result in increased development costs for our product candidates, or the inability to complete development of our product candidates, which would cause our value to decline, limit our ability to obtain additional financing, and materially impair our ability to generate revenues.
Our developmentData from preclinical studies and commercialization strategy for OCU300 depends,early-stage clinical trials may not be predictive of success in part, on published scientific literaturelater clinical trials.
The results of preclinical studies, preliminary study results, and early-stage clinical trials of our product candidates may not be predictive of the FDA’s prior findings regardingresults of later-stage clinical trials or the ultimately completed clinical trial. Preliminary and final results from such studies may not be representative of study results that are found in larger, controlled, blinded, and more long-term studies. Product candidates in later stages of clinical trials may fail to show the desired safety and efficacy traits despite having progressed through preclinical studies and initial clinical trials. A number of approved products. If we are not ablecompanies have suffered significant setbacks in advanced clinical trials, notwithstanding promising results in earlier trials. In some instances, there can be significant variability in safety or efficacy results between different clinical trials of the same product candidate due to pursue this strategy, we will neednumerous factors, including changes in trial procedures set forth in protocols, differences in the size and type of the patient populations, changes in and adherence to conduct additional development activities beyond what we currently plan, our development costs will increase,the clinical trial protocols, and the rate of dropout among clinical trial participants.
In addition, from time to time, we may be delayed in receiving regulatory authority approval. The submission of 505(b)(2) New Drug Applications may alsopublish interim, “top-line,” initial, or preliminary data from our clinical trials. Interim data from clinical trials are subject us to the risk of patent infringement lawsuitsthat one or regulatory actions that would delay or prevent our submission of a marketing application to the FDA, or the FDA’s review and approval of our marketing applications.
The Hatch-Waxman Act added Section 505(b)(2) to the FDCA. Section 505(b)(2) permits the filing of an NDA, where at least somemore of the information required for approval comes from investigationsclinical outcomes may materially change as patient enrollment continues and more patient data becomes available. Preliminary, initial, or “top-line” data also remain subject to audit and verification procedures that were not conducted by or formay result in the applicant and for which the applicant has not obtained a right of reference or usefinal data being materially different from the person by or for whom the investigations were conducted. The FDA interprets Section 505(b)(2) of the FDCA, for purposes of approving an NDA, to permit the applicant to rely, in part, upon published literature and/or the FDA’s previous findings of safety and efficacy for an approved product. The FDA also requires companies to perform additional clinical trials or measurements to support any deviation from thepreliminary data previously approved product and to support the reliance on the applicable published literature or referenced product, referred to as bridging. The FDA may then approve the new product candidate for all or some of the label indications for which the referenced product has been approved, as well as for any new indication sought by the Section 505(b)(2) applicant, if such approval is supported by study data. The label, however, may require all or some of the limitations, contraindications, warnings or precautions or restrictions on use included in the reference product’s label, including a black box warning, or may require additional limitations, contraindications, warnings or precautions or restrictions on use.
We currently plan to pursue marketing approval for OCU300 in the United States through 505(b)(2) NDAs and will be completing bridging analyses prior to NDA submission. If the FDA disagrees with our conclusions regarding the appropriateness of our reliance on a reference listed drug or published literature or if we are not otherwise able to bridge to the reference listed drug or published literature to demonstrate that our reliance is scientifically appropriate, we could be required to conduct additional clinical trials or other studies to support our NDA, which could lead to unanticipated costs and delays or to the termination of our development program. If we are unable to obtain approval for our pharmaceutical formulations through the 505(b)(2) NDA process, we may be required to pursue the more expensive and time consuming 505(b)(1) approval process, which consists of full reports of investigations of safety and effectiveness conducted by or for the applicant.
There may also be circumstances under which the FDA would not allow us to pursue a 505(b)(2) application. For instance, should the FDA approve a pharmaceutically equivalent product to our product candidates, we would no longer be able to use the 505(b)(2) regulatory pathway. In that case, it is the FDA’s policy that the appropriate submission would be an ANDA, for a
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generic version ofpublished. As a result, interim, “top-line”, initial, and preliminary data should be viewed with caution until the approved product. We may, however, not be able to immediately submit an ANDAfinal data are available. Adverse changes between preliminary, initial, “top-line” or have an ANDA approval made effective, as we could be blocked by others’ periods of patent and regulatory exclusivity protection.
Notwithstanding the approval of a number of products by the FDA under Section 505(b)(2), pharmaceutical companies and others have objected to the FDA’s interpretation of Section 505(b)(2). If the FDA’s interpretation of Section 505(b)(2) is successfully challenged, the FDA may change our policies and practices with respect to Section 505(b)(2) regulatory approvals, which could delay or even prevent the FDA from approving any NDA that we submit pursuant to the 505(b)(2) process. It is also not uncommon for a sponsor of an approved product to file a citizen petition with the FDA seeking to delay approval of, or impose additional approval requirements for, pending competing products. If successful, such petitions can significantly delay, or even prevent, the approval of the new product. However, even if the FDA ultimately denies such a petition, the FDA may substantially delay approval while it considers and responds to the petition.
If we cannot seek approval for OCU300 through the 505(b)(2) regulatory pathway, we may need to conduct additional clinical trials, provide additionalinterim data and information and meet additional standards for regulatory approval. If this were to occur, the time and financial resources required to obtain FDA approval for OCU300, and the complications and risks associated with approval of OCU300, would likely substantially increase. Even if we are allowed to pursue the 505(b)(2) regulatory pathway to FDA approval, we cannot assure you that OCU300 will receive the requisite approvals for commercialization. Moreover, our inability to pursue a 505(b)(2) applicationfinal data could result in new competitive products reaching the market more quickly than our product candidates, which could hurt our competitive position andsignificantly harm our business prospects.
Our use of the 505(b)(2) regulatory pathway may also subject us to the risk of patent infringement lawsuits or other regulatory actions that could prevent our submission of a marketing application for OCU300, or prevent the FDA making the approval of a marketing application effective. Applicants submitting NDAs under Section 505(b)(2) of the FDCA must provide a patent certification for the patents listed in the FDA’s list of Approved Drug Products with Therapeutic Equivalence Evaluations, commonly referred to as the Orange Book, for all reference listed drugs and for all brand name products identified in published literature upon which the 505(b)(2) application relies. The possible certifications are that (1) no patent information has been submitted to the FDA; (2) such patent has expired; (3) the date on which such patent expires; or (4) such patent is invalid or will not be infringed upon by the manufacture, use or sale of the drug product for which the application is submitted. If there are any listed patents for the reference listed or brand name products that we rely upon for our 505(b)(2) applications, the FDA may not approve our 505(b)(2) product candidates until all listed patents have expired, unless we challenge the listed patents through the last type of certification, also known as a paragraph IV certification, or otherwise indicates that we are not seeking approval of a patented method of use.
If we do challenge a listed patent through a paragraph IV certification, under the Hatch Waxman Act, the holder of the patents or NDAs that the 505(b)(2) application references may file a patent infringement lawsuit after receiving notice of the paragraph IV certification. Filing of a patent infringement lawsuit against the filer of the 505(b)(2) application within 45 days of the patent or NDA owner’s receipt of notice triggers a one time, automatic, 30-month stay of the FDA’s ability to make the 505(b)(2) NDA approval effective. In such a case, the FDA may not make the 505(b)(2) NDA approval effective until the earlier of 30 months from the receipt of the notice of the paragraph IV certification, the expiration of the patent, when the infringement case concerning each such patent was favorably decided in the applicant’s favor or settled, or such shorter or longer period as may be ordered by a court. Accordingly, we may invest a significant amount of time and expense in the development of one or more product candidates only to be subject to significant delay and patent litigation before such product candidates may be commercialized, if at all. In addition, a 505(b)(2) application approval may, in some cases, not be submitted, or may, in other cases, not be made effective until any existing non-patent regulatory exclusivities have expired or, if possible, are carved out from the label.
Companies that produce branded reference listed drugs routinely bring litigation against applicants that seek regulatory approval to manufacture and market new forms of their branded products. These companies often allege patent infringement or other violations of intellectual property rights as the basis for filing suit. Likewise, patent holders may bring patent infringement suits against companies that are currently marketing and selling such products. Litigation to enforce or defend intellectual property rights is often complex and often involves significant expense and can delay or prevent introduction or sale of our product candidates. If patents are held to be valid and infringed by our product candidates in a particular jurisdiction, we may be required to cease selling, relinquish or destroy existing stock, or pay monetary damages in that jurisdiction unless we can obtain a license from the patent holder. There may also be situations where we use our business judgment and decide to market and sell its approved products, notwithstanding the fact that allegations of patent infringement(s) have not been finally resolved by the courts, which is known as an “at risk launch.” The risk involved in doing so can be substantial because the remedies available to the owner of a patent for infringement may include, among other things, damages measured by the profits lost by the patent owner which may be greater than the profits earned by the infringer. In the case of willful infringement, such
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damages may be increased up to three times. An adverse decision in patent litigation could have a material adverse effect on our business, financial position, and results of operations and could cause the market value of our common stock to decline.
Changes in product candidate manufacturing or formulation may result in additional costs or delay.
As product candidates are developed through preclinical studies to late-stage clinical trials toward approval and commercialization, it is common that various aspects of the development program, such as manufacturing methods, manufacturing sites, and formulation, are altered along the way in an effort to optimize processes and results. Any of these changes could cause our product candidates to perform differently and affect the results of planned clinical trials or other future clinical trials conducted with the altered materials. Such changes may also require additional testing, FDA notification, or FDA approval. For instance, the FDA may require that we conduct a comparability study that evaluates the potential differences in the product candidate resulting from the change. Delays in designing and completing such a study to the satisfaction of the FDA could delay or preclude our development and commercialization plans, and the regulatory approval of our product candidates. We may also require the repetition of one or more clinical trials, increase clinical trial costs, delay approval of our product candidates and jeopardize our ability to commence product sales and generate revenue. Any of the foregoing could limit our future revenues and growth. Any changes would also require that we devote time and resources to manufacturing development and would also likely require additional testing and regulatory actions on its part, which may delay the development of our product candidates.
We may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success.
Because we have limited financial and managerial resources, we focus on research programs and product candidates that we identify for specific indications. As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. Our spending on current and future research and development programs and product candidates for specific indications may not yield any commercially viable products. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing, or other royalty arrangements in cases in which we would have been more advantageous for us to retain sole development and commercialization rights to such product candidate.
We may, in the future, conduct clinical trials for product candidates at sites outside the United States, and the FDA may not accept data from trials conducted in such locations.
We may, in the future, choose to conduct one or more of our clinical trials outside the United States. Although the FDA may accept data from clinical trials conducted outside the United States, acceptance of these data is in either case subject to the respective conditions imposed by the FDA. For example, the clinical trial must be well designed and conducted and be performed by qualified investigators in accordance with ethical principles, such as IRB or ethics committee approval and informed consent. The trial population must also adequately represent the U.S. population, and the data must be applicable to the U.S. population and U.S. medical practice in ways that the FDA deems clinically meaningful. In addition, while these clinical trials are subject to the applicable local laws (and therefore failure to comply with such laws could result in regulatory enforcement action), acceptance of the data by the FDA will be dependent upon its determination that the trials were conducted consistent with all applicable U.S. laws and regulations. If the FDA does not accept the data from any trial that we conduct outside the United States, it would likely result in the need for additional trials, which would be costly and time-consuming and could delay or permanently halt our development of the applicable product candidates. For example, the Phase 1, Phase 2, and Phase 3 clinical trials of COVAXIN for use in the adult population, and Phase 2/3 clinical trial for use in the pediatric population, were conducted in India. It is uncertain to what extent, if any, the FDA will consider data from the studies conducted with COVAXIN at clinical trial sites in India.
Failure to obtain marketing approval in international jurisdictions would prevent our product candidates from being marketed abroad.
In order to market and sell our products in jurisdictions outside the United States, we must obtain separate marketing approvals in international jurisdictions and comply with numerous and varying regulatory requirements. For example, we are currently pursuing approval for COVAXIN in Canada. The approval procedures vary among countries and the time required to obtain approval may differ substantially from that required to obtain FDA approval. The regulatory approval process outside the United States generally includes all of the risks associated with obtaining FDA approval. In addition, in many countries outside the United States, it is required that the product be approved for reimbursement before the product can be approved for sale in that country. OurThe clinical trials of our product candidates may not be sufficient to support an application for marketing approval outside the United States. Seeking foreign regulatory approval could result in difficulties and costs for us and require additional preclinical studies or clinical trials which could be costly and time consuming.
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We do not have any product candidates approved for sale in any jurisdiction, including in international markets, and we do not have experience in obtaining regulatory approval in international markets. We, or any eventual collaborators, may not obtain approvals from regulatory authorities outside the United States on a timely basis, if at all. Approval by the FDA does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one regulatory authority outside the United States does not ensure approval by regulatory authorities in other countries or jurisdictions or by the FDA. However, the failure to obtain approval in one jurisdiction may compromise our ability to obtain approval elsewhere. We may not be able to file for marketing approvals and may not receive necessary approvals to commercialize our products in any market.
Additionally, onin June 23, 2016, the electorate in the United Kingdom voted in favor of leaving the European Union,EU, commonly referred to as Brexit. OnIn March 29, 2017, the United Kingdom formally notified the European UnionEU of its intention to withdraw pursuant to Article 50 of the Lisbon Treaty. In October 2019, the United Kingdom and European UnionEU agreed upon the terms of the U.K.'s withdrawal from the E.U.EU in the form of a Withdrawal Agreement. The Withdrawal Agreement was ratified by the U.K Parliament, and the European
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Parliament in Brussels, in late January 2020, with the consequence that Brexit formally occurred on January 31, 2020. AnThe 11-month transition period will endended on December 31, 2020. Following the transition period, the United Kingdom is no longer a part of the single market and customs union of the EU. In December 2020, the United Kingdom and EU announced they had entered into a post-Brexit deal on certain aspects of trade and other strategic and political issues. However, this deal may not avoid all disruption resulting from Brexit. Since a significant proportion of the regulatory framework in the United Kingdom is derived from European Unionthe EU's directives and regulations, the withdrawal could materially impact the regulatory regime with respect to the approval of our product candidates in the United Kingdom or the European Union.EU. Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, would prevent us from commercializing our product candidates in the United Kingdom and/or the European UnionEU, and restrict itsour ability to generate revenue and achieve and sustain profitability. If any of these outcomes occur, we may be forced to restrict or delay efforts to seek regulatory approval in the United Kingdom and/or European UnionEU for our product candidates, which could significantly and materially harm our business.
We may be subject to fines, penalties, injunctions, or other enforcement actions if we are determined to be promoting the use of our products, if approved, for unapproved or “off-label” uses, resulting in damage to our reputation and business.
We must comply with requirements concerning advertising and promotion for any product candidates for which we obtain marketing approval. Promotional communications with respect to therapeutics are subject to a variety of legal and regulatory restrictions and continuing review by the FDA, Department of Justice, Department of Health and Human Services’ Office of Inspector General, state attorneys general, members of Congress, and the public. When the FDA or comparable foreign regulatory authorities issue regulatory approval for a product candidate, the regulatory approval is limited to those specific uses and indications for which a product is approved. We may not market or promote them for other indications and uses, referred to as off-label uses. We further must be able to sufficiently substantiate any claims that we make for our products, if approved, including claims comparing our products to other companies’ products and must abide by the FDA’s strict requirements regarding the content of promotion and advertising. While physicians may choose to prescribe products for uses that are not described in the product’s labeling and for uses that differ from those tested in clinical studies and approved by the regulatory authorities, we are prohibited from marketing and promoting the products for indications and uses that are not specifically approved by the FDA.
If we are found to have impermissibly promoted any of our product candidates, we may become subject to significant liability and government fines. The FDA and other agencies actively enforce the laws and regulations regarding product promotion, particularly those prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted a product may be subject to significant sanctions. The federal government has levied large civil and criminal fines against companies for alleged improper promotion and has enjoined several companies from engaging in off-label promotion. The FDA has also requested that companies enter into consent decrees of permanent injunctions under which specified promotional conduct is changed or curtailed.
In the United States, engaging in the impermissible promotion of our products, following approval, for off-label uses can also subject us to false claims and other litigation under federal and state statutes, including fraud and abuse and consumer protection laws. Such litigation can lead to civil and criminal penalties and fines, agreements with governmental authorities that materially restrict the manner in which we promote or distribute therapeutic products and do business through, for example, corporate integrity agreements, suspension or exclusion from participation in federal and state healthcare programs, suspension and debarment from government contracts, and refusal of orders under existing government contracts. These false claims statutes include the federal civil FCA, which allows any individual to bring a lawsuit against a company on behalf of the federal government ("qui tam" action) alleging submission of false or fraudulent claims, or causing others to present such false or fraudulent claims, for payment by a federal program such as Medicare or Medicaid. If the government decides to intervene and prevails in the lawsuit, the individual will share in the proceeds from any fines or settlement funds. If the government declines to intervene, the individual may pursue the case alone. These FCA lawsuits against sponsors of drugs and biologics have increased significantly in volume and breadth, leading to several substantial civil and criminal settlements, up to $3.0 billion, pertaining to certain sales practices and promoting off-label uses. In addition, FCA lawsuits may expose sponsors to follow-on claims by private payerspayors based on fraudulent marketing practices. This growth in litigation has increased the risk that companies
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will have to defend a false claim action, and pay settlements fines or restitution, as well as criminal and civil penalties, agree to comply with burdensome reporting and compliance obligations, and be excluded from Medicare, Medicaid, or other federal and state healthcare programs. If we do not lawfully promote our approved products, if any, we may become subject to such litigation and, if we do not successfully defend against such actions, those actions may have a material adverse effect on our business, financial condition, results of operations, and prospects.
In the United States, the distribution of product samples to physicians must further comply with the requirements of the U.S. Prescription Drug Marketing Act,PDMA, and the promotion of biologic and pharmaceutical products are subject to additional FDA requirements and restrictions on promotional statements. If the FDA determines that our promotional activities violate our regulations and policies pertaining
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to product promotion, it could request that we modify our promotional materials or subject us to regulatory or other enforcement actions, including issuance of warning letters or untitled letters, suspension or withdrawal of an approved product from the market, requests for recalls, payment of civil fines, disgorgement of money, imposition of operating restrictions, injunctions or criminal prosecution, and other enforcement actions. These regulatory and enforcement actions could significantly harm our business, financial condition, results of operations, and prospects.
Even if our product candidates receive regulatory approval, we will be subject to ongoing obligations and continued regulatory review, which may result in significant additional expense.
Any product candidate for which we obtain marketing approval will be subject to extensive and ongoing requirements of and review by the FDA and other regulatory authorities, including requirements related to the manufacturing processes, post-approval clinical data, labeling, packaging, distribution, adverse event reporting, storage, recordkeeping, export, import, advertising, marketing, and promotional activities for such product. These requirements further include submissions of safety and other post-marketing information, including manufacturing deviations and reports, registration and listing requirements, the payment of annual fees, continued compliance with cGMPscGMP or cGMP-requirements relating to manufacturing, quality control, quality assurance, and corresponding maintenance of records and documents, requirements regarding the distribution of samples to physicians and GCPs, for any clinical trials that we conduct post-approval.
Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses and populations for which the product may be marketed or to the conditions of approval, including significant safety warnings, such as boxed warnings, contraindications, and precautions that are not desirable for successful commercialization. Any approved products may also be subject to a REMS that render the approved product not commercially viable or other post-market requirements, such as Phase 4 studies, or restrictions. If the FDA or comparable foreign regulatory authorities become aware of new safety information after the approval of any of our product candidates, they may, among other actions, withdraw approval, require labeling changes or establishment of a REMS or similar strategy, impose significant restrictions on a product’s indicated uses or marketing, or impose ongoing requirements for potentially costly post-approval studies or post-market surveillance.
We and any of our collaborators, including our contract manufacturer, could be subject to periodic unannounced inspections by the FDA to monitor and ensure compliance with cGMPscGMP and other FDA regulatory requirements. Application holders must further notify the FDA, and depending on the nature of the change, obtain FDA pre-approval for product and manufacturing changes.
In addition, later discovery of previously unknown adverse events or that the product is less effective than previously thought or other problems with our products, manufacturers, or manufacturing processes, or failure to comply with regulatory requirements both before and after approval, may yield various results, including:
restrictions on manufacturing, distribution, or marketing of such products;
restrictions on the labeling, including restrictions on the indication or approved patient population, and required additional warnings, such as black box warnings, contraindications, and precautions;
modifications to promotional pieces;
issuance of corrective information;
requirements to conduct post-marketing studies or other clinical trials;
clinical holds or termination of clinical trials;
requirements to establish or modify a REMS, or a comparable foreign authority may require that we establish or modify a similar strategy;
liability for harm caused to patients or subjects;
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reputational harm;
warning, untitled, Form 483s, or cyber letters;
suspension of marketing or withdrawal or recall of the products from the market;
regulatory authority issuance of safety alerts, Dear Healthcare Provider letters, press releases, or other communications containing warnings or other safety information about the product;
refusal to approve pending applications or supplements to approved applications that we submit;
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fines, restitution, or disgorgement of profits or revenues;
suspension or withdrawal of marketing approvals;
refusal to permit the import or export of our products;
product seizure or detention;
FDA debarment, suspension and debarment from government contracts, and refusal of orders under existing government contracts, exclusion from federal healthcare programs, consent decrees, or corporate integrity agreements; or
injunctions or the imposition of civil or criminal penalties, including imprisonment.
Any of these events could prevent us from achieving or maintaining market acceptance of the particular product candidate, if authorized or approved, or could substantially increase the costs and expenses of developing and commercializing such product, which in turn could delay or prevent us from generating significant revenues from its sale. Any of these events could further have other material and adverse effects on our operations and business and could adversely impact our stock price and could significantly harm our business, financial condition, results of operations, and prospects.
The FDA’s policies may change and additional government regulations may be enacted that could prevent, limit, or delay regulatory approval of our product candidates, that could limit the marketability of our product candidates, or that could impose additional regulatory obligations on us. Changes in medical practice and standard of care may also impact the marketability of our product candidates.candidates, if authorized or approved.
We will need to obtain FDA approval of any proposed product names, and any failure or delay associated with such approval may adversely affect itsour business.
Any name we intend to use for our product candidates will require approval from the FDA regardless of whether we have secured a formal trademark registration from the U.S. Patent and Trademark Office (the “USPTO”).USPTO. The FDA typically conducts a review of proposed product names, including an evaluation of the potential for confusion with other product names. The FDA may also object to a product name if it believes the name inappropriately implies medical claims or contributes to an overstatement of efficacy. If the FDA objects to any of our proposed product names, we may be required to adopt alternative names for our product candidates. If we adopt alternative names, we would lose the benefit of any existing trademark applications for such product candidate and may be required to expend significant additional resources in an effort to identify a suitable product name that would qualify under applicable trademark laws, not infringe upon the existing rights of third-parties, and be acceptable to the FDA. We may be unable to build a successful brand identity for a new trademark in a timely manner or at all, which would limit our ability to commercialize our product candidates.
In the future we may seek FDA designations to facilitate product candidate development, such as fast track or breakthrough designation. We may not receive any such designations orcandidates, if we receive such designations they may not lead to faster development or regulatory review or approval and it does not increase the likelihood that our product candidates will receive marketing approval.
In the future, we may seek product designations, such as fast track or breakthrough designation, which are intended to facilitate the development or regulatory review or approval process for product candidates. Receipt of such a designation is within the discretion of the FDA. Accordingly, even if we believe one of our product candidates meets the criteria for a designation, the FDA may disagree. In any event, the receipt of such a designation for a product candidate may not result in a faster development process, review, or approval compared to product candidates considered for approval under conventional FDA procedures and does not assure ultimate marketing approval by the FDA. In addition, the FDA may later decide that the product candidates no longer meet the designation conditions, in which case any granted designations may be revoked.
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OCU300 and OCU400 have received ODD from the FDA. However, there is no guarantee that we will be able to maintain this designation, receive this designation for any of our other product candidates, or receive or maintain any corresponding benefits, including periods of exclusivity.
We have obtained from the FDA Office of Orphan Products ODD for OCU300 for oGVHD and OCU400 for NR2E3 mutation-associated retinal diseases and CEP290 mutation-associated retinal diseases. We were the first company to receive ODD for oGVHD from the FDA. We may also seek ODD for its other product candidates, as appropriate. While ODD does provide us with certain advantages, it neither shortens the development time or regulatory review time of a product candidate nor gives the product candidate any advantage in the regulatory review or approval process.
Generally, if a product candidate with ODD subsequently receives marketing approval before another product considered by the FDA to be the same, for the same orphan indication, the product is entitled to a period of marketing exclusivity, which precludes the EMA or the FDA from approving another marketing application for the same drug or biologic for the same indication for a specified time period. The applicable period is seven years in the United States and 10 years in Europe. The European exclusivity period can be reduced to six years if a product no longer meets the criteria for ODD or if the product is sufficiently profitable so that market exclusivity is no longer justified.
We may not be able to obtain any future ODDs that we apply for, ODDs do not guarantee that we will be able to successfully develop our product candidates, and there is no guarantee that we will be able to maintain any ODDs that we receive. For instance, ODDs may be revoked if the FDA finds that the request for designation contained an untrue statement of material fact or omitted material information, or if the FDA finds that the product candidate was not eligible for designation at the time of the submission of the request.
Moreover, even if we are able to receive and maintain ODDs, we may ultimately not receive any period of regulatory exclusivity if our product candidates are approved. For instance, we may not receive orphan product regulatory exclusivity if the indication for which we receive FDA approval is broader than the ODD. Orphan exclusivity may also be lost for the same reasons that ODD may be lost. Orphan exclusivity may further be lost if we are unable to assure a sufficient quantity of the product to meet the needs of patients with the rare disease or condition.
Even if we obtain orphan exclusivity for any of our current or future product candidates, that exclusivity may not effectively protect the product from competition as different products can be approved for the same condition or products that are the same as ours can be approved for different conditions. Even after an orphan product is approved, the FDA can also subsequently approve a product containing the same principal molecular features for the same condition if the FDA concludes that the later product is clinically superior by means of greater effectiveness, greater safety, or providing a major contribution to patient care. The FDA may further grant ODD to multiple sponsors for the same compound or active molecule and for the same indication. If another sponsor receives FDA approval for such product before we do, we would be prevented from launching our product in the United States for the orphan indication for a period of at least seven years unless we can demonstrate clinical superiority. Moreover, third-party payors may reimburse for products off-label even if not indicated for the orphan condition.
Risks Related to the Commercialization of Our Product Candidates
We have no prior experience in the marketing, sale, and distribution of pharmaceutical or biologic and pharmaceutical products and there can be no assurance that our products, if authorized or approved, will be successfully commercialized.
We have no prior experience in the marketing, sale, and distribution of biologic and pharmaceutical products, and there are significant risks involved in the building and managing of a commercial infrastructure. The establishment and development of commercial capabilities, including compliance plans, to market any products we may develop will be expensive and time consuming and could delay any product launch, and we may not be able to successfully develop this capability. We will have to compete with other biologic, pharmaceutical and biotechnology companies to recruit, hire, train, manage, and retain marketing and sales personnel. Factors that may inhibit our efforts to commercialize our product candidates include:
the inability to recruit, train, manage, and retain adequate numbers of effective sales and marketing personnel;
the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe our product candidates;
our inability to effectively oversee a geographically dispersed sales and marketing team;
the costs associated with training sales and marketing personnel on legal and regulatory compliance matters and monitoring their actions;
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an inability to secure adequate coverage and reimbursement by government and private health plans;
reduced realization on government sales from mandatory discounts, rebates and fees, and from price concessions to private health plans and pharmacy benefit managers necessitated by competition for access to managed formularies;
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the clinical indications for which the products are approved and the claims that we may make for the products;
limitations or warnings, including distribution or use restrictions, contained in the products’ approved labeling;
any distribution and use restrictions imposed by the FDA or to whichHealth Canada, including those that we may agree to as part of a mandatory REMS or voluntary risk management plan;
liability for sales or marketing personnel who fail to comply with the applicable legal and regulatory requirements;
the lack of complementary products to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines; and
unforeseen costs and expenses associated with creating an independent sales and marketing organization or engaging a contract sales organization.
Should any of the foregoing occur, we may not be successful in commercializing any product candidates for which we receive marketing approval.
We face significant competition from other biologic, pharmaceutical and biotechnology companies, academic institutions, government agencies, and other research organizations. Our operating results will suffer if we fail to compete effectively.
The development and commercialization of new vaccines and therapeutic products is highly competitive. We face competition with respect to our current product candidates and will face competition with respect to any product candidates that we may seek to develop or commercialize in the future, from major biologic and pharmaceutical companies, specialty biologic and pharmaceutical companies, and biotechnology companies worldwide. Potential competitors also include academic institutions, government agencies, and other public and private research organizations that conduct research, seek patent protection, and establish collaborative arrangements for research, development, manufacturing, and commercialization.
We face, and will continue to face, intense competition from companies as well as institutions pursing research and development of vaccines, technologies, drugs, or other therapies that would compete with COVAXIN, if authorized and approved in the United States and Canada. Our competitors have and may continue to develop and commercialize vaccines or effective therapies or other treatments for COVID-19 more rapidly or more effectively than us. The competitive landscape of COVID-19 vaccines and therapies has been rapidly developing since the beginning of the COVID-19 pandemic and includes competitors such as Pfizer Inc./BioNTech SE, Moderna, Inc., Johnson & Johnson/Janssen Biotech, Inc., AstraZeneca PLC, Novavax, Inc., and Medicago Inc. The vaccine developed by Pfizer Inc./BioNTech SE has been granted full approval by the FDA for ages 16 years and older and has been granted EUA for ages five to 16 years. The vaccine developed by Moderna, Inc. has been granted full approval by the FDA for ages 18 years and older. The vaccine developed by Johnson & Johnson/Janssen Biotech has been granted EUA by the FDA for ages 18 years and older. Vaccines developed by Pfizer Inc./BioNTech SE, Moderna, Inc., Johnson & Johnson/Janssen Biotech, Inc., AstraZeneca PLC, Novavax, Inc., and Medicago Inc. have been authorized by Health Canada. We are also aware of other pharmaceutical companies that are working on inactivated virus-based COVID-19 vaccines. Furthermore, the FDA has authorized and many companies are developing therapeutics to treat COVID-19. The FDA requires us to conduct clinical trials for the approval of COVAXIN and enrollment in such trials may be impacted given the commercial availability of other approved or authorized vaccines. The success or failure of other vaccines, or perceived success or failure, may adversely impact our ability to obtain any future funding for our joint COVID-19 vaccine development efforts or for us to ultimately commercialize any vaccine candidate, if authorized or approved. In addition, we may not be able to compete effectively if our product candidate does not satisfy government procurement requirements with respect to biodefense products. If existing vaccines in the market or if competitors develop and commercialize additional COVID-19 vaccines before we can complete regulatory review and obtain an EUA or regulatory approval for COVAXIN, or if they develop and commercialize one or more COVID-19 vaccines that are safer, more effective, have fewer or less severe side effects, have broader market acceptance, are more convenient, or are less expensive than COVAXIN, our business, financial condition, and results of operations would be materially adversely affected.
The development and commercialization of gene therapy and biologic products is highly competitive. We are aware of several companies focusing on gene therapies for various ophthalmic indications including Applied Genetic Technologies Corporation, Editas Medicine, Allergan, Inc., Adverum Biotechnologies, MeiraGTx, IVERIC bio, Inc., Applied Genetic Technologies CorporationMeiraGTx Holdings plc, Nanoscope Therapeutics, Inc., ProQR Therapeutics N.V., REGENXBIO Inc., Novartis AG, and Roche Group, which acquired Spark Therapeutics, Inc. Luxturna™ (Spark Therapeutics)Spark Therapeutics, Inc.'s product Luxturna, which is currently the only gene therapy approved for an IRDto treat IRDs in the United States, addressingaddresses only one out of 150 known mutations of the RPE65 gene.gene mutations. The RPE65 gene represents just one of more than 175 mutations linked to RP and LCA. Companies that may compete with our OCU200 product candidate include theF. Hoffmann-La Roche Group,AG (Roche), Regeneron Pharmaceuticals, Inc., Graybug Vision, Inc., Kodiak Sciences Inc., and Novartis AG. F. Hoffmann-La Roche AG, Regeneron Pharmaceuticals, Inc., and Novartis AG which have marketed
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anti-VEGF products. We are also aware of other companies that are working on therapies for the whole eye, including Santen, Inc. and Ocular Therapeutix.
Our product candidates will target markets that are already served by a variety of competing products. Many of these existing products have achieved widespread acceptance among clinicians, patients, and payors.
Our ability to compete may further be affected in many cases by insurers or other third-party payors, particularly Medicare, seeking to encourage the use of generic or biosimilar products. Many of the products that will compete with our product candidates, if approved, are available on a generic basis, and our product candidates may not demonstrate sufficient additional clinical benefits to clinicians, patients or payors to justify a higher price compared to generic products. Additional competing products are expected to become available on a generic basis over the coming years. In many cases, insurers or other third-party payors, particularly Medicare, seek to encourage the use of generic products.
Our commercial opportunities could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we may develop. Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for our products, which could result in our competitors establishing a strong market position before we are able to enter the market. They may obtain patent protection or other intellectual property rights that allow them to develop and commercialize their products before us and could limit our ability to develop or commercialize our product candidates.
In addition, our ability to compete may be affected in many cases by insurers or other third-party payors' coverage decisions, particularly Medicare, seeking to encourage the use of generic or biosimilar products. Many of the products that will compete with our product candidates, if approved, are available on a generic basis, and our product candidates may not demonstrate sufficient additional clinical benefits to clinicians, patients, or payors coverage decisions.to justify a higher price compared to generic products. Additional competing products are expected to become available on a generic basis over the coming years. In many cases, insurers or other third-party payors, particularly Medicare, seek to encourage the use of generic products.
Many of the companies against which we are competing or against which we may compete in the future have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical
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trials, obtaining regulatory approvals, and marketing approved products than we do. Mergers and acquisitions in the biologic, pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors. Early stageEarly-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These third parties compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.
If we are unable to establish effective marketing and sales capabilities or enter into agreements with third parties to market and sell our product candidates, if they are authorized or approved, we may be unable to generate product revenues.
We currently do not have a commercial infrastructure for the marketing, sale, and distribution of biologic and pharmaceutical products. If authorized or approved, in order to commercialize itsour products, we must build our marketing, sales, and distribution capabilities or make arrangements with third parties to perform these services. If we do not establish sales, marketing, and distribution capabilities successfully, either on our own or in collaboration with third parties, we will not be successful in commercializing any product candidates for which we receive marketing approval.
Subject to FDAregulatory authorization or approval of any of itsour product candidates, we may build a commercial team of specialty sales and marketing representatives in support of OCU300 and possibly other preclinicalour product candidates that we develop in the United States or Canada, if and when they are authorized or approved, as well as distribution capabilities. There are risks involved with us establishing our own sales, marketing, and distribution capabilities. Recruiting and training a sales force is expensive and time-consuming, particularly to the extent that we seek to commercialize any product, if authorized or approved, for an indication, such as wet AMD, that has a large patient population significantly larger than those addressed by its current lead product candidate, and could delay any product launch.population. We will be competing with many companies that currently have extensive and well-funded marketing and sales operations to recruit, hire, train, and retain marketing and sales personnel. Further, we may underestimate the size of the sales force required for a successful product launch and may need to expand itsour sales force earlier and at a higher cost than it anticipated.we anticipate. If the commercial launch of our product candidates, if authorized or approved, for which we recruit a sales force and establish marketing capabilities is delayed or does not occur for any reason, we would have prematurely or unnecessarily incurred these commercialization expenses. This may be costly, and our investment would be lost if itwe cannot retain or reposition our sales and marketing personnel.
We may also or alternatively decide to collaborate with a third-party or contract sales organization to commercialize any authorized or approved product candidates, in which event, our ability to generate product revenues may be limited. By example, we may retain commercialization rights to OCU300 or utilize a variety of collaboration, distribution and other marketing arrangements with one or more third parties to commercialize OCU300. Our product revenues and our profitability, if any, under any such third-party collaboration, distribution, or other marketing arrangements are likely to be lower than if we were to market, sell, and distribute OCU300the applicable product candidate entirely ourselves. We may not be successful in entering into arrangements with third parties to sell, market, and distribute itsour product candidates or may be unable to do so on terms that are favorable to us. In addition, we would have less control over the sales efforts of any other third parties involved in our commercialization efforts and any of them may fail to devote the necessary resources and attention to sell and market our product candidates effectively. We could also be held liable if theysuch third parties failed to comply with applicable legal or regulatory requirements.
In the event we are unable to develop a team of marketing and sales representatives or to establish an effective third-party contractual relationship for such services, we may not be able to commercialize our product candidates, if authorized or
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approved, which would limit our ability to generate product revenues. Even if we are able to effectively hire a sales force and develop a marketing and sales infrastructure, our sales force and marketing teams may not be successful in commercializing our product candidates.

If our product candidates do not achieve broad market acceptance, the revenues that we generate from their sales will be limited.
Even if our product candidates are authorized or approved by the appropriate regulatory authorities for marketing and sale, they may not gain acceptance among physicians, patients, third-party payors, and others in the medical community. Physicians are often reluctant to switch their patients and patients may be reluctant to switch from existing therapies even when new and potentially more effective or safer treatments enter the market. We have never commercialized a product candidate for any indication, and efforts to educate the medical community and third-party payors on the benefits of our product candidates may require significant resources and may not be successful. With respect to our product candidates being developed based on our modifier gene therapy platform, market acceptance may also be constrained by ethical, social, and legal concerns about gene therapy and genetic research, which could result in additional regulations restricting or prohibiting the products and processes we may use. The novelty of the technology and any negative publicity surrounding adverse events associated with gene therapy may also prevent the medical community, patients, and third-party payors from accepting gene therapy products in general, and our product candidates in particular, as medically useful, cost-effective, and safe.
Market acceptance of our product candidates by the medical community, patients, and third-party payors will depend on a number of factors, some of which are beyond our control. If any product candidates for which we obtain regulatory approval does not gain an adequate level of market acceptance, it may not generate significant product revenues or become profitable.
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We can provide no assurance that our lead product candidate, OCU300 for the treatment of oGVHD, will achieve market acceptance. While there are no drugs currently approved in the United States for treatment of oGVHD, there are several product candidates in clinical development for treatment of oGVHD in the United States. It is possible that doctors may rely on these treatments rather than OCU300, if and when it is approved for marketing by the FDA.
It is also possible that physicians may prescribe other less expensive brimonidine tartrate products off label rather that prescribe OCU300. As a result, clinicians, patients and third-party payors may choose to rely on products other than our product candidates for the treatment of ocular redness and discomfort in patients with oGVHD.
The degree of market acceptance of any of our product candidates will depend on a number of factors, including:
the efficacy of our product candidates;
the prevalence and severity of adverse events associated with such product candidates;
interactions of our products with other medicines patients are taking and any restrictions on the use of our products together with other medications;
the clinical indications for which the products are approved and the approved claims that we may make for the products;
limitations or warnings contained in the product’s FDA-approved labeling, including potential limitations or warnings for such product candidates that may be more restrictive than other competitive products;
changes in the standard of care for the targeted indications for such product candidates, which could reduce the marketing impact of any claims that we could make following FDA approval, if obtained;
the relative convenience and ease of administration of such product candidates;
cost of treatment versus economic and clinical benefit in relation to alternative treatments or therapies;
the availability of third-party formulary coverage and adequate coverage or reimbursement by third parties, such as insurance companies and other healthcare payors, and by government healthcare programs, including Medicaid and particularly by Medicare in light of the prevalence of DEDretinal diseases in persons over age 55;
the price concessions required by third party payors to obtain coverage;
the extent and strength of our manufacturing, marketing, and distribution of such product candidates;
the safety, efficacy, and other potential advantages over, and availability of, alternative treatments already used or that may later be approved;
distribution and use restrictions imposed by the FDA with respect to such product candidates or to which we agree as part of a REMS or voluntary risk management plan;
the timing of market introduction of such product candidates, as well as competitive products;
its ability to offer such product candidates for sale at competitive prices;
the extent of availability of generic or biosimilar versions of any products that compete with any of our product candidates and the extent to which they are offered at a substantially lower price than we expect to offer for our product candidates, if authorized or approved;
the extent and strength of our third-party manufacturer and supplier support;
the approval of other new products;
adverse publicity about the product or favorable publicity about competitive products; and
potential product liability claims.
With respect to our product candidates being developed based on our modifier gene therapy platform, market acceptance may also be constrained by ethical, social and legal concerns about gene therapy and genetic research, which could result in additional regulations restricting or prohibiting the products and processes we may use. The novelty of the technology and any negative publicity surrounding adverse events associated with gene therapy may also prevent the medical community, patients, and third-party payors from accepting gene therapy products in general, and our product candidates in particular, as medically useful, cost-effective and safe.
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If the market opportunities for our product candidates are smaller than we believe, our revenue may be adversely affected and our business may suffer.
The potential market opportunities for our product candidates are difficult to precisely estimate. Our estimates of the potential market opportunities are predicated on many assumptions, which may include industry knowledge and publications, third-party
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research reports, and other surveys, some of which we may have commissioned. Industry publications and third-party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. While we believe these industry publications and third-party research, surveys, and studies are reliable, we have not independently verified such data. In addition, while we believe that our internal assumptions are reasonable, these assumptions involve the exercise of significant judgment on the part of our management, are inherently uncertain, and the reasonableness of these assumptions has not been assessed by an independent source. If any of the assumptions proves to be inaccurate, the actual markets for our product candidates could be smaller than our estimates of the potential market opportunities, and as a result, our product revenue may be limited, and it may be more difficult for us to achieve or maintain profitability.
If third-party payors do not reimburse patients for OCU300 or our other products candidates, if authorized or approved, or if reimbursement levels are set too low for us to sell our product candidates at a profit, our ability to successfully commercialize our product candidates, if authorized or approved, and our results of operations will be harmed.
Our ability to successfully commercialize OCU300 and our other product candidates, if authorized or approved, will depend in part on the extent to which coverage and adequate reimbursement for our product candidates will be available in a timely manner from third-party payors, including governmental healthcare programs such as Medicare and Medicaid, commercial health insurers, and managed care organizations. This is particularly true with respect to OCU200, our novel biologic product candidates designed to treat DED,candidate, in the case of wet AMD, which is most prevalent in persons over age 55. Government authorities and other third-party payors, such as private health insurers and health maintenance organizations, determine which medications they will cover and establish reimbursement levels. Reimbursement decisions by particular third-party payors depend upon a number of factors, including each third-party payor’s determination that use of a product is:
a covered benefit under its health plan;
appropriate and medically necessary for the specific condition or disease;
cost effective; and
neither experimental nor investigational.
Obtaining coverage and reimbursement approval for our product candidates from government authorities or other third-party payors may be a time consuming and costly process that could require us to provide supporting scientific, clinical, and cost-effectiveness data, including expensive pharmacoeconomic studies beyond the data required to obtain marketing approval, for the use of each product candidate to each government authority or other third-party payor. We may not be able to provide data sufficient to gain acceptance with respect to coverage and reimbursement.
Third-party payors may deny reimbursement for covered products if they determine that a medical product was not used in accordance with cost-effective diagnosis methods, as determined by the third-party payor, or was used for an unapproved indication. Third-party payors also may refuse to reimburse for procedures and devices deemed to be experimental. Third-party payors may also limit coverage to specific products on an approved list, or formulary, which might not include all of the approved products for a particular indication.
Increasingly, third-party payors are also requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products. These third-party payors could also impose price controls and other conditions that must be met by patients prior to providing coverage for use of our product candidates, if approved. For example, insurers may establish a “step-edit” system that requires a patient to first use a lower price alternative product prior to becoming eligible for reimbursement of a higher price product.
Third-party payors are increasingly attempting to contain healthcare costs by limiting both coverage and the level of reimbursement for medical products and services. The process for determining whether a payor will provide coverage for a product may be separate from the process forof setting the price or reimbursement rate that the payor will pay for the product once coverage is approved. Levels of reimbursement may also decrease in the future, and future legislation, regulation, or reimbursement policies of third-party payors may adversely affect the demand for and reimbursement available for our product candidates, which in turn, could negatively impact pricing. If patients are not adequately reimbursed for our product candidates,
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if approved, they may reduce or discontinue purchases of it, which would result in a significant shortfall in achieving revenue expectations and negatively impact our business, prospects, and financial condition.
Our product candidates may face competition sooner than anticipated.
Both our drug and biologic product candidates, if approved, may face competition from other products that are the same as or similar to our product candidates. If the FDA or comparable foreign regulatory authorities approve generic or similar versions of any of our product candidates that receive marketing approval, or such authorities do not grant our products appropriate periods of regulatory exclusivity before approving generic or similar versions of our products, the sales of our products could be adversely affected.
In the case of our drug product candidates, once an NDA is approved, the product will become a “reference listed drug” in the FDA’s Orange Book. Other applicants may then seek approval of generic versions of our products through submission of ANDAs in the United States. In support of an ANDA, a generic applicant would not need to conduct full clinical studies. Rather, the applicant generally must show that its product has the same active ingredient(s), dosage form, strength, route of administration, conditions of use and labeling, among other commonalities, as the reference listed drug and that the generic version is bioequivalent to the reference listed drug, meaning it is available at the site of action at the same rate and to the same extent as the reference listed drug. Generic products may be significantly less costly to bring to market than the reference listed drug and companies that produce generic products are generally able to offer them at lower prices and are generally preferred by third party payors. As a result, the FDA, the administration and Congress have recently taken steps to encourage increased generic drug competition in the market in an effort to bring down drug costs. Following the introduction of a generic drug, a significant percentage of the sales of any branded product or reference listed drug is typically lost to the generic product. Moreover, in addition to generic competition, we could face competition from other companies seeking approval of drug products that are similar to its products using the 505(b)(2) regulatory pathway. Such applicants may be able to rely on our product candidates, if approved, or other approved drug products or published literature to develop drug products that are similar to ours. The introduction of a drug product similar to our product candidates could expose us to increased competition.
Any ANDA or 505(b)(2) applicants seeking to rely upon any of our product candidates, if such product candidates are approved, would need to submit patent certification statements with their applications for any of our patents that are listed in the FDA’s Orange Book. There are detailed rules and requirements regarding the patents that may be submitted to the FDA for listing in the Orange Book. We may be unable to obtain patents covering our product candidates that contain one or more claims that satisfy the requirements for listing in the Orange Book. If one of our product candidates is approved and a patent covering that product candidate is not listed in the Orange Book, an ANDA or 505(b)(2) applicant would not have to submit a patent certification with regard to such patent to the FDA, in which case, we would not receive the protections provided by the Hatch Waxman Act.
Moreover, if an ANDA or 505(b)(2) applicant files a paragraph IV challenge to any patents that we may list in the FDA’s Orange Book and if we do not file a patent infringement lawsuit within 45 days of receiving notice of a paragraph IV certification, the ANDA or 505(b)(2) applicant would not be subject to a 30-month stay. If we did file such an action, the litigation or other proceedings to enforce or defend its intellectual property rights would likely be complex in nature, may be expensive and time consuming, may divert its management’s attention from its core business, and may result in unfavorable results that could adversely impact our ability to prevent third parties from competing with our products. Accordingly, upon approval of our product candidates We may be subject to generic competition or competition from similar products, or may need to commence patent infringement proceedings, which would divert our resources.
We currently anticipate that we may be eligible for three years of non-patent marketing exclusivity in the United States for OCU300 if it is approved. These three years, however, would only protect our modifications in formulation or approved uses in comparison to the reference listed drug, would not prevent other companies from submitting full NDAs, and would not prevent physicians from prescribing other products off-label or third-party payors from reimbursing for them.
If the FDA licenses OCU400, OCU410 or OCU200, we may face competition from biosimilar products.
The enactment of the Biologics Price Competition and Innovation Act of 2009 ("BPCIA"), as part of the ACA, created an abbreviated pathway for the approval of biosimilar and interchangeable biological products. The abbreviated regulatory pathway establishes legal authority for the FDA to review and approve biosimilar biologics, including the possible designation of a biosimilar as “interchangeable” based on its similarity to an existing brand product. As in the generic drug product space, the FDA and the administration are taking steps to encourage increased biosimilar competition in the market in an effort to bring down the cost of biologic products, including actions aimed at deterring anti-competitive business practices. If another company pursues approval of a product that is biosimilar to any biologic product for which we receive FDA approval, we may
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need to pursue costly and time-consuming patent infringement actions, which may include certain statutorily specified regulatory steps before an infringement action may be brought. Biosimilar applicants may also be able to bring an action for declaratory judgment concerning our patents, requiring that we spend time and money defending the action.
Under the BPCIA, an application for a biosimilar product cannot be approved by the FDA until 12 years after the original branded product was approved under a BLA. Certain changes, however, and supplements to an approved BLA, and certain subsequent applications filed by the same sponsor, manufacturer, licensor, predecessor in interest, or other related entity do not qualify for the 12-year exclusivity period. Moreover, there have been efforts to decrease this period of exclusivity to a shorter timeframe. Future proposed budgets, international trade agreements and other arrangements or proposals may affect periods of exclusivity. Our biologic product candidates may qualify for the BPCIA’s 12-year period of exclusivity, however, there is a risk that the FDA will not consider our product candidates to be reference products for competing products, potentially creating the opportunity for biosimilar competition sooner than anticipated. Additionally, this period of regulatory exclusivity does not apply to companies pursuing regulatory approval via their own traditional BLA, rather than via the abbreviated pathway. Moreover, the extent to which a biosimilar, once approved, will be substituted for any one of our reference products in a way that is similar to traditional generic substitution for non-biological products is not yet clear, and will depend on a number of marketplace and regulatory factors that are still developing. It is also possible that payers will give reimbursement preference to biosimilars, even over reference biologics, absent a determination of interchangeability.
For certain of our drug and biologic product candidates, we may seek pediatric exclusivity, which is another type of non-patent marketing exclusivity in the United States. This is not a patent term extension, but it effectively extends the regulatory period during which the FDA cannot approve another application. We cannot provide any assurance that pediatric exclusivity will be obtained for any of our product candidates.
To the extent we do not receive any anticipated periods of regulatory exclusivity or to the extent FDA or foreign regulatory authorities approve any biosimilar, interchangeable, generic, similar, or other competing products, our business would be adversely impacted. Competition that our products may face from generic, biosimilar, interchangeable, similar, or other competing products could materially and adversely impact our future revenue, profitability, and cash flows and substantially limit our ability to obtain a return on the investments we have made in those product candidates.
If we obtain approval to commercialize our product candidates outside of the United States, a variety of risks associated with international operations could materially adversely affect our business.
If any of our product candidates are approved for commercialization, we may enter into agreements with third parties to market them on a worldwide basis or in more limited geographical regions. We expect that we will be subject to additional risks related to conducting marketing and sales activities in international jurisdictions and entering into international business relationships, including:
different regulatory requirements for approval of drugs and biologics in foreign countries;
the potential for so-called parallel importing, which is what happens when a local seller, faced with high or higher local prices, opts to import goods from a foreign market (with low or lower prices) rather than buying them locally;
challenges enforcing our contractual and intellectual property rights, especially in those foreign countries that do not respect and protect intellectual property rights to the same extent as the United States;
the need to seek additional patent approvals, licenses to patents held by third parties, and/or face claims of infringing third-party patent rights;
unexpected changes in tariffs, trade barriers, and regulatory requirements;
economic weakness, including inflation or political instability in particular foreign economies and markets;
compliance with tax, employment, immigration, and labor laws for employees living or traveling abroad;
foreign currency fluctuations, which could result in increased operating expenses and reduced revenues, and other obligations incident to doing business in another country;
difficulties staffing and managing foreign operations;
workforce uncertainty in countries where labor unrest is more common than in the United States;
potential liability under the FCPA, the U.K. Bribery Act 2010 (the "Bribery Act"), or other comparable foreign regulations;
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production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad; and
business interruptions resulting from geopolitical actions, including war and terrorism, or natural disasters including pandemics or other outbreaks of infectious disease, earthquakes, typhoons, floods, and fires.
These and other risks associated with international operations may materially adversely affect our ability to attain or maintain profitable operations.
We face potential product liability exposure, and if successful claims are brought against us, we may incur substantial liability for our product candidates and may have to limit our commercialization.
The use of our product candidates in clinical trials, and the sale of any of our product candidates for which we obtain regulatory approval, exposes us to the risk of product liability claims. Product liability claims might be brought against us by consumers, healthcare providers, pharmaceutical companies or others selling or otherwise coming into contact with our products. For example, we may be sued if any product candidate we develop allegedly causes injury or is found to be otherwise unsuitable during clinical testing, manufacturing, marketing or sale. Any such product liability claims may include allegations of defects in manufacturing, defects in design, a failure to warn of dangers inherent in the product, negligence, strict liability or a breach of warranties. Claims could also be asserted under state consumer protection acts. If we cannot successfully defend ourself against these claims, we will incur substantial liabilities or be required to limit development or commercialization of our product candidates. Even successful defense would require significant financial and management resources. Regardless of merit or eventual outcome, liability claims may result in:
loss of revenue from decreased demand for our products and/or product candidates;
impairment of our business reputation or financial stability;
costs of related litigation;
substantial monetary awards to patients or other claimants;
exhaustion of any available insurance and our capital resources;
diversion of management attention;
withdrawal of clinical trial participants and potential termination of clinical trial sites or entire clinical programs;
the inability to commercialize our product candidates;
significant negative media attention;
decrease in our stock price; or
initiation of investigations, and enforcement actions by regulators; and product recalls, withdrawals, revocation of approvals, or labeling, marketing or promotional restrictions.
We currently hold $5.0 million in product liability insurance coverage in the aggregate, with a per incident limit of $5.0 million, which may not be adequate to cover all liabilities that we may incur. We may need to increase our insurance coverage as we expand our clinical trials. We will need to further increase our insurance coverage if we commence commercialization of any of our product candidates for which we obtain marketing approval. Insurance coverage is increasingly expensive. We may not be able to maintain insurance coverage at a reasonable cost or in an amount adequate to satisfy any liability that may arise. On occasion, large judgments have been awarded in class action lawsuits based on therapeutics that had unanticipated side effects. Our insurance policies also have various exclusions, and we may be subject to a product liability claim for which we have no coverage. A successful product liability claim or series of claims brought against us could cause our stock price to fall and, if judgments exceed our insurance coverage, could decrease our cash and adversely affect our business and our prospects.
Risks Related to Our Dependence on Third Parties
We have selected a manufacturing partner for COVAXIN, if authorized or approved, to provide commercial supply for the United States and Canada. We may still encounter difficulties with respect to the manufacturing of COVAXIN, including with respect to our third-party manufacturers, which could impair our ability to commercialize COVAXIN, if authorized or approved. Further, if we encounter difficulties in negotiating commercial manufacturing and supply agreements with third-party manufacturers and suppliers of our other product candidates or any product components, our ability to commercialize our other product candidates, if approved, would be impaired.
We do not currently have the internal capacity to manufacture COVAXIN, if authorized for pediatric use or approved for adult use. Accordingly, we are dependent upon third parties for the manufacture of COVAXIN for clinical trials and commercial supply, if authorized or approved. Bharat Biotech has agreed to provide preclinical and clinical data, and to transfer to us certain proprietary technology owned or controlled by Bharat Biotech, that is necessary for the successful commercial manufacture and supply of COVAXIN to support commercial sale in the United States and Canada, if authorized or approved. Until the completion of the technology transfer and until we are capable and primarily responsible for the manufacture and supply of COVAXIN in the United States and Canada through the third-party manufacturer we have selected, Bharat Biotech has the exclusive right to manufacture COVAXIN and we will be wholly dependent on Bharat Biotech for the manufacture and supply of clinical testing materials required for our development activities and all of our requirements of commercial quantities of COVAXIN, if authorized or approved. We and Bharat Biotech have entered into a separate Supply Agreement setting forth the terms of such supply arrangements. Although the Supply Agreement is in effect, there can be no assurance that Bharat Biotech will in fact provide such doses, whether due to shortages in supply, diversion of vaccine resources to other uses deemed more immediate, or other factors.
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We have selected Jubilant HollisterStier of Spokane, Washington, as our manufacturing partner for COVAXIN, if authorized or approved, to prepare for the potential commercial manufacturing of COVAXIN for the U.S. and Canadian markets. We have initiated the technology transfer process to Jubilant HollisterStier that is required to enable Jubilant HollisterStier to manufacture our commercial requirements of COVAXIN, if authorized or approved. There can be no assurance that we will be successful in transitioning the manufacture of COVAXIN for the U.S. or Canadian markets from Bharat Biotech to Jubilant HollisterStier or any other third-party manufacturer. A technology transfer of a manufacturing process can be time-consuming and expensive and there can be no assurance that such transfer will be successful or that Jubilant HollisterStier will be able to manufacture our drug products successfully, if authorized or approved. Certain manufacturing processes for COVAXIN are novel and complex. Due to the nature of this vaccine candidate, we may encounter difficulties in manufacturing, product release, shelf life, testing, storage and supply chain management, or shipping. These difficulties could be due any number of reasons including, but not limited to, complexities of producing batches at a larger scale, equipment failure, choice, availability, and quality of raw materials, analytical testing technology, and product instability. Insufficient stability or shelf life of COVAXIN could materially delay our ability to continue any potential commercialization activities due to the need to manufacture additional commercial supply of COVAXIN, if authorized or approved. Moreover, notwithstanding our selection of Jubilant HollisterStier as our commercial manufacturing partner, we expect to continue to be dependent on Bharat Biotech as a single-source supplier for the supply of certain raw materials necessary for the manufacture of COVAXIN, including the adjuvant and active pharmaceutical ingredient. If, for any reason, Bharat Biotech is unable to provide an adequate supply of these materials, our ability to timely complete the technology transfer to Jubilant HollisterStier and to obtain adequate quantities of commercial supply of COVAXIN, if authorized or approved, could be jeopardized.
Engaging Jubilant HollisterStier as our commercial manufacturing partner may also require additional testing, notification, or approval by the FDA, Health Canada, or other regulatory authorities. If Jubilant HollisterStier proceeds to scale up its manufacturing of COVAXIN for commercialization, if authorized or approved, we may encounter unexpected issues relating to the manufacturing process or the quality, purity, and stability of the product candidate, and we may be required to refine or alter our manufacturing processes to address these issues, which may not be successful. This could jeopardize our ability to commence COVAXIN sales and generate revenue, if authorized or approved. Moreover, we have not yet entered into a master services agreement with Jubilant HollisterStier and we may not be successful in doing so on commercially favorable terms or at all. If we have to engage another third-party manufacturer, this will entail additional cost and cause delay.
If our third-party manufacturing partners cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the FDA, Health Canada, or comparable regulatory authorities in other jurisdictions, we may not be able to rely on our third-party manufacturing partners’ facilities for the manufacture of COVAXIN, if authorized or approved. If the FDA, Health Canada, or another comparable regulatory authority finds their facilities inadequate for the manufacture of COVAXIN, or if such facilities are subject to enforcement action in the future or are otherwise inadequate, we may need to find alternative manufacturing facilities, which would significantly impact our ability to develop, obtain regulatory authorization or approval for, or market COVAXIN. If we are unable to obtain and maintain adequate supply of COVAXIN, our U.S. and Canadian development and commercialization efforts would be impaired.
Additionally, we have entered into a strategic partnership with CanSinoBIO to manufacture our modifier gene therapy pipeline product candidates. Under this agreement, CanSinoBIO will provide all CMC development and clinical supplies for the development of OCU400 and OCU410. The agreement also provides commercialization rights to CanSinoBIO in Greater China. This agreement may be adversely affected if the U.S. government were to impose restrictions related to goods manufactured in or imported form China. We expect to rely on our qualified suppliers and other third parties to manufacture clinical supplies of other product candidates and commercial supplies of our products, if and when approved for marketing by applicable regulatory authorities, as well as for packaging, serialization, storage, distribution, and other production logistics. We, however, may not succeed in our efforts to establish manufacturing relationships or other alternative arrangements for any of our product candidates, components, and programs, or may be unable to do so on commercially favorable terms. If we are unable to enter into such agreements on commercially favorable terms, our future profit margins would be adversely affected and our ability to commercialize any products that receive marketing approval on a timely and competitive basis would be impaired. As a result, our business, financial condition, and results of operations would be materially adversely affected.
We rely, and expect to continue to rely, on third parties to conduct, supervise, and monitor our preclinical studies and clinical trials we may initiate, and those third parties may not perform satisfactorily, including failing to meet deadlines for the completion of such trials or failing to comply with regulatory requirements.
We rely on third parties, study sites, and others to conduct, supervise, and monitor our preclinical and clinical trials for our product candidates and do not currently plan to independently conduct clinical or preclinical trials of any other potential product candidates. We expect to continue to rely on third parties, such as CROs,CDMOs, clinical data management organizations, medical and
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scientific institutions, and clinical and preclinical investigators to conduct our preclinical studies and clinical trials. For example, for the clinical studies completed to date concerning the use
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Table of brimonidine tartrate for the treatment of ocular discomfort and ocular redness in patients with oGVHD, we relied on an investigator to sponsor and conduct the studies. For the clinical study concerning the use of brimonidine tartrate for the treatment of the signs and symptoms of DED, while we sponsored the study, we relied on third-party vendors and investigators for the conduct of the study.Contents
While we have, or expect to have, agreements governing the activities of such third parties, we will have limited influence and control over their actual performance and activities. Our third-partyThird-party service providers are not our employees, and except for remedies available to us under our agreements with such third parties, we cannot control whether or not they devote sufficient time and resources to our ongoingpreclinical studies or planned clinical non-clinical, and preclinical programs.trials. Nevertheless, we arewill be responsible for ensuring that each of our preclinical studies and planned clinical trials is conducted in accordance with the applicable protocol and legal, regulatory, and scientific standards, and our reliance on third parties doeswill not relieve us of our regulatory responsibilities. For example, we will remain responsible for ensuring that each of our trials is conducted in accordance with the general investigational plan and protocols for the trial. We must also ensure that our preclinical trials are conducted in accordance with GLP and under cGMP conditions, as appropriate. Moreover, the FDA and comparable foreign regulatory authorities require us to comply with GCPs for conducting, recording, and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial participants are protected. The FDA enforces these GCPs through periodic inspections of trial sponsors, principal investigators, clinical trial sites, and institutional review boards.IRBs.
If these third parties do not successfully carry out their contractual duties, meet expected deadlines, or conduct our preclinical studies or any planned clinical trials in accordance with regulatory requirements or our stated protocols, if they need to be replaced or if the quality or accuracy of the data they obtain is compromised due to the failure to adhere to our protocols, regulatory requirements or for other reasons:
we, or our CROsCDMOs, or other third-party collaborators may be subject to regulatory enforcement or other legal actions;
the data generated in our preclinical studies or planned clinical trials may be deemed unreliable and our such studies and trials may need to be repeated, extended, delayed, or terminated;
we may not be able to obtain, or may be delayed in obtaining, marketing approvals for our product candidates; or
we may not be able to, or may be delayed in our efforts to, successfully commercialize our product candidates.
We cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine that any of our preclinical studies or planned clinical trials complieswill comply with the applicable regulatory requirements. To the extent we are unable to successfully identify and manage the performance of third-party service providers in the future, our business may be materially and adversely affected. As a result, our results of operations and the commercial prospects for our product candidates would be harmed, our costs could increase, and our ability to generate revenues could be delayed.
Our anticipated reliance on third parties in connection with ourfor clinical trials will entail additional risks. Our third-party service providers may have relationships with other entities, some of which may be our competitors, for whom they may also be conducting trials or other therapeutic development activities that could harm our competitive position. In addition, we will be required to report certain financial interests of our third-party investigators if these relationships exceed certain financial thresholds or meet other criteria. The FDA or comparable foreign regulatory authorities may question the integrity of the data from those clinical trials conducted by investigators who may have conflicts of interest. Lastly, we are required to register certain clinical trials and post the results of certain completed clinical trials on a government-sponsored database, ClinicalTrials.gov,clinicaltrials.gov, within specified timeframes. Failure to do so can result in enforcement actions and adverse publicity.
Agreements with third parties conducting or otherwise assisting with our clinical or preclinical studies might terminate for a variety of reasons, including a failure to perform by the third parties. If any of our relationships with these third parties terminate, we may not be able to enter into arrangements with alternative providers or to do so on commercially reasonable terms. Switching or adding additional third parties involves additional cost and requires management time and focus. In addition, there is a natural transition period when a new third party commences work. As a result, if we need to enter into alternative arrangements, it could delay our product development activities and adversely affect our business. Though we intend to carefully manage our relationships with its third parties, there can be no assurance that we will not encounter challenges or delays in the future or that these delays or challenges will not have a material adverse impact on our business, financial condition, and prospects, and results of operations.
We will also rely on other third parties to store and distribute our productsproduct candidates for the clinical and preclinical trials that we conduct.conduct or for clinical trials we plan to conduct in the future. Any performance failure on the part of itsour distributors could delay development, marketing approval, or commercialization of our product candidates, producing additional losses and depriving us of potential product revenue.
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If we encounter difficulties in negotiating commercial manufacturing and supply agreements with third-party manufacturers and suppliers of our product candidates or any product components, our ability to commercialize our product candidates, if approved, would be impaired.
We do not manufacture any of our product candidates or any product components, and we do not currently plan to develop any capacity to do so. We expect to rely on a qualified supplier to manufacture and supply to us a minimum amount of brimonidine tartrate (the drug substance used in the manufacture of OCU300) for use in process validation campaigns and future commercial needs. We expect to rely on our qualified supplier and other third parties to manufacture clinical supplies of other product candidates and commercial supplies of all of our products, if and when approved for marketing by applicable regulatory authorities, as well as for packaging, serialization, storage, distribution and other production logistics. We, however, may not succeed in our efforts to establish manufacturing relationships or other alternative arrangements for any of our product candidates, components and programs, or may be unable to do so on commercially favorable terms. If we are unable to enter into such agreements on commercially favorable terms, our future profit margins would be adversely affected and our ability to commercialize any products that receive marketing approval on a timely and competitive basis would be impaired. As a result, our business, financial condition and results of operations would be materially adversely affected.
If the manufacturers upon whom we rely fail to produce our product candidates or components pursuant to the terms of contractual arrangements with us or fail to comply with stringent regulations applicable to biologic and pharmaceutical manufacturers, we may face delays in the development and commercialization of, or be unable to meet demand for, our product candidates and may lose potential revenues.
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As with the third parties on which we rely or expect to rely for our preclinical activities and planned clinical trial activities,trials, we have agreements governing the activities of our manufacturers but have limited influence and control over their actual performance and activities. Our third-party manufacturers are not our employees, and except for remedies available to us under our agreements with such third parties, we cannot control whether or not they devote sufficient time and resources to itsour manufacturing requirements. If these third-party manufacturers do not successfully carry out their contractual duties, meet expected deadlines or manufacture our product candidates in accordance with regulatory requirements, and if there are disagreements between us and such parties, clinical development or marketing approval of our product candidates could be delayed.
The manufacture of biologicpharmaceutical and pharmaceuticalbiologic products requires significant expertise and capital investment, including the development of advanced manufacturing techniques and process controls. Manufacturers of therapeutics often encounter difficulties in production, particularly in scaling up initial production. These problems include difficulties with production costs and yields, quality control, including stability of the product candidate and quality assurance testing, shortages of qualified personnel, and compliance with strictly enforced federal, state, and foreign regulations. If our manufacturers were to encounter any of these difficulties and were unable to perform as agreed, our ability to provide product candidates to patients in our planned clinical trials and for commercial use, if authorized or approved, would be jeopardized.
In addition, all manufacturers of our product candidates and therapeutic substances must comply with cGMP requirements enforced by the FDA that are applicable to both finished products and their active components used for both, for clinical and commercial supply. The FDA enforces these requirements through its facilities inspection program. Our manufacturers must be approved by the FDA pursuant to inspections that will be conducted after we submit our marketing applications to the agency. Our manufacturers will also be subject to continuing FDA and other regulatory authority inspections should we receive marketing approval. Further, we, in cooperation with our contract manufacturers, must supply all necessary chemistry, manufacturing, and controlCMC documentation to the FDA in support of a marketing application on a timely basis.
The cGMP requirements include quality control, quality assurance, and the maintenance of records and documentation. Manufacturers of our product candidates, and the therapeutic substances, and the active pharmaceutical ingredients necessary to produce our product candidates may be unable to comply with itsour specifications, cGMP requirements and with other FDA, state, and foreign regulatory requirements. Poor control of production processes can lead to the introduction of adventitious agents or other contaminants, or to inadvertent changes in the properties or stability of a product candidate that may not be detectable in final product testing. If our contract manufacturers cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the FDA or other regulatory authorities, they will not be able to secure or maintain regulatory approval for their manufacturing facilities. Any such deviations may also require remedial measures that may be costly and/or time-consuming for us or a third party to implement and that may include the temporary or permanent suspension of a clinical trial or commercial sales or the temporary or permanent closure of a facility. Any resulting delays in obtaining products, if authorized or approved, or product candidates that comply with the applicable regulatory requirements may result in delays to clinical trials, product approvals, and commercialization. It may also require that we conduct additional studies.
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While we are ultimately responsible for the manufacture of our product candidates, other than through our contractual arrangements, we have little control over our manufacturers’ compliance with these regulations and standards. A failure to comply with the applicable regulatory requirements may result in regulatory enforcement actions against our manufacturers or us, including fines and civil and criminal penalties, including imprisonment, suspension or restrictions of production, injunctions, delay, withdrawal or denial of product approval or supplements to approved products, clinical holds or termination of clinical studies, warning or untitled letters, regulatory authority communications warning the public about safety issues with the product, refusal to permit the import or export of the products, product seizure, detention, or recall, operating restrictions, suits under the civil FCA, corporate integrity agreements, or consent decrees. Depending on the severity of any potential regulatory action, our clinical or commercial supply could be interrupted or limited, which could have a material adverse effect on our business.
Any problems or delays we experience in preparing for commercial-scale manufacturing of a product candidate or component, including manufacturing validation, may result in a delay in FDA approval or commercial launch of the product candidate or may impair our ability to manufacture commercial quantities or such quantities at an acceptable cost, which could result in the delay, prevention, or impairment of commercialization of our product candidates and could adversely affect our business. The risks associated with any problems or delays may be greater should the U.S. government impose restrictions relating to goods manufactured in or imported from China.
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We or our third-party manufacturers may also encounter shortages in the materials necessary to produce our product candidates in the quantities needed for our clinical trials or, if our product candidates are authorized or approved, in sufficient quantities for commercialization.
We or our third-party manufacturers may also encounter shortages in the raw materials, therapeutic substances, or active pharmaceutical ingredients necessary to produce our product candidates in the quantities needed for our clinical trials or, if our product candidates are authorized or approved, in sufficient quantities for commercialization or to meet an increase in demand. Such shortages may occur for a variety of reasons, including capacity constraints, delays or disruptions in the market, and shortages caused by the purchase of such materials by our competitors or others. We or our third-party manufacturers’ failure to obtain the raw materials, therapeutic substances, or active pharmaceutical ingredients necessary to manufacture sufficient quantities of our product candidates may cause the manufacturers to fail to deliver the required commercial quantities of our product candidates on a timely basis and at commercially reasonable prices. If such failure occurs, we would likely be unable to meet the demand for our products, if authorized or approved, and we would lose potential revenues.
The number of available, qualified third-party manufactures is limited, and if we are compelled to locate an alternative manufacturing partner, our product development activities and commercialization could be delayed and additional expense would be incurred.
There are a limited number of manufacturers that operate under cGMP regulations, and that are both capable of manufacturing for us and willing to do so, and therefore our product candidates may compete with other products and product candidates for access to manufacturing facilities. Moreover, because our product candidates must be manufactured under sterile conditions, the number of manufacturers who can meet this requirement are even more limited. If our existing third-party manufacturers, or the third parties that we engage in the future to manufacture a product, if authorized or approved, or component for commercial sale or for ourany clinical trials we expect to initiate in the future should cease to continue to do so for any reason (including the termination of our agreements with such manufacturers, which can occur for a variety of reasons, or the bankruptcy of such manufacturers), it would be difficult to obtain a suitable alternative manufacturer. We would likely experience delays in obtaining sufficient quantities of our product candidates for us to meet commercial demand or to advance our clinical trials while we identify and qualify replacement suppliers. Any change in our manufacturers could be costly because the commercial terms of any new arrangement could be less favorable and because the expenses relating to the transfer of necessary technology and processes could be significant.
If the FDA or a comparable foreign regulatory authority does not approveinspects the facilities for the manufacture of our product candidates and finds that they are not in compliance with cGMP now or if the FDA withdraws any such approval in the future, we may need to find alternative manufacturing facilities. Any new manufacturers would need to either obtain or develop the necessary manufacturing know-how, and obtain the necessary equipment and materials, which may take substantial time and investment. We must also receive FDA approval for the use of any new manufacturers for commercial supply. Any such developments would significantly impact our ability to develop, obtain, and maintain regulatory authorization or approval for or market our product candidates, if authorized or approved.
The number of available third-party facilities may also be further limited by natural disasters, such as pandemics, including the ongoing COVID-19 pandemic, floods, or fire, or such facilities could face manufacturing issues, such as contamination or regulatory findings following a regulatory inspection of such facility. In such instances, an appropriate replacement third-party relationship may not be readily available to us or on acceptable terms, which would cause additional delay and increased expense and may have a material adverse effect on our business.
We recently entered into a non-binding LOI to acquire a commercial manufacturing plant, which is preliminary and subject to the negotiation and execution of definitive transaction agreements. We cannot assure you that the acquisition will be completed on a timely basis, if at all. Assuming the acquisition is completed, we have limited experience developing manufacturing facilities or manufacturing COVAXIN, and we cannot assure you that we will be able to develop such manufacturing plant or manufacture COVAXIN at full capacity and in compliance with regulations at a cost or in quantities necessary to make it commercially viable.
In January 2022, we announced that we signed a non-binding LOI with Liminal for the acquisition of Liminal’s manufacturing site in Belleville, Ontario, which, assuming the completion of the acquisition, we intend to further develop and upgrade. Completion of the proposed transaction is subject to finalization of due diligence investigations by us and Liminal, the negotiation and execution of definitive transaction agreements, and other customary closing conditions including certain funding requirements. There can be no assurance that a definitive agreement will be entered into on acceptable terms, if at all, or that the proposed transaction will be consummated. Further, although we intend to further develop and refurbish the
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We may rely on third parties to perform many essential services for any productsmanufacturing site following closing of the acquisition, we cannot at this time predict the cost or extent of the upgrades that we commercialize. If these third parties fail to perform as expected or to comply with legal and regulatory requirements, our ability to commercialize our product candidates will be significantly impactedneeded or the timeline for completing such upgrades.
The development of manufacturing facilities and the manufacture of pharmaceutical products requires significant expertise and capital investment, including the development of advanced manufacturing techniques and process controls. Further, the equipment and facilities employed in the manufacture of pharmaceuticals are subject to stringent qualification requirements by regulatory agencies, including validation of facility, equipment, systems, processes and analytics.
Assuming we maysuccessfully close the acquisition, we will be subject to regulatory sanctions.
We may retain third-party service providers to perform a variety of functions related to the saleenvironmental, health, and distribution of our product candidates, key aspects of which will be out of our direct control. These service providers may provide key services related to warehousing and inventory control, distribution, customer service, accounts receivable management, and cash collection. If these third-party service providers fail to comply with applicablesafety laws and regulations failconcerning, among other things, the use, storage, generation, handling, transportation and disposal of hazardous substances or wastes, the cleanup of hazardous substance releases, exposure to meet expected deadlines,hazardous substances and emissions or otherwise do not carry out their contractual dutiesdischarges into the air or water. Violations of these laws and regulations can result in significant business interruptions and/or civil and criminal penalties. New laws and regulations, violations of or amendments to existing laws or regulations, or stricter enforcement of existing requirements, could require us or encounter physical or natural damage at their facilities, our ability to deliver product to meet commercial demand would be significantly impaired and we may be subject to regulatory enforcement action.
In addition, we may engage third parties to perform various other services for us relating to pharmacovigilance and adverse event reporting, safety database management, fulfillment of requests for medical information regarding our product candidates and related services. If the quality or accuracy of the data maintained by these service providers is insufficient, or these third parties otherwise fail to comply with regulatory requirements, we could be subject to regulatory sanctions.
We may also contract with a third party to calculate and report pricing information mandated by various government programs. If a third party fails to timely report or adjust prices as required, or errors in calculating government pricing information from transactional data in our financial records, it could impact our discount and rebate liability, and potentiallyincur material costs, subject us to regulatory sanctionsnew or FCA lawsuits.increased liabilities, and cause disruptions to our manufacturing activities that could be material.
Manufacturers of pharmaceutical products often encounter difficulties in production, especially in scaling up initial production. These problems include difficulties with production costs and yields, quality control and assurance and shortages of qualified personnel, as well as compliance with strictly enforced regulations. If we are unable to effectively produce commercial supplies of COVAXIN at our manufacturing plant, if authorized or approved, we will be required to rely on new or existing third-party manufacturers to meet our commercial manufacturing needs, which may materially adversely affect our business, results of operations, and financial condition.
Any of these risks could entail higher costs, cause us to delay production, and may result in us being unable to effectively support commercialization of COVAXIN, if authorized or approved. Furthermore, if we fail to deliver the required commercial quantities of product on a timely basis, and at commercially reasonable prices and acceptable quality, we would likely be unable to meet demand, if any, for COVAXIN, if authorized or approved, and we would lose potential revenues.
We may seek to collaborate with third parties for the development or commercialization of our product candidates. We may not be successful in establishing or maintaining collaborative relationships, any of which could adversely affect our ability to develop and commercialize our product candidates.
InWe are currently party to the Covaxin Agreement with Bharat Biotech for the development and commercialization of COVAXIN in the United States and Canada and the CanSinoBIO Agreement with CanSinoBIO for the development and commercialization of our modifier gene therapy product candidates, OCU400 and OCU410. Our joint development efforts are in the early stages and in the future, we may seek to enter into additional collaboration arrangements with biologic, pharmaceutical or biotechnology companies for the development or commercialization of ourother product candidates. We may utilize a variety of types of collaboration, distribution, and other marketing arrangements with third parties to develop and commercialize our product candidates, both inside and outside the United States. WeStates and Canada. In particular, we may also enter into arrangements with third parties to perform thesecertain services in the United States or Canada if we do not establish our own sales, marketing, and distribution capabilities in the United States or Canada, or if we determinesdetermine that such third-party arrangements are otherwise beneficial. We may also consider potential collaborative partnership opportunities for sales, marketing, distribution, development, or licensing or broader collaboration arrangements, including with largemid-size and mid-sizelarge pharmaceutical companies, regional and national pharmaceutical companies, and biotechnology companies. We are not currently party to any such arrangement.
The success of our current and future collaboration arrangements that we may enter into will depend heavily on the efforts and activities of our collaborators. Collaborators generally have significant discretion in determining the efforts and resources that they will apply to collaboration arrangements. Accordingly, if we do enter intowith respect to any such arrangements with any third parties, in the future, we will likely have limited control over the amount and timing of resources that our collaborators dedicate to the development or commercialization of our product candidates. Our ability to generate revenues from these arrangements will depend in part on our collaborators’ abilities and efforts to successfully perform the functions assigned to them in these arrangements. DisagreementsFor example, if the FDA or Health Canada does not accept the clinical trial results for COVAXIN performed by Bharat Biotech in India, our ability to develop COVAXIN in the United States or Canada would be impaired.
Moreover, disagreements between parties to a collaboration arrangement regarding clinical development and commercialization matters can lead to delays in the development process or commercializingcommercialization of the applicable product candidate and, in some cases, termination of the collaboration arrangement. These disagreements can be difficult to resolve if neither of the parties has final decision-making authority. Moreover, collaborations with biologic and pharmaceutical companies and other third parties are often terminated or allowed to expire. Any such termination or expiration would adversely affect us financially and could harm our
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business reputation. In particular, any termination of the Covaxin Agreement would prevent us from developing COVAXIN for the U.S. and Canadian markets.
We may also license the right to marketOur current and sell our product candidates under our collaborators’ labeler codes. Alternatively, we may enter into agreements with collaborators to market and sell our product candidates under our own labeler code, in which case errors and omissions by collaborators in capturing and transmitting transactional data may impact the accuracy of our government price reporting.
Any future collaborations we might enter into may pose a number of additional risks, including the following:
collaborators may not pursue development of product candidates and commercialization of any product candidates that achieve regulatory authorization or approval or may elect not to continue or renew development or commercialization
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programs based on clinical trial results, changes in the collaborators’ strategic focus or available funding, or external factors, such as an acquisition, that divert resources or create competing priorities;
collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials, or require a new formulation of a product candidate for clinical testing;
collaborators could fail to make timely regulatory submissions for a product candidate;
collaborators may not comply with all applicable regulatory requirements or may fail to report safety data in accordance with all applicable regulatory requirements, which could subject them or us to regulatory enforcement actions;
collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours;
product candidates discovered in collaboration with us may be viewed by our collaborators as competitive with their own product candidates or products, which may cause collaborators to cease to devote resources to the commercialization of our product candidates;
a collaborator with marketing and distribution rights to one or more of our product candidates that achieve regulatory approval may not commit sufficient resources to the marketing and distribution of such product candidate or product;
disagreements with collaborators, including disagreements over proprietary rights, contract interpretation, or the preferred course of development, might cause delays or termination of the research, development, or commercialization of product candidates, might lead to additional responsibilities for us with respect to product candidates, or might result in litigation or arbitration, any of which would be time consuming and expensive;
collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation;
collaborators may infringe the intellectual property rights of third parties or fail to maintain intellectual property rights which they license to us, which may expose us to litigation and potential liability; and
collaborations may be terminated for the convenience of the collaborator and, if terminated, we could be required to raise additional capital to pursue further development or commercialization of the applicable product candidates.
Collaboration agreements may not lead to development or commercialization of our product candidates in the most efficient manner, or at all. If any collaborations we might enter into in the future do not result in the successful development and commercialization of our product candidates or if one of our collaborators subsequently terminates our agreement with us, we may not receive any future research funding, or milestone, or royalty payments under the collaboration.collaboration, as applicable. If we do not receive the funding we expect under the agreements, our development of our product candidates could be delayed, and we may need additional resources to develop our product candidates and our product platform. All of the risks relating to product development, regulatory approval, and commercialization described in this report also apply to the activities of our collaborators.
Additionally, if any future collaborator of ours is involved in a business combination, the collaborator might deemphasizede-emphasize or terminate development or commercialization of any product candidate licensed to itthem by us. If one of our collaborators terminates its agreement with us, we may find it more difficult to attract new collaborators and our reputation in the business and financial communities could be adversely affected.
Should we desire to pursue a collaboration agreement but are not able to establish collaborations, we may have to alter our development and commercialization plans and our business could be adversely affected.
For some of our product candidates, we may decide to collaborate with pharmaceutical or biotechnology companies for the development and potential commercialization of those product candidates. We face significant competition in seeking
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appropriate collaborators and whether we reach a definitive agreement for a collaboration will depend, among other things, upon our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration, and the proposed collaborator’s evaluation of a number of factors. Those factors may include the design or results of clinical trials, the likelihood of approval by the FDA or similar regulatory authorities outside the United States, the potential market for the
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subject product candidate, the costs and complexities of manufacturing and delivering such product candidate to patients, the potential of competing products, the existence of uncertainty with respect to our ownership of technology, which can exist if there is a challenge to such ownership without regard to the merits of the challenge, and industry and market conditions generally. We may also be restricted under future license agreements from entering into agreements on certain terms with potential collaborators. Collaborations are complex and time-consuming to negotiate and document. Should we desire to pursue a collaboration agreement but are unable to reach agreements with suitable collaborators on a timely basis, on acceptable terms, or at all, we may have to curtail the development of a product candidate, reduce or delay our development program or one or more of itsour other development programs, delay our potential commercialization or reduce the scope of any sales or marketing activities, or increase our expenditures and undertake development or commercialization activities at our own expense. If we fail to enter into collaborations and do not have sufficient funds or expertise to undertake the necessary development and commercialization activities, we may not be able to further develop our product candidates or bring them to market or continue to develop our product platform and our business may be materially and adversely affected.
Risks Related to Legal and Compliance Matters
We are currently, and may in the future be, subject to securities litigation, which is expensive and could divert management attention.
On June 17, 2021, a securities class action lawsuit was filed against us and certain of our officers and directors in the U.S. District Court for the Eastern District of Pennsylvania (Case No. 2:21-cv-02725) that purported to state a claim for alleged violations of Sections 10(b) and 20(a) of the Exchange Act and Rule 10b-5 promulgated thereunder, based on statements made by us concerning the announcement of our decision to pursue the submission of a BLA for COVAXIN for ages 18 years and older rather than pursuing an EUA for the vaccine candidate. On July 16, 2021, a second securities class action complaint was filed against us and certain of our officers and directors in the U.S. District Court for the Eastern District of Pennsylvania (Case No. 2:21-cv-03182) that also purported to state a claim for alleged violations of Sections 10(b) and 20(a) of the Exchange Act and Rule 10b-5 promulgated thereunder, based on the same statements as the first complaint.
On August 30, 2021, a stockholder derivative lawsuit was filed derivatively on behalf of our company against certain of our officers and directors and the nominal defendant Ocugen in the U.S. District Court for the Eastern District of Pennsylvania (Case No. 2:21-cv-03876) that purported to state a claim for breach of fiduciary duty and contribution for violations of Sections 10(b) and 21(d) of the Exchange Act, based on facts and circumstances relating to the securities class action lawsuits and seeking contribution and indemnification in connection with claims asserted in the securities class action lawsuits. On September 22, 2021, a second stockholder derivative lawsuit was filed derivatively on behalf of our company against certain of our officers and directors and the nominal defendant Ocugen in the U.S. District Court for the Eastern District of Pennsylvania (Case No. 2:21-cv-04169) that purported to state a claim for breach of fiduciary duties, unjust enrichment, abuse of control, waste of corporate assets, and contribution for violations of Sections 10(b) and 21(d) of the Exchange Act, based on the same allegations as the first complaint. The parties to both stockholder derivative lawsuits have stipulated to the consolidation of the two stockholder derivative lawsuits and also have submitted to the court in each action a proposed order requesting a stay of the litigation pending a decision on any motion to dismiss filed in the securities class action lawsuits, which remain pending before the court, and this status could change.
The complaints seek unspecified damages, interest, attorneys’ fees, and other costs. We believe that the lawsuits are without merit and intend to vigorously defend against them. At this time, no assessment can be made as to their likely outcome or whether the outcome will be material to us. We may also become subject to additional securities class action lawsuits in the future. This risk is especially relevant for us because life sciences companies have experienced significant stock price volatility in recent years.
The cost of defending against these types of claims against us or the ultimate resolution of such claims, whether by settlement or adverse court decision, may harm our business. Further, potential claimants may be encouraged to bring lawsuits based on a settlement from us or adverse court decisions against us. We cannot currently assess the likely outcome of such suits, but the commencement and/or resolution of such suits (particularly if the outcome were negative), could have a material adverse effect on our reputation, results of operations, financial condition, and cash flows. They could also cause a decline in the market price of our common stock.
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If we fail to comply with federal and state healthcare laws, including fraud, and abuse, and health and other information privacy and security laws, we could face substantial penalties and our business, financial condition, results of operations, and prospects could be adversely affected.
As a biologic and pharmaceutical company, we are subject to many federal and state healthcare laws, such as the federal Anti-Kickback Statute, the federal civil and criminal FCA, the civil monetary penalties statute, the Medicaid Drug Rebate statute and other price reporting requirements, the VHCA, the HIPAA, the FCPA, the ACA, and similar state laws. We may also be subject to laws regarding transparency and patient privacy. Even though we do not and will not control referrals of healthcare services or billbills directly to Medicare, Medicaid, or other third-party payors, certain federal and state healthcare laws, and regulations pertaining to fraud and abuse, reimbursement programs, government procurement, and patients’ rights are and will be applicable to our business.
It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations, or case law involving applicable fraud, and abuse, or other healthcare laws and regulations. If we or our operations are found to be in violation of any federal or state healthcare law, or any other governmental laws or regulations that applies to us, we may be subject to penalties, including civil, criminal, and administrative penalties, damages, fines, imprisonment, disgorgement, suspension and debarment from government contracts, and refusal of orders under existing government contracts, exclusion from participation in U.S. federal or state health care programs, corporate integrity agreements, and the curtailment or restructuring of our operations, any of which could materially adversely affect our ability to operate our business and our financial results. Although an effective compliance program can mitigate the risk of investigation and prosecution for violations of these laws, the risks cannot be entirely eliminated. Moreover, achieving and sustaining compliance with applicable federal and state privacy, security, reimbursement, and fraud laws may prove costly. Any action against us for the violation of these laws, even if we successfully defendsdefend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business.
We are subject to new legislation,Healthcare legislative or regulatory proposalsreform measures may have a negative impact on our business and healthcare payor initiatives that may increase our costsresults of compliance, and adversely affect our ability to market our products, obtain collaborators, and raise capital.operations.
In theThe United States and somemany foreign jurisdictions there have been a number ofenacted or proposed legislative and regulatory changes and proposed changes regardingaffecting the healthcare system that could prevent or delay marketing approvalsystem. The United States government, state legislatures, and foreign governments also have shown significant interest in implementing cost-containment programs to limit the growth of our product candidates, restrict or regulate post-approval activitiesgovernment-paid healthcare costs, including price controls, restrictions on reimbursement, and affect our ability to profitably sell anyrequirements for substitution of generic products for which we obtain marketing approval. The biopharmaceutical industry has been a particular focus of these efforts and has been significantly affected by legislative initiatives. We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we may receive for any approved products.
In 2010, the ACA, included provisions of importance to our business, including, without limitation, our ability to commercialize and the prices we may obtain for any of our product candidates that are approved for sale. These provisions include:
an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugsdrugs.
The ACA substantially changed the way healthcare is financed by both governmental and biologic agents, including products approved throughprivate insurers, and significantly impacts the 505(b)(2) regulatory pathway;
an increase inpharmaceutical industry. The ACA is intended to broaden access to health insurance, reduce or constrain the statutory minimum rebates a sponsor must pay under the Medicaid Drug Rebate Program;
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a Medicare Part D coverage gap discount program, in which participating sponsors must agree to offer 50% point-of-sale discounts off negotiated drug prices of drugs and biologics approved under an NDA or BLA (including drugs approved pursuant to the 505(b)(2) regulatory pathway) during the coverage gap period as a condition for the sponsors’ outpatient drugs to be covered under Medicare Part D;
expansion ofhealthcare spending, enhance remedies against healthcare fraud and abuse, laws, includingadd new transparency requirements for healthcare and health insurance industries, impose new taxes and fees on pharmaceutical and medical device manufacturers, and impose additional health policy reforms. Among other things, the federal FCA andAffordable Care Act expanded manufacturers’ rebate liability under the federal Anti-Kickback Statute, andMDRP by increasing the addition of new government investigative powers, and enhanced penalties for noncompliance;
extension of sponsor’sminimum Medicaid rebate liabilityfor both branded and generic drugs, expanded the 340B program, and revised the definition of AMP, which could increase the amount of Medicaid drug rebates manufacturers are required to pay to states. The legislation also extended Medicaid drug rebates, previously due only on fee-for-service Medicaid utilization, to include the utilization of Medicaid managed Medicaid plans;
expansioncare organizations as well and created an alternative rebate formula for certain new formulations of eligibility criteria for Medicaid programs;
expansioncertain existing products that is intended to increase the amount of rebates due on those drugs. On February 1, 2016, CMS issued final regulations to implement the entities eligible for discountschanges to the MDRP under the PHSA pharmaceutical pricing program; and
creation of a special Medicare Part B payment methodology for biosimilars approved under PHSA Section 351(k) in which providers are paidACA. These regulations became effective on April 1, 2016. Since that time, there have been significant ongoing efforts to modify or eliminate the ASP of the biosimilar plus the margin based on ASP of the reference biologic.ACA.
The ACA has been subject to challenges in the courts. On December 14, 2018, a Texas U.S. District Court Judge ruled that the ACA is unconstitutional in its entirety because the “individual mandate” was recently amended to repealrepealed by Congress. On December 18, 2019, the Fifth Circuit U.S. Court of Appeals held that the individual insurance mandate is unconstitutional and effortsremanded the case to repeal and replace portionsthe Texas District Court to reconsider its earlier invalidation of the entire ACA. An appeal was taken to the U.S. Supreme Court. On June 17, 2021, the Supreme Court ruled that the plaintiffs lacked standing to challenge the law may continue. It remainsas they had not alleged personal injury traceable to be seen, however, whether new legislation will be enacted and, if so, precisely what any new legislation could provide and what impact it will havethe allegedly unlawful conduct. As a result, the Supreme Court did not rule on the availabilityconstitutionality of healthcare and containing or lowering the cost of healthcare. For example, it is possible that any repeal and replacement initiatives, if enacted into law, could ultimately result in fewer individuals having health insurance coverage or in individuals having insurance coverage with less generous benefits. Accordingly, such reforms, if enacted, could have an adverse effect on anticipated revenue from product candidates that we may successfully develop and for which we may obtain marketing approval and may affect our overall financial condition and ability to develop or commercialize product candidates. The timing and scope of any potential future legislation to repeal and replace ACA provisions is highly uncertain in many respects.
Since the ACA was enacted in 2010, otheror any of its provisions.
Other legislative and regulatory changes have been proposed and adopted. These changes include,adopted since passage of the ACA. The Budget Control Act of 2011, among other things, created the Joint Select Committee on Deficit Reduction to recommend proposals in spending reductions to Congress. The Joint Select Committee did not achieve its targeted deficit reduction of an amount greater than $1.2 trillion for the fiscal years 2012 through 2021, triggering the legislation’s automatic reductions to several government programs. These reductions included aggregate reductions to Medicare payments to healthcare providers of up to 2%2.0% per fiscal year, which went effective on April 1, 2013 and will remain in effect through 2024 unless additional Congressional action is taken. More recently, theyear. The Bipartisan Budget Act of 2018 retained the federal budget “sequestration” Medicare payment reductions of 2%, and extended it
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through 2027 unless congressional action is taken, and also increased sponsorlabeler responsibility for prescription costs in the Medicare Part D coverage gap, and also extended sponsor responsibility for prescription costs in the Medicare Part D coverage gap to biosimilars, which had previously been exempt. In addition,gap. On January 2, 2013, the American Taxpayer Relief Act of 2012,was signed into law, which, among other things, further reduced Medicare payments to several types of providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. CMS promulgated regulations governing sponsors’ obligations
Further legislative and reimbursementregulatory changes under the Medicaid Drug Rebate Program,ACA remain possible, although the Biden Administration has signaled that it plans to build on the ACA and recently promulgated a regulationexpand the number of people who are eligible for subsidies under it. President Biden indicated that limited Medicare Part B paymenthe intends to certain hospitalsuse executive orders to undo changes to the ACA made by the Trump administration and would advocate for outpatient drugs purchased underlegislation to build on the 340B program. ToACA. It is unknown what form any such changes or any law would take, and how or whether it may affect our business in the extent that we license the right to sell a product to another entity under that entity’s labeler code, the licensee would further have healthcare reimbursement and pricing regulatory responsibilities.
future. We expect that current lawchanges or additions to the ACA, the Medicare and Medicaid programs, changes allowing the federal government to directly negotiate drug prices and statechanges stemming from other healthcare reform measures, that may be adopted in the future, may result in additional reductions in Medicare and otherespecially with regard to healthcare funding, more rigorous coverage criteria, increased regulatory burdens and operating costs, decreased net revenue from our biologic and pharmaceutical products, decreased potential returns from our development efforts, new payment methodologies and in additional downward pressure on the price that we receive for any approved product and/or the level of reimbursement physicians receive for administering any approved product we might bring to market. Reductions in reimbursement levels may negatively impact the prices we receive or the frequency with which any products we may develop are prescribed or administered. Any reduction in reimbursement from Medicareaccess, financing or other government healthcare programs may resultlegislation in a similar reduction in payments from private payors. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability or commercialize our products.
The pricing of prescription pharmaceuticals and biologics is also subject to governmental control outside the United States. In certain countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product. To obtain reimbursement or pricing approval in some countries, we may be required to conduct a clinical trial that compares the cost-effectiveness of our product candidates to other available therapies. If reimbursement of our products is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our ability to generate revenues and become profitable could be impaired.
In addition, there have been a number of other legislative and regulatory proposals aimed at changing the biologic and pharmaceutical industry. For instance, the Drug Quality and Security Act (the “DQSA”), imposes obligations on sponsors of
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biologic and pharmaceutical products related to product tracking and tracing. Among the requirements of this legislation, sponsors are required to provide certain information regarding the product to individuals and entities to which product ownership is transferred, will be required to label products with a product identifier, and are required keep certain records regarding the product. The transfer of information to subsequent product owners by manufacturers is also required to be done electronically. Sponsors are also required to verify that purchasers of the sponsors’ products are appropriately licensed. Further, manufacturers have product investigation, quarantine, disposition, and FDA and trading partner notification responsibilities related to counterfeit, diverted, stolen, and intentionally adulterated products that would result in serious adverse health consequences of death to humans, as well as products that are the subject of fraudulent transactions or which are otherwise unfit for distribution such that they would be reasonably likely to result in serious health consequences or death. Future licensees or affiliates may also have responsibilities under DQSA.
Compliance with the federal track and trace requirements may increase our operational expenses and impose significant administrative burdens. As a result of these and other new proposals, we may determine to change its current manner of operation, provide additional benefits or change our contract arrangements, any of whichindividual states, could have a material adverse effect on the healthcare industry.
We expect that additional federal, state, and foreign healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in limited coverage, reimbursement, and reduced demand for our business, financial condition, and results of operations.products, if approved, or additional pricing pressures.
Our employees, independent contractors, consultants, commercial partners, principal investigators, or CROsCDMOs may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements, which could have a material adverse effect on our business.
We are exposed to the risk of employee fraud or other misconduct. Misconduct by employees, independent contractors, consultants, commercial partners, manufacturers, investigators, or CROsCDMOs could include intentional, reckless, negligent, or unintentional failures to (i) comply with FDA regulations or other similar regulatory requirements, (ii) comply with manufacturing standards, including cGMP requirements, (iii) comply with applicable fraud and abuse laws, (iv) comply with federal and state data privacy, security, fraud and abuse, and other healthcare laws and regulations in the U.S.United States and abroad, (v) provide accurate information to the FDA, (vi) properly calculate pricing information required by federal programs, (vii) comply with federal procurement rules or contract terms, (viii) report financial information or data accurately, or (ix) disclose unauthorized activities to us. This misconduct could also involve the improper use or misrepresentation of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation.
It is not always possible to identify and deter this type of misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting it from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations.
If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business and financial results, including, without limitation, the imposition of significant civil, criminal and administrative penalties, damages, monetary fines, disgorgements, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, individual imprisonment, contractual damages, reputational harm, diminished profits and future earnings, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, and curtailment of our operations, any of which could adversely affect our ability to operate our business and our results of operations.
Our business and operations would suffer in the event of system failures, and we face risks related to our collection and use of data, which could result in investigations, inquiries, litigation, fines, legislative and regulatory action and negative press about our privacy and data protection practices.
Our internal computer systems and those of our CROs and other contractors and consultants are vulnerable to damage from computer viruses, unauthorized access, natural disasters, terrorism, war, and telecommunication and electrical failures. If such an event were to occur and cause interruptions in our operations, it could result in a material disruption of our product candidate development and, if such product candidates are approved, commercialization programs.
Additionally, our business processes personal data, including some data related to health. When conducting clinical trials, we face risks associated with collecting trial participants’ data, especially health data, in a manner consistent with applicable laws and regulations. We also face risks inherent in handling large volumes of data and in protecting the security of such data. We could be subject to attacks on our systems by outside parties or fraudulent or inappropriate behavior by our service providers or employees. Third parties may also gain access to the company’s systems using stolen or inferred credentials, computer malware, viruses, spamming, phishing attacks or other means, and may use such access to obtain personal data. Data breaches could subject us to individual or consumer class action litigation and governmental investigations and proceedings by federal,
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state and local regulatory entities in the U.S. and by international regulatory entities, resulting in exposure to material civil and/or criminal liability. As our operations and business grow, we may become subject to or affected by new or additional data protection laws and regulations and face increased scrutiny or attention from regulatory authorities, including various domestic and international privacy and security regulations. The legislative and regulatory landscape for privacy and data protection continues to evolve. In the United States, certain states may adopt privacy and security laws and regulations that may be more stringent than applicable federal law. For example, California enacted the California Consumer Privacy Act (the “CCPA”), which took effect on January 1, 2020. The CCPA creates individual privacy rights for California consumers and increases the privacy and security obligations of entities handling certain personal data. We may also in the future be subject to data protection laws and regulations of other jurisdictions, such as the EU's General Data Protection Regulation (“GDPR”), which provides data subjects with certain rights and requires organizations to adopt technical and organizational safeguards to protect personal data. In the event that we are subject to or affected by privacy and data protection laws, including the CCPA or GDPR and other domestic or international privacy and data protection laws, we may expend significant resources to comply with such laws, and any liability from failure to comply with the requirements of these laws could adversely affect our financial condition.
We are subject to anti-corruption laws, as well as export control laws, customs laws, sanctions laws, and other laws governing our operations. If we fail to comply with these laws, we could be subject to civil or criminal penalties, other remedial measures and legal expenses, be precluded from developing, manufacturing, and selling certain products outside the United States, which could adversely affect our business, results of operations, and financial condition.
If we expand our operations outside of the United States, we must dedicate additional resources to compliancecomply with anti-corruption laws, including the Bribery Act, the FCPA, and other anti-corruption laws that apply into countries where we do business and may do business in the future. The Bribery Act, FCPA, and these other laws generally prohibit us, our officers, and our employees and intermediaries from bribing, being bribed, or making other prohibited payments to government officials or other persons to obtain or retain business or gain some other business advantage.
Compliance with the FCPA, in particular, is expensive and difficult, particularly in countries in which corruption is a recognized problem. The FCPA presents particular challenges in the pharmaceutical industry, because, in many countries,
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hospitals are operated by the government, and doctors and other hospital employees are considered foreign officials. Certain payments to hospitals in connection with clinical trials and other work have been deemed to be improper payments to government officials and have led to FCPA enforcement actions. The FCPA also obligates companies whose securities are listed in the United States to comply with certain accounting provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.
We may in the future operate in jurisdictions that pose a high risk of potential Bribery Act or FCPA violations, and we may participate in collaborations and relationships with third parties whose actions could potentially subject us to liability under the Bribery Act, FCPA, or local anti-corruption laws. We are also subject to other laws and regulations governing our international operations, including regulations administered by the governments of the United Kingdom, and the United States, Canada, and authorities in the European Union, including applicable export control regulations, economic sanctions on countries and persons, customs requirements, and currency exchange regulations, collectively referred to as the Trade Control laws. In addition, various laws, regulations, and executive orders also restrict the use and dissemination outside of the United States, or the sharing with certain non-U.S. nationals, of information classified for national security purposes, as well as certain products and technical data relating to those products. If we expand our presence outside of the United States, it will require us to dedicate additional resources to comply with these laws, and these laws may preclude us from developing, manufacturing, or selling certain products and product candidates outside of the United States, which could limit our growth potential and increase our development costs.
If we are not in compliance with the Bribery Act, the FCPA, and other anti-corruption laws or Trade Control laws, we may be subject to criminal and civil penalties, disgorgement and other sanctions and remedial measures, and legal expenses, which could have an adverse impact on our business, financial condition, results of operations, and liquidity. The SEC also may suspend or bar issuers from trading securities on U.S. exchanges for violations of the FCPA’s accounting provisions. Any investigation of any potential violations of the Bribery Act, the FCPA, other anti-corruption laws or Trade Control laws by U.K., U.S., or other authorities could also have an adverse impact on our reputation, our business, results of operations, and financial condition.
Risks Related to Our Intellectual Property
We may be unable to obtain and maintain patent protection for our technology and product candidates, or the scope of the patent protection obtained may not be sufficiently broad or enforceable, such that our competitors could develop and
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commercialize technology and products similar or identical to ours, and our ability to successfully commercialize our technology and product candidates may be impaired.
Our success depends in large part on itsour ability to obtain and maintain patent protection in the United States and other countries, with respect to itsour proprietary technology and product candidates. We have sought to protect our proprietary position by filing in the United States and in certain foreign jurisdictions, patent applications related to our novel technologies and product candidates.
The patent prosecution process is expensive and time-consuming, and we may not have filed, maintained, or prosecuted and may not be able to file, maintain, and prosecute all necessary or desirable patents or patent applications at a reasonable cost or in a timely manner. We may also fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection.
The patent position of pharmaceutical and biotechnology companies generally is highly uncertain, involves complex legal and factual questions, and has in recent years been the subject of much litigation. As a result, the issuance, scope, validity, enforceability, and commercial value of our patent rights are highly uncertain. Our pending and future patent applications may fail to result in issued patents in the United States or in other foreign countries which protect our technology or product candidates, or which effectively prevent others from commercializing competitive technologies and products. In addition, the laws of foreign countries may not protect our rights to the same extent as the laws of the United States, and the standards applied by the USPTO and foreign patent offices in granting patents are not always applied uniformly or predictably. For example, unlike patent law in the United States, European patent law precludes the patentability of methods of treatment of the human body and imposes substantial restrictions on the scope of claims it will grant, of broader than specifically disclosed embodiments. Publications of discoveries in the scientific literature often lag behind the actual discoveries, and patent applications in the United States and other jurisdictions are typically not published until 18 months after filing, or in some cases not at all. Therefore, we cannot be certain whether we or our licensors were the first to make the inventions claimed in our owned or licensed patents or pending patent applications, or that we or our licensors were the first to file for patent protection of such inventions. Databases for patents and publications, and methods for searching them, are inherently limited so we may not
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know the full scope of all issued and pending patent applications. As a result, the issuance, scope, validity, enforceability, and commercial value of our patent rights are uncertain. Our pending and future patent applications may not result in patents being issued which protect our technology or product candidates, in whole or in part, or which effectively prevent others from commercializing competitive technologies and products. In particular, during prosecution of any patent application, the issuance of any patents based on the application may depend upon our ability to generate additional preclinical or clinical data that support the patentability of itsour proposed claims. We may not be able to generate sufficient additional data on a timely basis, or at all. Moreover, changes in either the patent laws or interpretation of the patent laws in the United States and other countries may diminish the value of our patents or narrow the scope of our patent protection.
Even if our owned and licensed patent applications issue as patents, they may not issue in a form that will provide us with any meaningful protection for our proprietary technology and product candidates, prevent competitors from competing with us, or otherwise provide us with any competitive advantage. Our competitors may be able to circumvent our owned or licensed patents by developing similar or alternative technologies or products in a non-infringing manner. In particular, a competitorsome instances, we may develop an approachneed to deliver drugs through the mucus layerlicense additional patents and trade secrets to the underlying target tissue that uses a different approach thancommercialize our OcuNanoE™ nanoemulsion formulation, and therefore may not infringe on our patent rights.product candidates in certain territories.
The issuance of a patent is not conclusive as to our inventorship, ownership, scope, validity, or enforceability, and our owned and licensed patents may be challenged in the courts or patent offices in the United States and abroad. Such challenges may result in loss of exclusivity or in patent claims being narrowed, invalidated, or held unenforceable, in whole or in part, which could limit itsour ability to stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our technology and product candidates. Given the amount of time required for the development, testing, and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized. As a result, our patent portfolio may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours.
Patent reform legislation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents.
On September 16,In 2011, the Leahy-Smith America Invents Act or the Leahy-Smith Act,(the "Leahy-Smith Act") was signed into law. The Leahy-Smith Act includes a number of significant changes to United StatesU.S. patent law. These include provisions that affect the way patent applications are prosecuted and may also affect patent litigation. The USPTO developed new regulations and procedures to govern administration of the Leahy-Smith Act, and many of the substantive changes to patent law associated with the Leahy-
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SmithLeahy-Smith Act, and in particular, the first to file provisions, became effective on March 16,in 2013. The first to file provisions limit the rights of an inventor to patent an invention if not the first to file an application for patenting that invention, even if such invention was the first invention. The Leahy-Smith Act and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, which could have a material adverse effect on our business, financial condition, results of operations, and prospects. For example, the Leahy-Smith Act created a new administrative tribunal known as the Patent Trial and Appeals Board or PTAB,("PTAB"), that provides a venue for companies to challenge the validity of competitor patents at a cost that is much lower than district court litigation and on timelines that are much faster. Although it is not clear what, if any, long term impact the PTAB proceedings will have on the operation of our business, the outcome of patent challenge proceedings before the PTAB since its inception in 2013 have resulted in the invalidation of many U.S. patent claims. The availability of the PTAB as a lower-cost, faster, and potentially more potent tribunal for challenging patents could therefore increase the likelihood that our own patents will be challenged, thereby increasing the uncertainties and costs of maintaining, defending, and enforcing them.
If we are not able to obtain patent term extension in the United States under the Hatch-Waxman Act and in foreign countries under similar legislation, thereby potentially extending the term of our marketing exclusivity for our product candidates, our business may be materially harmed.
Depending upon the timing, duration, and specifics of FDA marketing approval of our product candidates, one of the U.S. patents covering each of such product candidates or the use thereof may be eligible for up to five years of patent term extension under the Hatch-Waxman Act. The Hatch-Waxman Act allows a maximum of one patent to be extended per FDA approved product to account for the patent term lost during the FDA regulatory review process. A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only those claims covering such approved drug product, a method for using it, or a method for manufacturing it may be extended. Patent term extension also may be available in certain foreign countries upon regulatory approval of our product candidates. Nevertheless, we may not be granted patent term extension either in the United States or in any foreign country because of, for example, failing to exercise due diligence during the testing phase or regulatory review process, failing to apply within applicable deadlines, failing to apply prior to expiration of relevant patents, or otherwise failing to satisfy applicable requirements. Moreover, the term of extension,
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as well as the scope of patent protection during any such extension, afforded by the governmental authority could be less than we request.
If we are unable to obtain patent term extension or restoration, or the term of any such extension is less than we request, the period during which we will have the right to exclusively market our product may be shortened and our competitors may obtain approval of competing products following our patent expiration sooner, and our revenue could be reduced, possibly materially.
It is possible that we will not obtain patent term extension under the Hatch-Waxman Act for a U.S. patent covering one of our product candidates even where that patent is eligible for patent term extension, or if we obtain such an extension, it may be for a shorter period than we had sought. Further, for our licensed patents, we do not have the right to control prosecution, including filing with the USPTO, a petition for patent term extension under the Hatch-Waxman Act. Thus, if one of our licensed patents is eligible for patent term extension under the Hatch-Waxman Act, we may not be able to control whether a petition to obtain a patent term extension is filed, or obtained, from the USPTO.
We may become involved in lawsuits to protect or enforce our patents or other intellectual property, which could be expensive, time-consuming, and unsuccessful.
Competitors and other third parties may infringe, misappropriate, or otherwise violate itsour owned and licensed patents, trade secrets, or other intellectual property. As a result, to counter infringement, misappropriation, or unauthorized use, we may be required to file infringement or misappropriation claims or other intellectual property related proceedings, which can be expensive and time-consuming. Any claims we assert against perceived infringers could provoke such parties to assert counterclaims against us alleging that we infringed their patents or that our asserted patents are invalid. In addition, in a patent infringement or other intellectual property related proceeding, a court may decide that a patent of ourours is invalid or unenforceable, in whole or in part, construe the patent’s claims narrowly or refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question. An adverse result in any litigation proceeding could put one or more of our patents at risk of being invalidated, held unenforceable, or interpreted narrowly, and could put any of our patent applications at risk of not yielding an issued patent. Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information or trade secrets could be compromised by disclosure during this type of litigation.
We may be subject to a third-party preissuance submission of prior art to the USPTO, or become involved in other contested proceedings such as opposition, derivation, reexamination, inter partes review, post-grant review, or interference proceedings in
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the United States or elsewhere, challenging our patent rights or the patent rights of others. An adverse determination in any such submission, proceeding, or litigation could reduce the scope of, or invalidate, our patent rights, allow third parties to commercialize our technology or product candidates and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize products without infringing third-party patent rights. In addition, if the breadth or strength of protection provided by our patents and patent applications is threatened, it could dissuade companies from collaborating with us to license, develop, or commercialize current or future product candidates.
In the United States, the FDA does not prohibit clinicians from prescribing an approved product for uses that are not described in the product’s labeling. Although use of a product directed by off-label prescriptions may infringe our method-of-treatment patents, the practice is common across medical specialties, particularly in the United States, and such infringement is difficult to detect, prevent, or prosecute.
Third parties may initiate legal proceedings alleging that we are infringing, misappropriating, or otherwise violating their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of our business.
Our commercial success depends upon our ability to develop, manufacture, market, and sell OCU300, and otherour product candidates and use our proprietary technologies without infringing, misappropriating, or otherwise violating the intellectual property and other proprietary rights of third parties. There is a considerable amount of intellectual property litigation in the biotechnology and pharmaceutical industries. We may become party to, or threatened with, infringement litigation claims regarding our products and technology, including claims from competitors or from non-practicing entities that have no relevant product revenue and against whom our own patent portfolio may have no deterrent effect. Moreover, we may become party to future adversarial proceedings or litigation regarding our patent portfolio or the patents of third parties. Such proceedings could also include contested post-grant proceedings such as oppositions, inter partes review, reexamination, interference, or derivation proceedings before the USPTO or foreign patent offices.
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The legal threshold for initiating litigation or contested proceedings is low, so even lawsuits or proceedings with a low probability of success might be initiated and require significant resources to defend. Litigation and contested proceedings can also be expensive and time-consuming, and our adversaries in these proceedings may have the ability to dedicate substantially greater resources to prosecuting these legal actions than we do. The risks of being involved in such litigation and proceedings may increase as our product candidates near commercialization and as we gain the greater visibility associated with being a public company. Third parties may assert infringement claims against us based on existing patents or patents that may be granted in the future. We may not be aware of all such intellectual property rights potentially relating to our product candidates and their uses.
Thus, we do not know with certainty that OCU300 or any of our other product candidates, or our development and commercialization thereof, do not and will not infringe or otherwise violate any third party’s intellectual property.
If we are found to infringe, misappropriate, or otherwise violate a third party’s intellectual property rights, we could be required to obtain a license from such third party to continue developing and marketing its products and technology. However, we may not be able to obtain any required license on commercially reasonable terms or at all. Even if we are able to obtain a license, it could be non-exclusive, thereby giving our competitors access to the same technologies licensed to us and could require us to make substantial licensing and royalty payments. We could be forced, including by court order, to cease commercializing the infringing technology or product. In addition, we could be found liable for monetary damages, including treble damages and attorneys’ fees if we are found to have willfully infringed a patent, and could be forced to indemnify our customers or collaborators. A finding of infringement could also result in an injunction that prevents us from commercializing our product candidates or forces us to cease some of our business operations, which could materially harm our business. In addition, we may be forced to redesign our product candidates, seek new regulatory approvals, and indemnify third parties pursuant to contractual agreements. Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on our business.
Obtaining and maintaining patent protection depends on compliance with various procedural, document submission, fee payment, and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.
Periodic maintenance, renewal, and annuity fees on any issued patent must be paid to the USPTO and foreign patent agencies in several stages or annually over the lifetime of our owned and licensed patents and patent applications. The USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment, and other similar provisions during the patent application process. In certain circumstances, we rely on our licensing partners to pay these
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fees to, or comply with the procedural and documentary rules of the relevant patent agency. While an inadvertent lapse can in many cases be cured by payment of a late fee or by other means in accordance with the applicable rules, there are situations in which noncompliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. Non-compliance events that could result in abandonment or lapse of a patent or patent application include failure to respond to official actions within prescribed time limits, non-payment of fees, and failure to properly legalize and submit formal documents. If we or our licensors fail to maintain the patents and patent applications covering our product candidates, it would have a material adverse effect on our business.
Certain aspects of OCU300 and our other product candidates and certain aspects of our OcuNanoE nanoemulsion formulation, are protected by patents exclusively licensed from other companies or institutions. If these third parties terminate their agreements with us or fail to maintain or enforce the underlying patents or licenses thereto, or we otherwise lose our rights to these patents, our competitive position and our market share in the markets for any of our approved products will be harmed.
A substantial portion of our patent portfolio is in-licensed. As such, we are a party to license agreements, and certain aspects of itsour business depend on patents and/or patent applications owned by other companies or institutions. In particular, we hold exclusive licenses for patent families relating to OCU300, other of our product candidates,OCU400, OCU410, and some aspects of our OcuNanoE™ nanoemulsion formulation.OCU200 and an exclusive license in the United States and Canada with respect to COVAXIN.
Pursuant to the license arrangement with UIC, which relates to OCU300, we are responsible for and control patent prosecution of licensed patent families developed jointly pursuant to the license arrangement with UIC, while we and UIC are each responsible for and control patent prosecution of licensed patent families developed or held individually by us or UIC, respectively.
Pursuant to the license arrangement with CU Agreement, which primarily relates to OCU200, we are responsible for and control the patent prosecution of all patent families licensed under the CU license arrangement.Agreement.
Pursuant to the license arrangement with SERI Agreement, which relates to NHR genes NR1D1, NR2E3(OCU400), RORA(OCU410), NUPR1, and NR2C1, from and after December 19, 2017, we have the right to assume responsibility and control patent prosecution of licensed patent families relating to these NHR genes. Additionally, we are responsible for and control patent prosecution for any patent applications developed in connection with the SERI licensing arrangementAgreement filed after December 19, 2017 that are owned jointly by us and SERI, or solely by us.
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Our rights with respect to in-licensed patents and patent applications may be lost if the applicable license agreement expires or is terminated. We are likely to enter into additional license agreements to in-license patents and patent applications as part of the development of our business in the future, under which we may not retain control of the preparation, filing, prosecution, maintenance, enforcement, and defense of such patents. If we are unable to maintain these patent rights for any reason, our ability to develop and commercialize our product candidates could be materially harmed.
Our licensors may not successfully prosecute certain patent applications, the prosecution of which they control, under which we are licensed and on which our business depends. Even if patents issueare issued from these applications, our licensors may fail to maintain these patents, may decide not to pursue litigation against third-party infringers, may fail to prove infringement, or may fail to defend against counterclaims of patent invalidity or unenforceability. In some cases, our licensors may in-license certain patents licensed to us. If our licensors were to fail to maintain such licenses, we may need to obtain additional licenses with respect to the applicable product candidates.
Risks with respect to parties from whom we have obtained intellectual property rights may also arise out of circumstances beyond our control. In spite of our best efforts, our licensors might conclude that we have materially breached our intellectual property agreements and might therefore terminate the intellectual property agreements, thereby removing our ability to market products covered by these intellectual property agreements. If our intellectual property agreements are terminated, or if the underlying patents fail to provide the intended market exclusivity, our competitors would have the freedom to seek regulatory approval of, and to market, products similar or identical to ours. Moreover, if our intellectual property agreements are terminated, our former licensors and/or assignors may be able to prevent us from utilizing the technology covered by the licensed or assigned patents and patent applications. This could have a material adverse effect on our competitive business position and our business prospects.
Some intellectual property which we own or have licensed may have been discovered through government funded programs and thus may be subject to federal regulations such as “march-in” rights, certain reporting requirements, and a preference for U.S. industry. Compliance with such regulations may limit our exclusive rights, subject us to expenditure of resources with respect to reporting requirements, and limit our ability to contract with non-U.S. manufacturers.
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Some of the licenses or intellectual property rights that we own or licenses have been generated through the use of United StatesU.S. government funding and may therefore be subject to certain federal regulations under the Bayh-Dole Act. To the best of our knowledge, our intellectual property for OCU400 for the treatment of NR2E3 mutation-associated inherited retinal degenerative disease and other inherited retinal degenerative diseases is subject to the Bayh-Dole Act. As a result, the United StatesU.S. government may have certain rights to intellectual property embodied in these patents and patent applications. In general, the Bayh-Dole Act provides the U.S. government certain rights in inventions developed using a government funded program, such as U.S. government’s right to a non-exclusive, non-transferable, irrevocable worldwide license to use inventions for any governmental purpose. In addition, under the Bayh-Dole Act, the U.S. government has the right to require any invention developed using U.S. government funding to be granted exclusive, partially exclusive, or non-exclusive licenses to any of these inventions to a third party if it determines that: (i) adequate steps have not been taken to commercialize the invention; (ii) government action is necessary to meet public health or safety needs; or (iii) government action is necessary to meet requirements for public use under federal regulations (also referred to as “march-in rights”). Under the Bayh-Dole Act, the U.S. government also has the right to take title to inventions developed using a U.S. government funded program, if one fails to disclose the invention to the government and failfails to file an application to register the intellectual property within specified time limits. In addition, the U.S. government may acquire title to these inventions in any country in which a patent application is not filed within specified time limits. Intellectual property generated under a government funded program is also subject to certain reporting requirements. In addition, the Bayh-Dole Act requires that any products subject to the Bayh-Dole Act be manufactured substantially in the United States. However, under the Bayh-Dole Act, this manufacturing preference requirement can be waived if the owner of the intellectual property can show that reasonable efforts to manufacture the product substantially in the United States were unsuccessful, or that under the circumstances, domestic manufacture is not commercially feasible. Any exercise by the government of any of the foregoing rights under the Bayh-Dole Act may affect our competitive position, business, financial condition, results of operations, and prospects.
If we fail to comply with our obligations in our intellectual property licenses and funding arrangements with third parties, we could lose rights that are important to our business.
Our license agreements with CU, UIC, and SERI under which we license certain of our patent rights and a significant portion of the technology for OCU300 and otherour product candidates, impose royalty and other financial obligations on us and other substantial performance obligations. We may also enter into additional licensing and funding arrangements with third parties that may impose diligence, development, and commercialization timelines and milestone payment, royalty, insurance, and other obligations on us. If we fail to comply with our obligations under current or future license and collaboration agreements, our counterparties may have the right to terminate
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these agreements, in which event we might not be able to develop, manufacture, or market any product that is covered by these agreements or may face other penalties under the agreements. Such an occurrence could diminish the value of our products and product candidates. Termination of these agreements or reduction or elimination of our rights under these agreements may result in us having to negotiate new or reinstated agreements with less favorable terms or cause us to lose our rights under these agreements, including our rights to important intellectual property or technology.
In addition, it is possible that CU, UIC or SERIour licensors may conclude that we have materially breached the applicable license agreement and might therefore terminate the agreement, thereby removing our ability to market products covered by our license agreements with CU, UIC, or SERI, respectively.such agreements. If any license agreement is terminated, or if the underlying patents fail to provide the intended market exclusivity, competitors would have the freedom to seek regulatory approval of, and to market, products similar or identical to ours. Moreover, if any of our license agreements isare terminated, the counterparty and/or its assignors may be able to prevent us from utilizing the technology covered by the licensed or assigned patents and patent applications. This could have a materialmaterially adverse effect on our competitive business position and our business prospects.
In addition, the agreements under which we currently licenseslicense intellectual property or technology from third parties are complex, and certain provisions in such agreements may be susceptible to multiple interpretations. The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology or increase what we believe to be our financial or other obligations under the relevant agreement, either of which could have a material adverse effect on our business, financial condition, results of operations, and prospects. Moreover, if disputes over intellectual property that we have licensed prevent or impair our ability to maintain our current licensing arrangements on commercially acceptable terms, we may be unable to successfully develop and commercialize the affected product candidates, which could have a material adverse effect on our business, financial conditions, results of operations, and prospects.
We may not be able to protect our intellectual property and proprietary rights throughout the world.
Filing, prosecuting, and defending patents on product candidates in all countries throughout the world would be prohibitively expensive, and the laws of foreign countries may not protect our rights to the same extent as the laws of the United States.
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Consequently, we may not be able to prevent third parties from practicing our inventions in all countries outside the United States, or from selling or importing products made using our inventions in and into the United States or other jurisdictions. Competitors may use our technologies in jurisdictions where we have not obtained patent protection to develop their own products and, further, may export otherwise infringing products to territories where we have patent protection or licenses, but enforcement is not as strong as that in the United States. These products may compete with our products, and our patents or other intellectual property rights may not be effective or sufficient to prevent them from competing.
Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions. The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents, trade secrets, and other intellectual property protection, particularly those relating to biotechnology products, which could make it difficult for us to stop the infringement of our patents or marketing of competing products in violation of our intellectual property and proprietary rights generally. Proceedings to enforce our intellectual property and proprietary rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly, could put our patent applications at risk of not issuing,being issued, and could provoke third parties to assert claims against us. We may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded, if any, may not be commercially meaningful. Accordingly, our efforts to enforce our intellectual property and proprietary rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or license.
Many countries have compulsory licensing laws under which a patent owner may be compelled to grant licenses to third parties. In addition, many countries limit the enforceability of patents against government agencies or government contractors. In these countries, the patent owner may have limited remedies, which could materially diminish the value of such patent. If we or any of our licensors are forced to grant a license to third parties with respect to any patents relevant to our business, our competitive position may be impaired, and our business, financial condition, results of operations, and prospects may be adversely affected.
We may be subject to claims by third parties asserting that our employees or we have misappropriated their intellectual property or claiming ownership of what we regard as our own intellectual property.
Many of our and our licensors’ employees and contractors were previously employed at other biotechnology, medical device, or pharmaceutical companies, including our competitors or potential competitors. Although we try to ensure that our employees and contractors do not use the proprietary information or know-how of others in their work for us, we may be subject to claims
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that these individuals or we have used or disclosed intellectual property, including trade secrets or other proprietary information, of any such employee’s former employer. Litigation may be necessary to defend against these claims.
In addition, while it is our policy to require our employees and contractors who may be involved in the development of intellectual property to execute agreements assigning such intellectual property to us, we may be unsuccessful in executing such an agreement with each party who in fact develops intellectual property that we regard as our own. Furthermore, we are unable to control whether itsour licensors have obtained similar assignment agreements from their own employees and contractors. Our and their assignment agreements may not be self-executing or may be breached, and we or our licensors may be forced to bring claims against third parties, or defend claims they may bring against us, to determine the ownership of what we regard as our intellectual property.
If we or our licensors fail in prosecuting or defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel which could have a material adverse effect on our competitive business position and prospects. Such intellectual property rights could be awarded to a third party, and we could be required to obtain a license from such third party to commercialize our technology or products, which may not be available on commercially reasonable terms or at all. Even if we are successful in prosecuting or defending against such claims, litigation could result in substantial costs and be a distraction to management.
Intellectual property litigation or other legal proceedings relating to intellectual property could cause us to spend substantial resources and distract our personnel from their normal responsibilities.
Even if resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses and could distract our technical and management personnel from their normal responsibilities. In addition, there could be public announcements of the results of hearings, motions, or other interim proceedings or developments and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock. Such litigation or proceedings could substantially increase our operating losses and reduce the resources available for development activities or any future sales, marketing, or distribution activities. We may not have sufficient financial or other resources to conduct such litigation or proceedings adequately. Some of our competitors may be able to
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sustain the costs of such litigation or proceedings more effectively than we can because of their greater financial resources and may also have an advantage in such proceedings due to their more mature and developed intellectual property portfolios. Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings could have an adverse effect on our ability to compete in the marketplace.
If we are unable to protect the confidentiality of our trade secrets, our business and competitive position would be harmed.
In addition to seeking patents for our technology and product candidates, we also rely on trade secrets, including unpatented know-how, technology and other proprietary information, to maintain our competitive position. We seek to protect these trade secrets, in part, by entering into non-disclosure and confidentiality agreements with parties who have access to them, such as our employees, corporate collaborators, outside scientific collaborators, contract manufacturers, consultants, advisors, and other third parties. We also enter into confidentiality and invention or patent assignment agreements with our employees and consultants. Despite these efforts, any of these parties may breach the agreements and disclose our proprietary information, including our trade secrets, and we may not be able to obtain adequate remedies for such breaches. Detecting the disclosure or misappropriation of a trade secret and enforcing a claim that a party illegally disclosed or misappropriated a trade secret is difficult, expensive, and time-consuming, and the outcome is unpredictable. In addition, some courts inside and outside the United States are less willing or unwilling to protect trade secrets. If any of our trade secrets were to be lawfully obtained or independently developed by a competitor, we would have no right to prevent them, or those to whom they communicate it, from using that technology or information to compete with us. If any of our trade secrets were to be disclosed to or independently developed by a competitor, our competitive position would be harmed.
Risks Related to Employee Matters and Managing Growth
Our future success depends on our ability to retain key executives and to attract, retain and motivate qualified personnel.
We are highly dependent on the research and development, clinical and business development expertise of Shankar Musunuri, Ph.D., MBA, our Chief Executive Officer, Chairman of the Board and Co-Founder, Daniel Jorgensen, M.D., M.P.H., MBA, our Chief Medical Officer, and Rasappa Arumugham, Ph.D., our Chief Scientific Officer, as well as the other principal members of our management, scientific and clinical teams. Although we have entered into employment agreements with our executive officers, each of them may terminate their employment with us at any time. We do not maintain “key person” insurance for any of our executives or other employees.
Recruiting and retaining qualified scientific, clinical, manufacturing, legal and sales and marketing personnel will also be critical to our success. The loss of the services of our executive officers or other key employees could impede the achievement of our research, development and commercialization objectives and seriously harm our ability to successfully implement our business strategy. Furthermore, replacing executive officers and key employees may be difficult and may take an extended period of time because of the limited number of individuals in our industry with the breadth of skills and experience required to successfully develop, gain regulatory approval of and commercialize products. Competition to hire from this limited pool is intense, and we may be unable to hire, train, retain or motivate these key personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies for similar personnel. We also experience competition for the hiring of scientific and clinical personnel from universities and research institutions. In addition, we rely on consultants and advisors, including scientific and clinical advisors, to assist us in formulating our research and development and commercialization strategy. Our consultants and advisors may be employed by employers other than us and may have commitments under consulting or advisory contracts with other entities that may limit their availability to us. If we are unable to continue to attract and retain high quality personnel, our ability to pursue our growth strategy will be limited.
We expect to expand our development, regulatory and manufacturing capabilities and potentially implement sales, marketing and distribution capabilities, and as a result, we may encounter difficulties in managing our growth, which could disrupt our operations.
We expect to experience significant growth in the number of our employees and the scope of our operations, particularly in the areas of drug development, clinical, regulatory affairs, manufacturing, sales, marketing and distribution. To manage our anticipated future growth, we must continue to implement and improve our managerial, operational and financial systems, expand our facilities and continue to recruit and train additional qualified personnel. Our management may need to devote a significant amount of our attention to managing these growth activities. Due to our limited financial resources and our limited experience in managing such anticipated growth, we may not be able to effectively manage the expansion of our operations or recruit and train additional qualified personnel. Our inability to manage the expansion of our operations effectively may result in weaknesses in our infrastructure, give rise to operational mistakes, loss of business opportunities, loss of employees and reduced productivity among remaining employees. Our expected growth could also require significant capital expenditures and
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may divert financial resources from other projects, such as the development of additional product candidates. If we are unable to effectively manage our expected growth, our expenses may increase more than expected, our ability to generate revenues could be reduced and we may not be able to implement our business strategy, including the successful commercialization of our product candidates.
Risks Related to Our Common Stock
The trading price of the shares of the our Common Stock could be highly volatile, and purchasers of the Common Stock could incur substantial losses.
Our stock price has been, and will likely continue to be volatile. The stock market in general and the market for stock of biopharmaceutical companies in particular have experienced extreme volatility that has often been unrelated to the operating performance of particular companies. As a result of this volatility, investors may not be able to sell their common stock at or above their purchase price. The market price for our common stock may be influenced by those factors discussed in this “Risk Factors” section and many others, including:
our ability to enroll subjects in its ongoing and planned clinical trials;
results of our clinical trials and preclinical studies, and the results of trials of our competitors or those of other companies in our market sector;
regulatory approval of our product candidates, or limitations to specific label indications or patient populations for our use, or changes or delays in the regulatory review process;
the level of expenses related to any of our product candidates or clinical development programs;
regulatory developments in the United States and foreign countries;
reports of adverse events in other of our products, competing biologics or gene therapy products;
changes in the structure of healthcare payment systems, especially in light of current reforms to the U.S. healthcare system;
the success or failure of our efforts to acquire, license or develop additional product candidates;
innovations or new products developed by us or our competitors;
announcements by us or our competitors of significant acquisitions, strategic partnerships, joint ventures or capital commitments;
manufacturing, supply or distribution delays or shortages;
any changes to our relationship with any manufacturers, suppliers, licensors, future collaborators or other strategic partners;
achievement of expected product sales and profitability;
variations in our financial results or those of companies that are perceived to be similar to ours;
market conditions in the biopharmaceutical sector and issuance of securities analysts’ reports or recommendations;
trading volume of our common stock;
an inability to obtain additional funding;
sales of our stock by insiders and stockholders or the perception that such sales could occur;
our ability to effectively manage its growth;
ineffectiveness of our internal control over financial reporting;
additions or departures of key personnel, including major changes in our board or management;
intellectual property, product liability or other litigation against us; and
general economic, industry and market conditions other events or factors, many of which are beyond our control.
In addition, in the past, stockholders have initiated class action lawsuits against biopharmaceutical companies following periods of volatility in the market prices of these companies’ stock. Such litigation, if instituted against us, could cause us to incur
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substantial costs and divert management’s attention and resources, which could have a material adverse effect on our business, financial condition and results of operations.
An active trading market for our common stock may not be sustainable. If an active trading market is not sustained, our ability to raise capital in the future may be impaired.
Following the consummation of our reverse merger, our shares of common stock continue to be listed and are trading on the Nasdaq. However, an active trading market for our shares of common stock may not be sustained. If an active market for our common stock is not sustained, it may be difficult for our stockholders to sell shares of our common stock without depressing the market price for the shares or at all. An inactive trading market may also impair our ability to raise capital to continue to fund operations by selling shares and may impair our ability to acquire other companies or technologies by using our shares as consideration.
Our failure to meet the continued listing requirements of the Nasdaq could result in a delisting of the Common Stock.
We must continue to satisfy Nasdaq continued listing requirements, including, among other things, certain corporate governance requirements and a minimum closing bid price requirement of $1.00 per share. If a company fails for 30 consecutive business days to meet the $1.00 minimum closing bid price requirement, Nasdaq will send a deficiency notice to the company, advising that it has been afforded a “compliance period” of 180 calendar days to regain compliance with the applicable requirements.
On December 27, 2019, we received a deficiency letter from the Nasdaq notifying us that, for the last 30 consecutive business days, the closing bid price for our common stock has been below the minimum $1.00 per share required for continued listing on The Nasdaq Capital Market pursuant to the minimum closing bid price requirement. The Nasdaq deficiency letter had no immediate effect on the listing of our common stock. In accordance with Nasdaq Listing Rule 5810(c)(3)(A), we have been given 180 calendar days, or until June 24, 2020, to regain compliance with the minimum closing bid price requirement by causing its stock to close above $1.00 for a minimum of 10 consecutive trading days. If we do not regain compliance with the minimum closing bid price requirement by June 24, 2020, we may be afforded a second 180 calendar day period to regain compliance. To qualify, we would be required to meet the continued listing requirement for market value of publicly held shares and all other initial listing standards for Nasdaq, except for the minimum bid price requirement. In addition, we would be required to notify Nasdaq of our intent to cure the deficiency during the second compliance period.
We can provide no assurance that we will be able to regain compliance with the minimum closing bid price requirement by June 24, 2020, or by any date, or that we will be able to remain in compliance with other Nasdaq continued listing requirements. A delisting of our common stock from Nasdaq could materially reduce the liquidity of our common stock, impairing your ability to sell or purchase shares of common Stock when you wish to do so, and could result in a corresponding material reduction in the price of our common stock. In addition, delisting could harm our ability to raise capital through alternative financing sources on terms acceptable to us, or at all, and may result in the potential loss of confidence by investors and employees. In the event of a delisting, we can provide no assurance that any action taken by us to restore compliance with listing requirements would allow the common stock to become listed again, stabilize the market price or improve the liquidity of the common stock, prevent the common stock from dropping below the Nasdaq minimum bid price requirement or prevent future non-compliance with Nasdaq’s listing requirements.
If shares of our common stock cease to be listed on a national exchange they may become subject to the “penny stock” rules of the SEC and the trading market in our securities may become limited, which will make transactions in its stock cumbersome and may reduce the value of an investment in the stock.
If shares of our common stock cease to be listed on the Nasdaq or another national exchange, they may be subject to regulation as a “penny stock” under Rule 15g-9 under the Exchange Act. That rule establishes the definition of a “penny stock,” for the purposes relevant to us, as any equity security that is no longer trading on a national exchange and has a market price of less than $5.00 per share or with an exercise price of less than $5.00 per share, subject to certain exceptions. For any transaction involving a penny stock, unless exempt, the rules require: (a) that a broker or dealer approve a person’s account for transactions in penny stocks; and (b) the broker or dealer receive from the investor a written agreement to the transaction, setting forth the identity and quantity of the penny stock to be purchased.
In order to approve a person’s account for transactions in penny stocks, the broker or dealer must: (a) obtain financial information and investment experience objectives of the person and (b) make a reasonable determination that the transactions in penny stocks are suitable for that person and the person has sufficient knowledge and experience in financial matters to be capable of evaluating the risks of transactions in penny stocks. The broker or dealer must also deliver, prior to any transaction
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in a penny stock, a disclosure schedule prescribed by the SEC relating to the penny stock market, which, in highlight form: (x) sets forth the basis on which the broker or dealer made the suitability determination; and (y) confirms that the broker or dealer received a signed, written agreement from the investor prior to the transaction.
Disclosure also has to be made about the risks of investing in penny stocks in both public offerings and in secondary trading and about the commissions payable to both the broker or dealer and the registered representative, current quotations for the securities and the rights and remedies available to an investor in cases of fraud in penny stock transactions. Finally, monthly statements have to be sent disclosing recent price information for the penny stock held in the account and information on the limited market in penny stocks.
Generally, brokers may be less willing to execute transactions in securities subject to the “penny stock” rules. This may make it more difficult for investors to dispose of our common stock and cause a decline in the market value of our common stock.
If shares of our common stock cease to be listed on a national exchange, our securities will not be eligible for federal preemption rights and be subject to state “blue sky” laws which may affect our capabilities of raising capital.
Each state has its own securities laws, often called “blue sky” laws, which (i) limit sales of securities to a state’s residents unless the securities are registered in that state or qualify for an exemption from registration, and (ii) govern the reporting requirements for broker-dealers doing business directly or indirectly in the state. Before a security is sold in a state, there must be a registration in place to cover the transaction, or the transaction must be exempt from registration. The applicable broker must be registered in that state. We do not know whether securities will be registered or exempt from registration under the laws of any state. If our securities cease to be listed on the national exchange, a determination regarding registration will be made by those broker-dealers, if any, who agree to serve as the market-makers for our common stock. Registering or qualifying shares with states can be time consuming. Compliance and regulatory costs may vary from state to state and may adversely affect future financings and our ability to raise capital.
If our common stock is delisted from a national exchange, some institutional investors may not be allowed to purchase our shares and may be required to liquidate their current positions in our stock which could negatively affect the price and volatility of our shares.
Institutional investors may be restricted by their investment policies from investing in shares of companies that are not listed on a national exchange and may be required to liquidate their positions if our securities are delisted from a national exchange. Liquidations, should they occur, may increase volatility and cause wide fluctuations and further declines in the prices of our securities.
We do not currently intend to pay dividends on our common stock, and, consequently, your ability to achieve a return on your investment will depend on appreciation, if any, in the price of our common stock.
We have never declared or paid any cash dividend on our common stock. We currently anticipate that we will retain future earnings for the development, operation, and expansion of our business and doesdo not anticipate declaring or paying any cash dividends for the foreseeable future. In addition, the terms of any future debt agreements may preclude us from paying dividends. Any return to stockholders will therefore be limited to the appreciation of their stock. There is no guarantee that the common stock will appreciate in value or even maintain the price at which stockholders have purchased their shares.
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Sales of a substantial number of common stock by our stockholders in the public market could cause our stock price to fall.
If our existing stockholders sell, or indicate an intention to sell, substantial amounts of common stock in the public market, the market price of our common stock could decline. We had 52.6199.4 million shares of common stock outstanding as of December 31, 2019. Of these shares, 46.9 million shares of common stock2021, which were all freely tradable, without restriction, in the public market as of December 31, 2019. Upon the expiration of lock-up agreements entered into by our directors, executive officers and certain other stockholders in connection with the reverse merger, which expiration occurred on March 25, 2020, approximately 5.7 million shares of our common stock became eligible for sale in the public market to the extent permitted by the provisions of Rule 144 and Rule 701 under the Securities Act.2021.
If these additionala substantial number of shares of common stock are sold, or if it is perceived that they will be sold, in the public market, the market price of our common stock could decline and we are unable to predict the effect that sales may have on the prevailing market price of our common stock.
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We will incur significant increased costs as a result of operating as a public company, and our management will be required to devote substantial time to new compliance initiatives.
We began operating as a public company as a result of the Merger. As a public company, we will incur significant legal, accounting and other expenses that we did not incur as a private company prior to the reverse merger. We are subject to the reporting requirements of the Exchange Act, which require, among other things, that we file with the SEC annual, quarterly and current reports with respect to our business and financial condition.
In addition, Sarbanes-Oxley, as well as rules subsequently adopted by the SEC and Nasdaq to implement provisions of Sarbanes-Oxley, impose significant requirements on public companies, including requiring establishment and maintenance of effective disclosure and financial controls and changes in corporate governance practices. During the period we were considered an “emerging growth company” as defined in the Jumpstart Our Business Startups Act of 2012, we were able to take advantage of certain exemptions from various reporting requirements that are applicable to public companies that are not emerging growth companies. As of December 31, 2019, we are no longer an emerging growth company, and accordingly we will no longer be able to take advantage of exemptions available by virtue of having emerging growth company status. Further, pursuant to the Dodd-Frank Wall Street Reform and Consumer Protection Act of 2010, the SEC has adopted additional rules and regulations in these areas, such as mandatory “say on pay” voting requirements that are applicable to us following its ceasing to be an emerging growth company. Stockholder activism, the current political environment and the current high level of government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which may lead to additional compliance costs and impact the manner in which we operate our business in ways we cannot currently anticipate.
We expect the rules and regulations applicable to public companies to substantially increase our legal and financial compliance costs and to make some activities more time consuming and costly. If these requirements divert the attention of our management and personnel from other business concerns, they could have a material adverse effect on our business, financial condition and results of operations. The increased costs will increase our net loss, and may require us to reduce costs in other areas of our business or increase the prices of our products or services. For example, we expect these rules and regulations to make it more difficult and more expensive for us to obtain director and officer liability insurance, and we may be required to incur substantial costs to maintain the same or similar coverage. We cannot predict or estimate the amount or timing of additional costs we may incur to respond to these requirements. The impact of these requirements could also make it more difficult for us to attract and retain qualified persons to serve on our Board of Directors, our board committees or as executive officers.
If securities or industry analysts do not publish research or reports or publish unfavorable research or reports about our business, our stock price and trading volume could decline.
The trading market for our common stock depends in part on the research and reports that securities or industry analysts publish about us, our business, our market or our competitors. We do not currently have and may never obtain research coverage by securities and industry analysts. If no securities or industry analysts commence coverage of us, the trading price for our stock would be negatively impacted. In the event we obtain securities or industry analyst coverage, if one or more of the analysts who covers us downgrades our stock, our stock price would likely decline. If one or more of these analysts ceases to cover us or fails to regularly publish reports on us, interest in our stock could decrease, which could cause our stock price or trading volume to decline.
If we fail to maintain proper and effective internal control over financial reporting, our ability to produce accurate and timely financial statements could be impaired, investors may lose confidence in our financial reporting and the trading price of our common stock may decline.
Pursuant to Section 404 of Sarbanes-Oxley, our management is required to report upon the effectiveness of our internal control over financial reporting. Additionally, if we reach an accelerated filer threshold, our independent registered public accounting firm will be required to attest to the effectiveness of our internal control over financial reporting. The rules governing the standards that must be met for management to assess our internal control over financial reporting are complex and require significant documentation, testing and possible remediation. To comply with the requirements of being a reporting company under the Exchange Act, we will need to upgrade our information technology systems; implement additional financial and management controls, reporting systems and procedures; and hire additional accounting and finance staff. If we or, if required, our auditors are unable to conclude that our internal control over financial reporting is effective, investors may lose confidence in our financial reporting and the trading price of our common stock may decline.
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We cannot assure you that there will not be material weaknesses or significant deficiencies in our internal control over financial reporting in the future. Any failure to maintain internal control over financial reporting could severely inhibit our ability to accurately report our financial condition, results of operations or cash flows. If we are unable to conclude that our internal control over financial reporting is effective, or, if applicable, if our independent registered public accounting firm determines we have a material weakness or significant deficiency in our internal control over financial reporting, investors may lose confidence in the accuracy and completeness of our financial reports, the market price of our common stock could decline, and we could be subject to sanctions or investigations by Nasdaq, the SEC or other regulatory authorities. Failure to remedy any material weakness in our internal control over financial reporting, or to implement or maintain other effective control systems required of public companies, could also restrict our future access to the capital markets.
Provisions in our charter documents and under Delaware law could discourage a takeover that stockholders may consider favorable and may lead to entrenchment of management.
Our amended and restated certificate of incorporation and amended and restated bylaws contain provisions that could significantly reduce the value of our shares to a potential acquiror or delay or prevent changes in control or changes in our management without the consent of our Board of Directors. The provisions in our charter documents include the following:
a classified Board of Directors with three-year staggered terms, which may delay the ability of stockholders to change the membership of a majority of our Board of Directors;
no cumulative voting in the election of directors, which limits the ability of minority stockholders to elect director candidates;
the exclusive right of our Board of Directors, unless the Board of Directors grants such right to the stockholders, to elect a director to fill a vacancy created by the expansion of the Board of Directors or the resignation, death, or removal of a director, which prevents stockholders from being able to fill vacancies on our Board of Directors;
the prohibition on removal of directors without cause due to the classified Board of Directors;
the ability of our Board of Directors to authorize the issuance of shares of preferred stock and to determine the price and other terms of those shares, including preferences and voting rights, without stockholder approval, which could be used to significantly dilute the ownership of a hostile acquiror;
the ability of our Board of Directors to alter our amended and restated bylaws without obtaining stockholder approval;
the required approval of at least 66-2/3% of the shares entitled to vote to adopt, amend, or repeal our amended and restated bylaws or repeal certain provisions of our amended and restated certificate of incorporation;
a prohibition on stockholder action by written consent, which forces stockholder action to be taken at an annual or special meeting of our stockholders;
an exclusive forum provision providing that the Court of Chancery of the State of Delaware will be the exclusive forum for certain actions and proceedings;
the requirement that a special meeting of stockholders may be called only by the chairman of the Board of Directors, the chief executive officer, or the Board of Directors, which may delay the ability of our stockholders to force consideration of a proposal or to take action, including the removal of directors; and
advance notice procedures that stockholders must comply with in order to nominate candidates to our Board of Directors or to propose matters to be acted upon at a stockholders’ meeting, which may discourage or deter a potential acquiror from conducting a solicitation of proxies to elect the acquiror’s own slate of directors or otherwise attempting to obtain control of us.
We are also subject to the anti-takeover provisions contained in Section 203 of the Delaware General Corporation Law.Law ("DGCL"). Under Section 203, a corporation may not, in general, engage in a business combination with any holder of 15% or more of its capital stock unless the holder has held the stock for three years or, among other exceptions, the board of directors has approved the transaction.
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Our sixth amended and restated certificate of incorporation, as amended, provides that the Court of Chancery of the State of Delaware is the exclusive forum for substantially all disputes between us and our stockholders, which could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us or our directors, officers, or employees.
Our sixth amended and restated certificate of incorporation, as amended, provides that, unless we consent in writing to the selection of an alternative forum, the Court of Chancery of the State of Delaware is the exclusive forum for any derivative
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action or proceeding brought on our behalf, any action asserting a breach of fiduciary duty, any action asserting a claim against us arising pursuant to the Delaware General Corporation Law,DGCL, our amended and restated certificate of incorporation or our amended and restated bylaws, or any action asserting a claim against us that is governed by the internal affairs doctrine. This exclusive forum provision would not apply to suits brought to enforce any liability or duty created by the Securities Act or the Exchange Actof 1933, as amended (the "Securities Act"), or any other claim for which the federal courts have exclusive jurisdiction. These choice of forum provisions may limit a stockholder’s ability to bring a claim in a judicial forum that it finds favorable for disputes with us or our directors, officers, or other employees, which may discourage such lawsuits against us and our directors, officers, and other employees. By agreeing to this provision, however, stockholders will not be deemed to have waived our compliance with the federal securities laws and the rules and regulations thereunder. Furthermore, the enforceability of similar choice of forum provisions in other companies’ certificates of incorporation has been challenged in legal proceedings, and it is possible that a court could find these types of provisions to be inapplicable or unenforceable. If a court were to find the choice of forum provisions in our certificate of incorporation to be inapplicable or unenforceable in an action, we may incur additional costs associated with resolving such action in other jurisdictions, which could adversely affect our business and financial condition.
CertainGeneral Risk Factors
The trading price of the warrants issuedshares of our Common Stock could be highly volatile, and purchasers of the Common Stock could incur substantial losses.
Our stock price has been, and will likely continue to be volatile. The stock market in general and the market for stock of biopharmaceutical companies in particular have experienced extreme volatility that has often been unrelated to the operating performance of particular companies. As a result of this volatility, investors may not be able to sell their common stock at or above their purchase price. The market price for our common stock may be influenced by those factors discussed in this "Risk Factors" section and many others, including:
our ability to enroll subjects in our ongoing and planned clinical trials;
results of our clinical trials and preclinical studies, and the results of trials of our competitors or those of other companies in our market sector;
regulatory authorization or approval of our product candidates, or limitations to specific label indications or patient populations for use, or changes or delays in the Pre-Merger Financing contain price-based adjustment provisions which, if triggered, may cause substantialregulatory review process;
the level of expenses related to any of our product candidates or clinical development programs;
regulatory developments in the United States and foreign countries;
reports of adverse events in any of our products, competing biologics, or gene therapy products;
changes in the structure of healthcare payment systems, especially in light of current reforms to the U.S. healthcare system;
the success or failure of our efforts to acquire, license, or develop additional dilutionproduct candidates;
innovations or new products developed by us or our competitors;
announcements by us or our competitors of significant acquisitions, strategic partnerships, joint ventures, or capital commitments;
manufacturing, supply, or distribution delays or shortages;
any changes to our stockholders.relationship with any manufacturers, suppliers, licensors, future collaborators, or other strategic partners;
achievement of expected product sales and profitability;
variations in our financial results or those of companies that are perceived to be similar to ours;
market conditions in the biopharmaceutical sector and issuance of securities analysts’ reports or recommendations;
trading volume of our common stock;
an inability to obtain additional funding;
sales of our stock by insiders and stockholders or the perception that such sales could occur;
our ability to effectively manage our growth;
ineffectiveness of our internal control over financial reporting;
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additions or departures of key personnel, including major changes in our board or management;
intellectual property, product liability, or other litigation against us; and
general economic, industry, market conditions, and other events or factors, many of which are beyond our control.
In addition, in the past, stockholders have initiated class action lawsuits against biopharmaceutical companies following periods of volatility in the market prices of these companies’ stock. Such litigation, if instituted against us, could cause us to incur substantial costs and divert management’s attention and resources, which could have a material adverse effect on our business, financial condition, and results of operations.
If securities or industry analysts do not publish research or reports or publish unfavorable research or reports about our business, our stock price and trading volume could decline.
The trading market for our common stock depends in part on the research and reports that securities or industry analysts publish about us, our business, our market, or our competitors. We currently have research coverage by four securities and industry analysts. If one or more of the analysts who currently or in the future may cover us downgrades our stock, our stock price would likely decline. If one or more of these analysts ceases to cover us or fails to regularly publish reports on us, interest in our stock could decrease, which could cause our stock price or trading volume to decline.
Our Series A Warrantsfuture success depends on our ability to purchase common stock (the "Series A Warrants"retain key executives and to attract, retain, and motivate qualified personnel.
We are highly dependent on the research and development, clinical, and business development expertise of Shankar Musunuri, Ph.D., MBA, our Chief Executive Officer, Chairman of the Board, and Co-Founder, as well as the other principal members of our management, scientific, and clinical teams. Although we have entered into employment agreements with our executive officers, each of them may terminate their employment with us at any time. We do not maintain "key person" insurance for any of our executives or other employees.
Recruiting and retaining qualified scientific, clinical, manufacturing, legal, and sales and marketing personnel will also be critical to our success. The loss of the services of our executive officers or other key employees could impede the achievement of our research, development, and commercialization objectives and seriously harm our ability to successfully implement our business strategy. Furthermore, replacing executive officers and key employees may be difficult and may take an extended period of time because of the limited number of individuals in our industry with the breadth of skills and experience required to successfully develop, gain regulatory approval of, and commercialize products. Competition to hire from this limited pool is intense, and we may be unable to hire, train, retain, or motivate these key personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies for similar personnel. We also experience competition for the hiring of scientific and clinical personnel from universities and research institutions. In addition, we rely on consultants and advisors, including scientific and clinical advisors, to assist us in formulating our research and development and commercialization strategy, including with respect to our development of COVAXIN for the U.S. and Canadian markets. Our consultants and advisors may be employed by employers other than us and may have commitments under consulting or advisory contracts with other entities that may limit their availability to us. If we are unable to continue to attract and retain high quality personnel, our ability to pursue our growth strategy will be limited.
We expect to expand our development, regulatory, and manufacturing capabilities and potentially implement sales, marketing, and distribution capabilities, and as a result, we may encounter difficulties in managing our growth, which could disrupt our operations.
We expect to experience significant growth in the number of our employees and the scope of our operations, particularly in the areas of drug development, clinical, regulatory affairs, manufacturing, sales, marketing, and distribution. To manage our anticipated future growth, we must continue to implement and improve our managerial, operational, and financial systems, expand our facilities, and continue to recruit and train additional qualified personnel. Our management may need to devote a significant amount of our attention to managing these growth activities. Due to our limited financial resources and our limited experience in managing such anticipated growth, we may not be able to effectively manage the expansion of our operations or recruit and train additional qualified personnel. Our inability to manage the expansion of our operations effectively may result in weaknesses in our infrastructure, give rise to operational mistakes, loss of business opportunities, loss of employees, and reduced productivity among remaining employees. Our expected growth could also require significant capital expenditures and may divert financial resources from other projects, such as the development of additional product candidates. If we are unable to effectively manage our expected growth, our expenses may increase more than expected, our ability to generate revenues could be reduced, and we may not be able to implement our business strategy, including the successful commercialization of our product candidates.
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We incur increased costs as a result of operating as a public company, and our management is required to devote substantial time to compliance initiatives and corporate governance practices.
As a public company we have incurred, and will continue to incur, significant legal, accounting, and other expenses that we did not incur as a private company. The Sarbanes-Oxley Act of 2002 ("Sarbanes-Oxley"), which were issuedthe Dodd-Frank Wall Street Reform, the Consumer Protection Act, the listing requirements of Nasdaq, and other applicable securities rules and regulations impose various requirements on public companies, including establishment and maintenance of effective disclosure and financial controls and corporate governance practices. We have had to hire additional accounting, finance, and other personnel in connection with our efforts to comply with the June 2019 common stockrequirements of being a public company and warrant financing entered intoour management and other personnel devote a substantial amount of time towards maintaining compliance with these requirements. These requirements increase our legal and financial compliance costs and make some activities more time-consuming and costly. These rules and regulations are often subject to varying interpretations, in many cases due to their lack of specificity, and, as a result, their application in practice may evolve over time as new guidance is provided by Former Ocugenregulatory and Histogenics with certain accredited investors for an aggregate purchase pricegoverning bodies. This could result in continuing uncertainty regarding compliance matters and higher costs necessitated by ongoing revisions to disclosure and governance practices.
In addition, Sarbanes-Oxley, as well as rules subsequently adopted by the SEC and Nasdaq to implement provisions of $25.0 million (the "Pre-Merger Financing"), contain price-based adjustment provisions,Sarbanes-Oxley, impose significant requirements on public companies, including requiring establishment and maintenance of effective disclosure and financial controls and changes in corporate governance practices. Further, pursuant to the Dodd-Frank Wall Street Reform and Consumer Protection Act of 2010, the SEC has adopted additional rules and regulations in these areas, such as mandatory “say on pay” voting requirements that are applicable to us. Stockholder activism, the current political environment, and the current high level of government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which may lead to additional compliance costs and impact the numbermanner in which we operate our business in ways we cannot currently anticipate.
If these requirements divert the attention of sharesour management and personnel from other business concerns, they could have a material adverse effect on our business, financial condition, and results of operations. The increased costs could impact our results of operations, and may require us to reduce costs in other areas of our business or increase the prices of our products or services. For example, these rules and regulations make it more difficult and more expensive for us to obtain director and officer liability insurance. We cannot predict or estimate the amount or timing of additional costs we may incur to respond to these requirements. The impact of these requirements could also make it more difficult for us to attract and retain qualified persons to serve on our Board of Directors, our board committees, or as executive officers.
If we or any contract manufacturers and suppliers we engage fail to comply with environmental, health, and safety laws and regulations, we could become subject to fines or penalties or incur costs that could have a material adverse effect on the success of our business.
We and any contract manufacturers and suppliers we engage are subject to numerous federal, state, and local environmental, health, and safety laws, regulations, and permitting requirements, including those governing laboratory procedures; the generation, handling, use, storage, treatment, and disposal of hazardous and regulated materials and wastes; the emission and discharge of hazardous materials into the ground, air, and water; and employee health and safety. Our operations involve the use of hazardous and flammable materials, including chemicals and biological materials. Our operations also produce hazardous waste. We generally contract with third parties for the disposal of these materials and wastes. We cannot eliminate the risk of contamination or injury from these materials. In the event of contamination or injury resulting from our use of hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources. Under certain environmental laws, we could be held responsible for costs relating to any contamination at our current or past facilities and at third-party facilities. We also could incur significant costs associated with civil or criminal fines and penalties.
Compliance with applicable environmental laws and regulations may be expensive, and current or future environmental laws and regulations may impair our research and product development efforts. In addition, we cannot entirely eliminate the risk of accidental injury or contamination from these materials or wastes. Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials, this insurance may not provide adequate coverage against potential liabilities. We do not carry specific biological agents coverage and our commercial general liability policy specifically excludes coverage for damages and fines arising from biological agents. Accordingly, we could be held liable for damages or be penalized with fines in an amount exceeding our resources, and our clinical trials or regulatory approvals could be suspended, which could have a material adverse effect on our business, financial condition, results of operations, and prospects.
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In addition, we may incur substantial costs in order to comply with current or future environmental, health, and safety laws, regulations, and permitting requirements. These current or future laws, regulations, and permitting requirements may impair our research, development, or production efforts. Failure to comply with these laws, regulations, and permitting requirements also may result in substantial fines, penalties, or other sanctions or business disruption, which could have a material adverse effect on our business, financial condition, results of operations, and prospects.
Any third-party contract manufacturers and suppliers we engage will also be subject to these and other environmental, health, and safety laws and regulations. Liabilities they incur pursuant to these laws and regulations could result in significant costs or an interruption in operations, which could have a material adverse effect on our business, financial condition, results of operations, and prospects.
If we fail to maintain proper and effective internal control over financial reporting, our ability to produce accurate and timely financial statements could be impaired, investors may lose confidence in our financial reporting, and the trading price of our common stock may decline.
Pursuant to Section 404 of Sarbanes-Oxley, our management is required to report upon the effectiveness of our internal control over financial reporting and our independent registered public accounting firm is required to attest to the effectiveness of our internal control over financial reporting. The rules governing the standards that must be met for management to assess our internal control over financial reporting are issuable upon exercise of such Series A Warrantscomplex and require significant documentation, testing, and possible remediation. If we or our auditors are unable to conclude that our internal control over financial reporting is effective, investors may be adjusted upwardlose confidence in our financial reporting and the event of certain dilutive issuances by us. Even if our stock increases in value, the number of sharestrading price of our common stock issuable upon exercisemay decline.
We cannot assure you that there will not be material weaknesses or significant deficiencies in our internal control over financial reporting in the future. Any failure to maintain internal control over financial reporting could severely inhibit our ability to accurately report our financial condition, results of operations, or cash flows. If we are unable to conclude that our internal control over financial reporting is effective or if our independent registered public accounting firm determines we have a material weakness in our internal control over financial reporting, investors may lose confidence in the Series A Warrants may still increase. The circumstances under whichaccuracy and completeness of our financial reports, the number of sharesmarket price of our common stock issuable upon exercisecould decline, and we could be subject to sanctions or investigations by Nasdaq, the SEC, or other regulatory authorities. Failure to remedy any material weakness in our internal control over financial reporting, or to implement or maintain other effective control systems required of public companies, could also restrict our future access to the Series A Warrantscapital markets.
We face potential product liability exposure, and if successful claims are brought against us, we may incur substantial liability for our product candidates and may have to limit our commercialization.
The use of our product candidates in clinical trials, and the sale of any of our product candidates for which we obtain regulatory approval, exposes us to the risk of product liability claims. Product liability claims might be brought against us by consumers, healthcare providers, pharmaceutical companies, or others selling or otherwise coming into contact with our products. For example, we may be adjusted upward are set forthsued if any product candidate we develop allegedly causes injury or is found to be otherwise unsuitable during clinical testing, manufacturing, marketing, or sale. Any such product liability claims may include allegations of defects in manufacturing, defects in design, a failure to warn of dangers inherent in the Series A Warrants.
Asproduct, negligence, strict liability, or a breach of December 31, 2019, the holderswarranties. Claims could also be asserted under state consumer protection acts. If we cannot successfully defend ourself against these claims, we will incur substantial liabilities or be required to limit development or commercialization of our Series B Warrantsproduct candidates. Even successful defense would require significant financial and Series C Warrants, which were also issued in connection with the Pre-Merger Financing, had exercised such warrantsmanagement resources. Regardless of merit or eventual outcome, liability claims may result in:
loss of revenue from decreased demand for an aggregate issuance of 40.5 million sharesour products and/or product candidates;
impairment of our common stock. If business reputation or financial stability;
costs of related litigation;
substantial monetary awards to patients or other claimants;
exhaustion of any available insurance and our capital resources;
diversion of management attention;
withdrawal of clinical trial participants and potential termination of clinical trial sites or entire clinical programs;
the Series A Warrants are exercised, additional sharesinability to commercialize our product candidates;
significant negative media attention;
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decrease in our stock price;
initiation of investigations and enforcement actions by regulators; or
product recalls, withdrawals, revocation of approvals, or labeling, marketing, or promotional restrictions.
While we currently hold product liability insurance coverage in an amount that we believe is customary for similarly situated companies, the amount of that coverage may not be adequate. We may need to increase our insurance coverage as we begin our clinical trials. We will need to further increase our insurance coverage if we commence commercialization of any of our commonproduct candidates for which we obtain marketing approval. Insurance coverage is increasingly expensive. We may not be able to maintain insurance coverage at a reasonable cost or in an amount adequate to satisfy any liability that may arise. On occasion, large judgments have been awarded in class action lawsuits based on therapeutics that had unanticipated side effects. Our insurance policies also have various exclusions, and we may be subject to a product liability claim for which we have no coverage. A successful product liability claim or series of claims brought against us could cause our stock will be issued,price to fall and, if judgments exceed our insurance coverage, could decrease our cash and adversely affect our business and our prospects.
Our internal computer systems or those of our development collaborators, third-party CDMOs, or other contractors or consultants may fail or suffer cybersecurity or other security breaches, which willcould result in dilutiona material disruption of our product development programs and cause our business and operations to suffer. We face risks related to our then-existing stockholderscollection and increaseuse of data, which could result in investigations, inquiries, litigation, fines, legislative and regulatory action, and negative press about our privacy and data protection practices.
Our internal computer systems and those of our CDMOs and other contractors and consultants are vulnerable to cybersecurity breaches and damage from computer viruses, unauthorized access, natural disasters, terrorism, war, and telecommunication and electrical failures. While we have not experienced any such material system failure, accident, or security breach to date, if such an event were to occur and cause interruptions in our operations, it could result in a material disruption of our business operations and product candidate development and, if any of our product candidates are approved, commercialization programs. Likewise, we intend to rely on third parties to manufacture our product candidates and conduct clinical trials, and similar events relating to their computer systems could also have a material adverse effect on our business and operations. To the numberextent that any disruption or cybersecurity or other security breach were to result in a loss of, shares eligible for resaleor damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability, the further development and commercialization of our product candidates could be delayed, and our reputation could be harmed. In addition, there are known cyberattacks against pharmaceutical companies engaged in development of therapeutic or vaccine products addressing COVID-19. Our COVAXIN program is one such program that could attract the attention of cyberattackers.
Additionally, our business processes personal data, including some data related to health. When conducting clinical trials, we face risks associated with collecting trial participants’ data, especially health data, in a manner consistent with applicable laws and regulations. We also face risks inherent in handling large volumes of data and in protecting the security of such data. We could be subject to attacks on our systems by outside parties or fraudulent or inappropriate behavior by our service providers or employees. Third parties may also gain access to our systems using stolen or inferred credentials, computer malware, viruses, spamming, phishing attacks, or other means, and may use such access to obtain personal data. Data breaches could subject us to individual or consumer class action litigation and governmental investigations and proceedings by federal, state, and local regulatory entities in the public market. IgnoringUnited States and by international regulatory entities, resulting in exposure to material civil and/or criminal liability. As our operations and business grow, we may become subject to or be affected by new or additional data protection laws and regulations and face increased scrutiny or attention from regulatory authorities, including various domestic and international privacy and security regulations. The legislative and regulatory landscape for privacy and data protection continues to evolve. In the United States, certain blocker provisionsstates may adopt privacy and security laws and regulations that may be more stringent than applicable federal law. For example, California enacted the California Consumer Privacy Act ("CCPA"), which prevent exercisestook effect on January 1, 2020. The CCPA creates individual privacy rights for California consumers and increases the privacy and security obligations of the Series A Warrants if the exercising holder would beneficially own in excess of 4.99% or 9.99%, as applicable, of the outstanding common stock (including the common stock issuable upon such exercise), following the issuance of the maximum number of shares issuable upon exercise of the Series A Warrants, the holders of such Series A Warrants would acquireentities handling certain personal data. We may also in the aggregate an additional 8.8 million sharesfuture be subject to data protection laws and regulations of our common stock, representing approximately 14.3% of our total outstanding common stock followingother jurisdictions, such issuance.as the EU's General Data Protection Regulation ("GDPR"), which provides data subjects with certain rights and requires organizations to adopt technical and organizational safeguards to protect personal data. In the event that we enter into a transactionare subject to or affected by privacy and data protection laws, including the CCPA or GDPR and other domestic or international privacy and data protection laws, we may expend significant resources to comply with holderssuch laws, and any liability from failure to comply with the requirements of the Series A Warrants to restructure the terms thereof, the number of shares of common stock into which such warrants are exercisablethese laws could be increased, resulting in even greater dilution to then-existing stockholders. Sales of substantial numbers of such shares in the public market could depress the market price of the common stock.adversely affect our financial condition.
Item 1B.    Unresolved Staff Comments.
None.
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Item 2.    Properties
Our headquarters are located in Malvern, Pennsylvania, and consist of an aggregate of approximately 8,03816,401 square feet of leased office, space under one lease that expires by February 28, 2022. We currently sublease laboratory, space from another company in Malvern, Pennsylvania, pursuant to an agreement that expires on June 30, 2020.and storage space.
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Item 3.    Legal Proceedings.
From time to time, we are subject to claims inFor a discussion of legal proceedings, arisingsee Note 14 in the normal course of its business. We do not believe that we are currently partynotes to any pending legal actions that could reasonably be expected to have a material adverse effectthe consolidated financial statements included elsewhere in this Annual Report on our business, financial condition, results of operations or cash flows.Form 10-K. This discussion is incorporated herein by reference.
Item 4.    Mine Safety Disclosures.
Not applicable.
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PART II
Item 5.    Market for Registrant's Common Equity, Related Shareholder Matters and Issuer Purchases of Equity Securities.
Market Information
Our common stock is traded on The NASDAQthe Nasdaq Capital Market under the symbol “OCGN."
StockholdersHolders
As of March 20, 2020,February 21, 2022, we had 52.6199.5 million shares of common stock outstanding held by approximately 3817 stockholders of record. The actual number of stockholders is greater than this number of record holders, and includes stockholders who are beneficial owners, but whose shares are held in “street” name by brokers and other nominees. This number of holders of record also does not include stockholders whose shares may be held in trust by other entities.
Dividend PolicyDividends
We have not declared or paid any cash dividends on our capitalcommon stock. We currently anticipate that we will retain future earnings, if any, to finance our operations and do not anticipate declaring or paying any cash dividends in the foreseeable future. As a result, we anticipate that only appreciation of the price of our common stock, if any, will provide a return to investors for at least the foreseeable future.
Unregistered Sales of Equity Securities and Use of Proceeds
During the periodperiods covered by this Annual Report, there were no sales by us of unregistered securities that were not previously reported by us in aan Annual Report on Form 10-K, Quarterly Report on Form 10-Q, or Current Report on Form 8-K.
Securities Authorized for Issuance Under Equity Compensation PlansPerformance Graph
Information aboutThe following graph compares the performance of our equity compensation plans is incorporated herein by reference to Part III, Item 12 of this Annual Report on Form 10-K.
Share Repurchase
On October 9, 2019, we announced that our Board of Directors unanimously approved a share repurchase program authorizing the repurchase of up to $2.0 million in value of the outstanding common stock. Pursuant to this repurchase program, we plan to repurchase the common stock provided that the timing, actual number and price per share of the common stock to The Nasdaq Biotechnology Index ("Nasdaq Biotechnology") and The Nasdaq Composite Index ("Nasdaq Composite") from December 31, 2016 to December 31, 2021. The comparison assumes an investment of $100 in our common stock and in each of the foregoing indices, and assumes reinvestment of dividends, if any. On September 27, 2019, we completed the Merger. The stock performance information prior to September 27, 2019 represents historical Histogenics stock prices as Histogenics was the legal acquirer. The comparisons shown in the graph below are based upon historical data. We caution that the stock price performance shown in the graph below is not necessarily indicative of, nor is it intended to forecast, the potential future performance of our common stock.
ocgn-20211231_g14.jpg
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The information required by this Item regarding the performance graph shall not be purchased willdeemed to be “soliciting material” or to be “filed” with the SEC or subject to management discretion and board guidance, market conditions, applicable legal requirements, including Rule 10b-18Regulation 14A or 14C, other than as provided in this Item, or to the liabilities of Section 18 of the Exchange Act, and various other factors. In November and December 2019,except to the extent that we repurchased 26,500 and 95,000 shares of common stock, respectively, at an average price of $0.25 and $0.42 per share, respectively.
Item 6. Selected Financial Data
Not required for smaller reporting companies.
specifically request that such information be treated as soliciting material or specifically incorporate it by reference into a filing under the Securities Act or the Exchange Act.
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Item 7.    Management’s Discussion and Analysis of Financial Condition and Results of Operations.
You should read the following discussion and analysis of our financial condition and results of operations in conjunction with the financial statements and the notes thereto included elsewhere in this Annual Report on Form 10-K. Some of the information contained in this discussion and analysis, including information with respect to our plans and strategy for our business and related financing, include forward-looking statements that involve risks, uncertainties, and assumptions. These statements are based on our beliefs and expectations about future outcomes and are subject to risks and uncertainties that could cause our actual results to differ materially from anticipated results. WeExcept as required by law, we undertake no obligation to publicly update these forward-looking statements, whether as a result of new information, future events, or otherwise. You should read the “Risk Factors” and “Special Note Regarding Forward-Looking Statements” sections of this Annual Report on Form 10-K for a discussion of important factors that could cause actual results to differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis.
On September 27, 2019, Ocugen completed its reverse merger with Ocugen OpCo Inc. (formerly known as Ocugen, Inc. (“Former Ocugen”)) in accordance with the terms of the Agreement and Plan of Merger and Reorganization, dated as of April 5, 2019, by and among Histogenics, Former Ocugen and Restore Merger Sub, Inc., a wholly owned subsidiary of Histogenics (“Merger Sub”), as amended (the “Merger Agreement”), pursuant to which Merger Sub merged with and into Former Ocugen, with Former Ocugen surviving as a wholly owned subsidiary of Histogenics (the “Merger”). Immediately after completion of the Merger, Histogenics changed its name to Ocugen, Inc. For accounting purposes, the Merger is treated as a “reverse asset acquisition” under generally acceptable accounting principles in the United States (“U.S. GAAP”) and Former Ocugen is considered the accounting acquirer. Accordingly, Former Ocugen’s historical results of operations replaced the Company’s historical results of operations for all periods prior to the Merger and, for all periods following the Merger, the results of operations of the combined company will be included in the Company’s financial statements.
Overview
We are a clinical-stage biopharmaceutical company focused on discovering, developing and commercializing transformativegene therapies to treatcure blindness diseases and developing a vaccine to save lives from COVID-19.
Our cutting-edge technology pipeline includes:
COVID-19 Vaccine Candidate — COVAXIN is a whole-virion inactivated COVID-19 vaccine candidate being developed to prevent COVID-19 infection in humans. We are co-developing COVAXIN with Bharat Biotech International Limited (“Bharat Biotech”) for the whole eye.U.S. and Canadian markets.
Our leadModifier Gene Therapy Platform — Based on nuclear hormone receptors ("NHRs"), we believe our modifier gene therapy platform has the potential to address many retinal diseases, including retinitis pigmentosa ("RP"), Leber congenital amaurosis ("LCA"), and dry age-related macular degeneration ("AMD").
Novel Biologic Therapy for Retinal Diseases — We are developing OCU200, a novel biologic product candidate, OCU300,to treat diabetic macular edema ("DME"), diabetic retinopathy ("DR"), and wet AMD.
COVID-19 Vaccine Candidate
In February 2021, we entered into a Co-Development, Supply and Commercialization Agreement with Bharat Biotech, pursuant to which we obtained an exclusive right and license under certain of Bharat Biotech’s intellectual property rights, with the right to grant sublicenses, to develop, manufacture, and commercialize COVAXIN for the prevention of COVID-19 caused by SARS-CoV-2 in the United States, its territories, and possessions. In June 2021, we entered into an amendment to the Co-Development, Supply and Commercialization Agreement (as so amended, the "Covaxin Agreement") pursuant to which we and Bharat Biotech agreed to expand our rights to develop, manufacture, and commercialize COVAXIN to include Canada in addition to the United States, its territories, and possessions (the "Ocugen Covaxin Territory").
COVAXIN is formulated with the inactivated SARS-CoV-2 virus, an antigen, and an adjuvant. COVAXIN requires a small molecule therapeutic currentlytwo-dose vaccination regimen given 28 days apart and is stored in Phase 3 clinical development for patients with ocular rednessstandard vaccine storage conditions (2-8°C). COVAXIN has been authorized or approved in more than a dozen countries and discomfort stemming from ocular graft-versus-host disease (“oGVHD”). As of March 20, 2020, we had completed over 95% of planned enrollment of ourwas granted an Emergency Use Listing by the World Health Organization in November 2021. Over 295 million doses globally have been administered to date.
The Phase 3 clinical trial for OCU300. OCU300conducted by Bharat Biotech in India in 25,798 adults, who were healthy or had stable chronic medical conditions ages 18 years and older, reported an overall estimated vaccine efficacy of COVAXIN against COVID-19 infection of 77.8%, with efficacy against severe COVID-19 infection of 93.4%, and efficacy against asymptomatic COVID-19 infection of 63.6%. Approximately 30% of participants were seropositive at baseline in each dosing group and were excluded from the per protocol analysis but contributed to the safety dataset. COVAXIN was generally well tolerated, with no clinically or statistically significant differences in reported adverse events in the vaccine and placebo groups. Additionally, a Phase 2/3 immuno-bridging clinical trial was conducted by Bharat Biotech in India to assess the protective immunity of COVAXIN in children ages two to 18 years. The results demonstrated a robust neutralizing antibody response comparable to that of the adults studied in the Phase 3 clinical trial, and that COVAXIN was generally well tolerated. This study demonstrated a favorable safety profile, including no hospitalizations, myocarditis, or vaccine-induced thrombotic thrombocytopenia. Additionally, data from the clinical trials and from research conducted by third parties has received Orphan Drug Designation (“ODD”) fromshown that COVAXIN has neutralizing potential against multiple variants of concern including both the Omicron (B.1.1.529) and Delta (B.1.617.2) variants.
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In June 2021, the U.S. Food and Drug Administration (the “FDA”"FDA"), provided feedback to us regarding the data and itinformation contained in a "Master File" that we previously submitted to the FDA and recommended that we pursue a Biologics License Application ("BLA") submission instead of the Emergency Use Authorization ("EUA") application for COVAXIN for adults ages 18 years and older in the United States. As part of the feedback provided, the FDA requested additional information and data. In October 2021, we submitted an Investigational New Drug ("IND") application to the FDA to initiate a Phase 2/3 immuno-bridging and broadening clinical trial evaluating COVAXIN for ages 18 years and older. The clinical trial is designed to evaluate whether the immune response experienced in participants in the aforementioned completed Phase 3 clinical trial in India is similar to a demographically representative, adult population in the United States. In November 2021, we were notified that the FDA issued a clinical hold on our IND application. In December 2021, the FDA sent us a letter setting forth the reasons for the clinical hold and specific guidance on steps that must be taken to have the clinical hold lifted. We provided the FDA responses to their comments and the FDA lifted its clinical hold in February 2022. We plan to initiate the Phase 2/3 immuno-bridging and broadening clinical trial for COVAXIN as soon as we are able to. We also plan to initiate a safety-bridging clinical trial in the first half of 2022, subject to discussions with the FDA. Subject to the foregoing, we anticipate submitting a BLA with the FDA near the end of 2022. In November 2021, we also submitted a request to the FDA for EUA for COVAXIN for pediatric use in ages two to 18 years in the United States. The EUA submission was based on the results of the aforementioned Phase 2/3 immuno-bridging pediatric clinical trial conducted by Bharat Biotech in India. Our EUA submission is currently under review by the FDA. In February 2022, Delta and only product candidateOmicron neutralization results along with a safety database of more than 36 million teenagers who had been vaccinated with COVAXIN were submitted to receive that designationthe FDA to support our EUA submission.
We are also pursuing approval for COVAXIN in Canada. In July 2021, we completed our rolling submission to Health Canada for COVAXIN. The rolling submission process, which permits companies to submit safety and efficacy data and information as they become available, was recommended and accepted under the Minister of Health’s Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 and transitioned to a New Drug Submission ("NDS") for COVID-19. The submission was conducted through our Canadian subsidiary, Vaccigen Ltd. We are in discussions with Health Canada regarding our NDS submission for COVAXIN. In December 2021, we were provided with a Notice of Deficiency ("NOD") from Health Canada regarding our NDS submission. Health Canada requested further analyses of the COVAXIN preclinical and clinical data, as well as additional information regarding chemistry, manufacturing, and controls ("CMC"). We have responded to and provided proposed resolutions for the treatment of symptoms associated with oGVHD. oGVHD, a severe chronic autoimmune disease that occursdeficiencies included in up to 60% of allogeneic hematopoietic stem cell transplantation (“HSCT”) patients, can result in light sensitivity, excessive ocular redness, severe ocular pain and, ultimately, vision impairment. the NOD. Our responses are currently under review by Health Canada.
We estimate the current prevalence of patients suffering from oGVHDare evaluating our commercialization strategy for COVAXIN in the United States and Canada, if authorized or approved in either jurisdiction. In June 2021, we selected Jubilant HollisterStier as our manufacturing partner for COVAXIN to be approximately 63,000. OCU300 is formulated using our proprietary nanoemulsionprepare for the potential commercial manufacturing for the Ocugen Covaxin Territory. We expect to enter into a master services agreement with Jubilant HollisterStier for the commercial manufacture of COVAXIN. The technology OcuNanoE—Ocugen’s ONE Platform (“OcuNanoE”),transfer process from Bharat Biotech to Jubilant HollisterStier for drug product manufacturing has been initiated. We expect to complete qualification manufacturing runs at Jubilant HollisterStier by mid-2022.
In September 2021, we entered into a Development and Commercial Supply Agreement with Bharat Biotech, pursuant to which we believe represents an effectiveBharat Biotech will supply us with clinical trial materials and commercial supplies of COVAXIN finished drug delivery mechanism to treat ocular surface disorders. We believe that OcuNanoE provides additional protectionproduct prior to the ocular surfacecompletion of a technology transfer. Following the completion of a technology transfer, Bharat Biotech will supply COVAXIN drug product components and continue to supply finished drug product as necessary for the potential for enhanced efficacy comparedcommercial manufacture and supply of COVAXIN subsequent to traditional formulations. a regulatory authorization or approval.
Modifier Gene Therapy Platform
We are the first company to use nanoemulsion technology in the ophthalmology space.
We were developing OCU310 for patients with dry eye disease, which is also formulated using OcuNanoE. We have completed a Phase 3 clinical trial for OCU310 that was initiated in September 2018. Although the trial showed that OCU310 is safe and well-tolerated, it did not meet its co-primary endpoints for symptom and sign. We are no longer pursuing the development of this product candidate.
We are also developing a modifier gene therapy platform to generate therapies designed to fulfill unmet medical needs in the area of retinal diseases, including inherited retinal diseases (“IRDs”("IRDs")., such as RP and LCA, and dry AMD. Our modifier gene therapy platform is being designed to target nuclear hormone receptors (“NHRs”),based on NHRs, which have the potential to restore homeostasis, tothe basic biological processes in the retina. Unlike single-gene replacement therapies, which only target one genetic mutation, we believe that our modifier gene therapy platform, through its use of NHRs, represents a novel approach in that it mayhas the potential to address multiple retinal diseases caused by mutations in multiple genes with one product. Ourproduct; and potentially address complex diseases, such as dry AMD, that are potentially caused by imbalances in multiple gene networks.
IRDs, such as RP and LCA, can lead to visual impairment and blindness and affect over two million people worldwide. RP and LCA are rooted in mutations of more than 175 different genes. We believe that OCU400, our first product candidate being developed with our modifier gene therapy candidate,platform, has the potential to be broadly effective in restoring retinal integrity and function across a range of IRDs, including RP and LCA. For example, we believe OCU400 has the potential to eliminate the need for developing more than 175 individual products and provide one treatment option for all RP and LCA patients. OCU400 has received two ODDsfour Orphan Drug Designations from the FDA one for the treatment of certain disease genotypes: nuclear receptor
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subfamily 2 group E member 3 ("NR2E3") mutation-associated retinal diseases and the other for the treatment of, centrosomal protein 290 ("CEP290"), rhodopsin ("RHO"), and phosphodiesterase 6B ("PDE6ß") mutation-associated inherited retinal diseases.degenerations. In November 2021, we submitted an IND application to the FDA for OCU400 for the treatment of the NR2E3 and RHO disease genotypes. Our IND application was accepted by the FDA in December 2021. We have initiated a Phase 1/2 clinical trial in the United States for the treatment of these disease genotypes and the first patient is expected to be dosed in the first half of 2022. This Phase 1/2 clinical trial is a multicenter, open-label, dose ranging study to assess the safety of unilateral subretinal administration of OCU400 in subjects with NR2E3-related RP. OCU400 has additionally received Orphan Medicinal Product Designation from the European Commission, based on the recommendation of the European Medicines Agency, for RP and LCA. We believe OCU400 has the potential for broad-spectrum application to treat many IRDs. We are planningcurrently evaluating options to initiate a Phase 1/2aOCU400 clinical trial for OCU400trials in the next two years. Europe.
Our second gene therapy candidate, OCU410, is being developed to utilize the nuclear receptor genes RAR-related orphan receptor A (“("RORA") for the treatment of dry age-related macular degeneration (“AMD”). This candidate isAMD. We are currently in preclinical development.
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Additionally, we are conducting preclinicalexecuting pre-IND studies consistent with FDA discussions to support a Phase 1/2 clinical trial. We have engaged CanSino Biologics, Inc. to manufacture clinical supplies and be responsible for the CMC development for a novelOCU400 and OCU410.
Novel Biologic Therapy for Retinal Diseases
Our pipeline also includes our biologic product candidate.candidate, OCU200, is a novel fusion protein designed to treat diabetic macular edema (“DME”), diabetic retinopathy (“DR”) and wet age-related macular degeneration (“wet AMD”). We expect to initiate a Phase 1/2 clinical trial for OCU200 within the next two years. We plan to expand the therapeutic applications of OCU200 beyondseverely sight-threatening diseases such as DME, DR, and wet AMDAMD. We are currently establishing a current Good Manufacturing Practice process for the production of clinical trial materials and executing pre-IND studies consistent with FDA discussions to potentially include macular edema following retinal vein occlusion (“RVO”)support a Phase 1/2a clinical trial. We have completed the technology transfer of manufacturing processes to our contract development and myopic choroidal neovascularization (“mCNV”).manufacturing organization that will manufacture OCU200 clinical supplies.
Impact of COVID-19 on our Business
The COVID-19 pandemic had an impact on our operations during 2021. For example, during the first half of 2021, India experienced a surge in COVID-19 infections, which created significant uncertainty as to the timing of completion for Bharat Biotech’s Phase 3 clinical trial, due in part to the diversion of medical resources and supplies of COVAXIN in India. During this time, we experienced delays in our receipt of certain additional data from Bharat Biotech’s Phase 3 clinical trial, which created uncertainty regarding our ability to timely submit required documentation to the FDA for COVAXIN. In addition, the COVID-19 pandemic adversely impacted many of the companies within our supply chain and other third parties upon which we rely to conduct our business.
The COVID-19 pandemic is continually evolving and we are closely monitoring the situation. Impacts from the COVID-19 pandemic remain highly uncertain and subject to change and, as such, we cannot predict the specific duration or impact that the COVID-19 pandemic may have on our operations going forward, including our preclinical activities, future clinical trials, and potential commercialization. The extent to which the COVID-19 pandemic may impact our operations is dependent on future developments, including but not limited to: (i) the duration of the spread of the SARS-CoV-2 virus, including the spread of variants, (ii) the future actions taken by governmental authorities and regulators with respect to the COVID-19 pandemic, and (iii) the impact on our partners, collaborators, and suppliers. We will continue to monitor the situation closely as these effects could have a material impact on our operations.
Financial Operations Overview
We have no products approved for commercial sale and have not generated anysignificant revenue from product sales.to date. We have never been profitable and have incurred operatingnet losses in each year since inception. We incurred net losses of approximately $20.2$58.4 million, $21.8 million, and $18.2$20.2 million for the fiscal years ended December 31, 20192021, 2020, and 2018,2019, respectively. As of December 31, 2019,2021, we had an accumulated deficit of $51.5$131.7 million and a cash, cash equivalents, and restricted cash balance of $7.6$95.1 million. Substantially all of our operatingnet losses resulted from expenses incurred in connection with our research and development programs and from general and administrative costs associated with our operations.
To date,Segment Information
As of December 31, 2021, we have viewed our operations and managemanaged our business as one operating segment.segment consistent with how our chief operating decision-maker, our Chief Executive Officer, makes decisions regarding resource allocation and assessing performance. As of December 31, 2019,2021, substantially all of our assets were located in the United States. Our headquarters and operations are located in Malvern, Pennsylvania.
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Research and development expense
Research and development costs are expensed as incurred. These costs consist of internal and external expenses.expenses, as well as depreciation expense on assets used within our research and development activities. Internal expenses include the cost of salaries, benefits, severance, and other related costs, including stock-based compensation, for personnel serving in our productresearch and development functions, as well as allocated rent and utilities expenses. External expenses include development, clinical trials, patent costs, and regulatory compliance costs incurred with research organizations, contract manufacturers, and other third-party vendors. License fees paid to acquire access to proprietary technology are expensed to research and development, unless it is determined that the technology is expected to have an alternative future use. All patent-related costs incurred in connection with filing and prosecuting patent applications are expensed as incurred to research and development expense due to the uncertainty about the recovery of the expenditure. We record costs for certain development activities, such as preclinical studies and clinical trials, based on our evaluation of the progress to completion of specific tasks using data such as patient enrollment, clinical site activations, or information provided to us by our vendors on their actual costs incurred.tasks. Payments for these activities are based on the terms of the individual arrangements, which may differ from the pattern of costs incurred, and are reflected in the consolidated financial statements as prepaid or accrued research and development expense, as applicable. Our recording of costs for certain development activities requires us to use estimates. We believe our estimates and assumptions are reasonable under the casecurrent conditions; however, actual results may be.differ from these estimates.
Research and development expenses account for a significant portion of our operating expenses. We plan to incur research and development expenses for the foreseeable future as we expect to continue the development and eventual commercialization of one or more of our product candidates, if approved.candidates. We anticipate that our research and development expenses will increase substantiallybe higher in fiscal year 2022 and subsequent periods as compared to the prior periods presented herein as we complete our Phase 3 trialprepare for the commercialization of COVAXIN in the United States and Canada, if authorized or approved, as well as conduct preclinical and clinical activities with respect to OCU300 and prepare to commence Phase 1/2a trials with respect to OCU400, OCU410 and OCU200, and otherwise develop and prepare for commercialization of our product candidates.
Our research and development expenses are not currently tracked on a program-by-program basis for indirect and overhead costs. We use our personnel and infrastructure resources across multiple research and development programs directed toward identifying, developing, and commercializing product candidates.
At this time, due to the inherently unpredictable nature of preclinical and clinical development,developments as well as regulatory approval (or authorization) and commercialization, we are unable to estimate with any certainty the costs we will incur and the timelines we will require in our continued development and commercialization efforts.
As a result of thethese uncertainties, discussed above, successful development and completion of clinical trials isas well as regulatory authorization or approval and commercialization are uncertain and may not result in authorized or approved and commercialized products. Completion dates and completion costs can vary significantly for each future product candidate and are difficult to predict. We will continue to make determinations as to which product candidates to pursue and how much funding to direct to each product candidate on an ongoing basis in response to our ability to enter into collaborations with respect to each product candidate, the scientific and clinical success of each product candidate as well as ongoing assessments as to the commercial potential of each product candidates.candidate.
General and administrative expense
General and administrative expense consists primarily of personnel expenses, including salaries, benefits, severance, insurance, and stock-based compensation expense, for employees in executive, accounting, commercialization, human resources, and other administrative functions. General and administrative expense also includes expenses related to pre-commercial activities, corporate facility costs, includingsuch as allocated rent and utilities, as well asinsurance premiums, legal fees related to corporate matters, and fees for auditing, accounting, and other consulting services.
We anticipate that our general and administrative expenseexpenses will increase in fiscal year 2022 as compared to the prior periods presented herein as a result of an expanded infrastructure and an increased headcount. We anticipate higher corporate infrastructure costs including, but not limited to accounting, legal, human resources, consulting, and investor relations, fees, as well as increased director and officerpublic company insurance premiums, associated with becoming a public company.fees. Additionally, if and when we believe a regulatory approval of a product candidate appears likely,
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we anticipate an increase in payrollgeneral and expenseadministrative expenses as a resultwe prepare to support the potential commercialization of its preparation for commercial operations, especially as it relates to the sales and marketing of our product candidates.COVAXIN, if authorized or approved.
Change in fair value of derivative liabilities
ChangeThe change in fair value of derivative liabilities includeswas $3.2 million during the year ended December 31, 2019. This change in fair value each reporting period of (a) the conversion and change in control features embedded inderivative liabilities was related to certain convertible notes issued in 2018 and 2019 (the "Convertible Notes") containing embedded conversion and change-in-control features, which were required to be bifurcated and recognizedrecorded at fair value as derivative liabilities and (b)revalued at each reporting date as well as the change in the fair value of the Company's Series B Warrants that were issued in connection with a Securities Purchase Agreement entered into with certain accredited investors in June 2019. The change in fair value of2019 and were classified as derivative liabilities related to the Series B Warrants was recognized through the date the Series B Warrants were reclassified to equity. The reclassification to equity occurred once the Series B Warrants were reassessedat issuance and determined to meetreevaluated each reporting period until they met the derivative scope exception allowing for stockholders' equity classification during the year ended December 31, 2019. The Convertible Notes were extinguished during the year ended
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December 31, 2019. There were no derivative instruments revalued on a recurring basis during the years ended December 31, 2021 and 2020.
Results of Operations
The following discussion and analysis of our results of operations includes a comparison of the year ended December 31, 2021 to the year ended December 31, 2020. For the discussion and analysis of our results of operations for the year ended December 31, 2020 compared with the year ended December 31, 2019, refer to Part II, Item 7 "Management’s Discussion and Analysis of Financial Condition and Results of Operations" included in our Annual Report on Form 10-K for the year ended December 31, 2020 filed with the U.S. Securities and Exchange Commission ("SEC") on March 19, 2021 (the "2020 Form 10-K"), which is incorporated herein by reference.
Year ended December 31,
(in thousands)20212020Change
Revenues
Collaboration revenue$— $43 $(43)
Total revenues— 43 (43)
Operating expenses
Research and development35,108 6,354 28,754 
In-process research and development— 7,000 (7,000)
General and administrative22,920 7,974 14,946 
Total operating expenses58,028 21,328 36,700 
Loss from operations(58,028)(21,285)(36,743)
Total other income (expense)(389)(537)148 
Loss before income taxes(58,417)(21,822)(36,595)
Income tax benefit(52)— (52)
Net loss$(58,365)$(21,822)$(36,543)
Research and development expense
Research and development expense increased by $28.8 million for the year ended December 31, 2021 compared to the year ended December 31, 2020. The increase was primarily due to the $15.0 million upfront payment to Bharat Biotech in connection with the amendment to the Covaxin Agreement to add rights to the Canadian market in June 2021 as well as increases of $4.6 million in COVAXIN development, regulatory, and manufacturing activities, $3.1 million in OCU400 preclinical and clinical activities, $2.8 million in employee-related expenses, $1.7 million in stock-based compensation expense, and $1.6 million in OCU200 preclinical activities. The increases were partially offset by a $1.1 million decrease for the discontinuation of a product candidate in 2020.
In-process research and development expense
In-process research and development expense decreased by $7.0 million for the year ended December 31, 2021 compared to the year ended December 31, 2020. The decrease was due to the write-off of an intangible asset held for sale during the year ended December 31, 2020 as a sale of the intangible asset was deemed not probable to be completed within one year from the date the intangible asset was initially recorded as held for sale.
General and administrative expense
General and administrative expenses increased by $14.9 million for the year ended December 31, 2021 compared to the year ended December 31, 2020. The increase was primarily due to increases of $4.6 million in stock-based compensation expense, $3.0 million in expenses for stockholder meetings and proxy solicitation, $2.5 million in professional expenses, including legal and consulting fees, $2.3 million in employee-related expenses, and $1.3 million in COVAXIN pre-commercial expenses.
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Total Other Income (Expense)
Total other income (expense) decreased by $0.1 million for the year ended December 31, 2021 compared to the year ended December 31, 2020. Other income (expense) during the year ended December 31, 2021 primarily relates to $0.8 million related to a loss on the write-off of the Promissory Note (as defined in Note 4 in the notes to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K) deemed uncollectible, partially offset by a gain on loan extinguishment of $0.4 million for the PPP Note (as defined in Note 8 in the notes to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K) forgiveness obtained in May 2021. Other income (expense) during the year ended December 31, 2020 primarily relates to debt discount interest expense on the Warrant Exchange Promissory Notes (as defined in Note 10 in the notes to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K) of $0.6 million, offset by the recognition of $0.2 million in deferred grant proceeds.
Liquidity and Capital Resources
As of December 31, 2021, we had $95.1 million in cash, cash equivalents, and restricted cash. We have not generated significant revenue to date and have primarily funded our operations to date through the sale of common stock, warrants to purchase common stock, the issuance of convertible notes, debt, and grant proceeds. Since our inception and through December 31, 2021, we have raised an aggregate of $219.6 million to fund our operations, of which $206.9 million was from gross proceeds from the sale of our common stock and warrants, $10.3 million was from the issuance of convertible notes, $2.2 million was from debt, and $0.2 million from grant proceeds.
In February 2022, we issued and sold 16.0 million shares of our common stock at an offering price of $3.13 per share in a public offering and received net proceeds of $49.8 million, after deducting the underwriting discounts and commissions and estimated offering expenses payable by us. In April 2021, we issued and sold 10.0 million shares of our common stock at an offering price of $10.00 per share in a registered direct offering pursuant to a securities purchase agreement with certain institutional investors (the "April 2021 Registered Direct Offering") and received net proceeds of $93.4 million. In February 2021, we issued and sold 3.0 million shares of our common stock at an offering price of $7.65 per share in a registered direct offering pursuant to a securities purchase agreement with certain institutional investors ("February 2021 Registered Direct Offering") and received net proceeds of $21.2 million. Additionally, during the year ended December 31, 2021, we sold 1.0 million shares of our common stock under an at-the-market offering ("ATM") and received net proceeds of $4.8 million. During the year ended December 31, 2020, we sold 108.1 million shares of our common stock under ATMs and received net proceeds of $36.3 million. See Note 9 in the notes to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K for additional information on our equity indexation allowingissuances.
Since our inception, we have devoted substantial resources to research and development and have incurred significant net losses and may continue to incur net losses in the future. We incurred net losses of approximately $58.4 million, $21.8 million, and $20.2 million for the years ended December 31, 2021, 2020, and 2019, respectively. As of December 31, 2021, we had an accumulated deficit of $131.7 million. In addition, as of December 31, 2021, we had accounts payable and accrued expenses and other current liabilities of $6.6 million and indebtedness of $1.7 million.
The following discussion and analysis of a summary of our cash flows includes a comparison of the year ended December 31, 2021 to the year ended December 31, 2020. For the discussion and analysis that compares our summary of cash flows for the year ended December 31, 2020 with the year ended December 31, 2019, refer to Part II, Item 7 "Management’s Discussion and Analysis of Financial Condition and Results of Operations" included in our 2020 Form 10-K, which is incorporated herein by reference.
Year ended December 31,
(in thousands)20212020
Net cash used in operating activities$(47,941)$(14,709)
Net cash used in investing activities(1,816)(307)
Net cash provided by financing activities120,676 31,611 
Net increase in cash, cash equivalents, and restricted cash$70,919 $16,595 
Operating activities
Cash used in operating activities was $47.9 million for the year ended December 31, 2021 compared with $14.7 million for the year ended December 31, 2020. The increase in cash used in operating activities was primarily driven by the $15.0 million
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upfront payment to Bharat Biotech in connection with the amendment to the Covaxin Agreement to add rights to the Canadian market in June 2021, an increase in our research and development expenses for our product candidates, specifically clinical trial and manufacturing expenses related to COVAXIN, an increase in employee-related expenses as we expand our headcount and continue to provide competitive compensation plans to support our development, commercialization, and business efforts, and an increase in expenses for stockholder meetings and proxy solicitation.
Investing activities
Cash used in investing activities was $1.8 million for the year ended December 31, 2021 compared with $0.3 million for the year ended December 31, 2020. The increase in cash used by investing activities was primarily driven by an increase of $0.6 million in purchases of property and equipment and the issuance of the Promissory Note (as defined in Note 4 in the notes to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K) of $0.8 million.
Financing activities
Cash provided by financing activities was $120.7 million for the year ended December 31, 2021 compared to $31.6 million for the year ended December 31, 2020. During the year ended December 31, 2021, cash provided by financing activities primarily consisted of gross proceeds of $100.0 million and $22.9 million received from the April 2021 Registered Direct Offering and the February 2021 Registered Direct Offering, respectively, and gross proceeds of $5.0 million received under an ATM, partially offset by payments of equity classification.issuance costs of $8.5 million. During the year ended December 31, 2020, cash provided by financing activities primarily consisted of gross proceeds of $37.8 million received under ATMs and $0.9 million in proceeds from the issuance of debt, partially offset by payments of equity issuance costs of $1.5 million and repayments of debt of $5.6 million.
Contractual Obligations
Licensing and Development Agreements

We have obligations under certain license and development agreements for our product candidates including annual payments, payments upon the achievement of certain milestones, and royalty payments based on net sales of licensed products. See Note 3 in the notes to the consolidated financial statements included in elsewhere in this Annual Report on Form 10-K for information regarding our obligations under licensing and development agreements.
Lease Obligations
We have obligations under our operating leases, which include leased office, laboratory, and storage space, located in Malvern, Pennsylvania. As of December 31, 2021, we had future minimum operating lease base rent payment obligations of $1.8 million, with $0.4 million payable within 12 months related to leases that have commenced. See Note 6 in the notes to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K for information regarding our obligations under lease obligations, including the aggregate estimated base rent payments for the lease not yet commenced.
Indebtedness
We have outstanding debt related to the funds borrowed from EB5 Life Sciences, L.P. ("EB-5 Life Sciences") pursuant to the U.S. government's Immigrant Investor Program, commonly known as EB-5 program. Pursuant to the EB-5 loan agreement entered into with EB-5 Life Sciences, we can borrow up to $10.0 million in $0.5 million increments. Borrowings are at a fixed interest rate of 4.0%. Outstanding borrowings pursuant to the EB-5 Program become due upon the seventh anniversary of the final disbursement. Under the terms and conditions of the EB-5 loan agreement, we borrowed $1.0 million in 2016 and an additional $0.5 million in March 2020. As of December 31, 2021, there was $1.5 million of principal outstanding under the EB-5 loan agreement. See Note 8 in the notes to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K for information regarding our obligations under the EB-5 loan agreement.
Consulting Agreements
We have obligations under a consulting agreement with an individual providing services to us with regard to our Canadian operations (the "Canada Consulting Agreement"). Compensation under the Canada Consulting Agreement includes, among other forms of compensation, cash payments of up to $3.0 million upon the achievement of certain milestones related to COVAXIN. See Note 10 in the notes to the consolidated financial statements included elsewhere in this reportAnnual Report on Form 10-K for additional information. The changeinformation regarding our obligations under the Canada Consulting Agreement.
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Supply Commitments
In February 2022, we entered into a commitment to purchase $14.3 million of COVAXIN drug product components from Bharat Biotech to support the technology transfer from Bharat Biotech to Jubilant HollisterStier. We previously issued Series B Convertible Preferred Stock in fair valueMarch 2021 as an advance payment of derivative liabilities$6.0 million for the supply of COVAXIN to be provided by Bharat Biotech pursuant to the Supply Agreement, which will be applied to this commitment. See Note 9 and Note 15 in the notes to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K for information regarding the Series B Convertible Preferred Stock and our supply commitments.
Funding requirements
We expect to continue to incur significant expenses in connection with our ongoing activities, particularly as we continue research and development, including preclinical and clinical development of our product candidates, contract to manufacture our product candidates, prepare for potential commercialization of our product candidates, add operational, financial, and information systems to execute our business plan, maintain, expand, and protect our patent portfolio, expand headcount to support our development, commercialization, and business efforts, and operate as a public company.
Factors impacting our future funding requirements include, without limitation, the following:
the initiation, progress, timing, costs, and results of clinical trials for our product candidates;
the outcome, timing, and cost of the regulatory authorization or approval process for our product candidates; including with respect to COVAXIN in the United States and Canada;
the costs of manufacturing and commercialization, including with respect to COVAXIN, if authorized or approved;
costs related to doing business internationally including our convertible notes was recognized throughproposed development and commercialization of COVAXIN in Canada;
the cost of filing, prosecuting, defending, and enforcing our patent claims and other intellectual property rights;
the cost of defending intellectual property disputes, including patent infringement actions brought by third parties against us;
the costs of expanding infrastructure to support our development, commercialization, and business efforts;
the expenses needed to attract and retain skilled personnel;
the extent to which we in-license or acquire other products, product candidates, or technologies; and
the impact of the COVID-19 pandemic.
As of December 31, 2021, we had cash, cash equivalents, and restricted cash of approximately $95.1 million. This amount will not meet our capital requirements over the next 12 months. We will need to raise significant additional capital in order to fund our future operations. Our operating and capital requirements may change as a result of many factors currently unknown to us. To the extent that cash generated from future potential revenues of COVAXIN, if authorized or approved, is not sufficient, our management is currently evaluating different strategies to obtain the required funding for future operations. These strategies may include, but are not limited to: public and private placements of equity and/or debt, payments from potential strategic research and development arrangements, sales of assets, government grants, licensing and/or collaboration arrangements with pharmaceutical companies or other institutions, or other funding from the government or other third parties. There can be no assurance that these funding efforts will be successful. If we cannot obtain the necessary funding, we will need to delay, scale back, or eliminate some or all of our research and development programs; consider other various strategic alternatives, including a merger or sale; or cease operations. If we cannot expand our operations or otherwise capitalize on our business opportunities because we lack sufficient capital, our business, financial condition, and results of operations could be materially adversely affected.
As a result of these factors, together with the anticipated increase in spending that will be necessary to continue to research, develop, and commercialize our product candidates, there is substantial doubt about our ability to continue as a going concern within one year after the date that the notes were converted or otherwise settled. There were no derivative liabilities valuedconsolidated financial statements included in this Annual Report on Form 10-K are issued.
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Off-Balance Sheet Arrangements
We did not have any off-balance sheet arrangements during the periods presented, and we do not currently have any off-balance sheet arrangements as of December 31, 2019.
Other income (expense)
Other income (expense) consists primarily of interest expense, includingdefined in the amortization of debt issuance costs related to our debtrules and accretionregulations of the discount created by the bifurcation of the embedded conversion features and embedded change in control features from certain of the convertible promissory notes, interest income earned on our cash and cash equivalents held with institutional banks, and foreign currency income (losses) due to exchange rate fluctuations on transactions denominated in a currency other than its functional currency.SEC.
Critical Accounting Policies and Significant Judgments and Estimates
Our consolidated financial statements are prepared in accordance with U.S. generally accepted accounting principles (“GAAP”).GAAP. The preparation of our financial statements requires us to make estimates and judgments that affect the reported amounts of assets and liabilities, disclosure of contingent assets and liabilities at the date of the consolidated financial statements, and the reported amounts of expenses during the reported period. We base our estimates on historical experience, known trends and events, and various other factors that we believe to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying values of assets and liabilities that are not readily apparent from other sources. We evaluate our estimates and assumptions on an ongoing basis. Our actual results may differ from these estimates under different assumptions and conditions.
While our significant accounting policies are described in more detail in the notes to the consolidated financial statements appearingincluded elsewhere in this report,Annual Report on Form 10-K, we believe that the following accounting policies and estimates are those most critical to the preparation of our consolidated financial statements:
Stock-based compensation
We account for our stock-based compensation awards in accordance with the Financial Accounting Standards Board’s (“FASB”) Accounting Standards Codification (“ASC”)FASB ASC Topic 718, Compensation—Stock Compensation (“("ASC 718”718"). We have issued stock-based compensation awards including stock options and restricted stock units ("RSUs"), and we also account for certain issuances of preferred stock and warrants in accordance with ASC 718. ASC 718 requires all stock-based payments, to employees, including grants of employee stock options and restricted stock units and modifications to existing agreements,RSUs, to be recognized in the consolidated statements of operations and comprehensive loss based on their grant date fair values. We use the Black-Scholes option-pricing model to determine the fair value of options granted. The fair value of the RSUs is determined by the market price of a share of our common stock on the grant date. We recognize forfeitures as they occur.
Our stock-based awards are subject to service-based vesting conditions. Compensation expense related to stock-based compensation awards subject to employees and directors with service-based vesting conditions is recognized on a straight-line basis based on the grant date fair value over the associated service period of the award, which is generally the vesting term. Stock-based awards generally vest over a one to three year requisite service period and have a contractual term of 10 years. To the extent a stock-based compensation award is subject to performance-based vesting conditions, the amount of compensation expense recorded reflects an assessment of the probability of achieving the performance conditions. Compensation expense for stock-based compensation awards with performance-based vesting conditions is only recognized when the performance-based vesting condition is deemed probable to occur. Shares issued upon stock option exercise and RSU vesting are newly issued shares of common stock.
Estimating the fair value of stock options requires the input of subjective assumptions, including the expected lifeterm of the option, stock price volatility, the risk-free interest rate, and expected dividends. The assumptions used in our Black-Scholes option-pricing model represent our best estimates and involve a number of variables, uncertainties, and assumptions, and the application of management’sour judgment, as they are inherently subjective. If any assumptions change, our stock-based compensation expense could be materially different in the future.
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TheseThe assumptions used in our Black-Scholes option-pricing model for stock options are as follows:
Expected Term. Due to the historical lack of a public market for the trading of our common stock and the lack of sufficient company-specific historical data, the expected term of employee options is determined using the “simplified” method, as prescribed in Securities and Exchange Commission's ("SEC")SEC’s Staff Accounting Bulletin No. 107, (“SAB No. 107”), whereby the expected lifeterm equals the arithmetic average of the vesting term and the original contractual term of the option. The expected term of non-employee options is equal to the contractual term.
Expected Volatility. The expected volatility is based on our historical volatilities and that of similar entities within our industry which werefor periods commensurate with the expected term assumption as described in SAB No. 107.assumption.
Risk-Free Interest Rate. The risk-free interest rate is based on the interest rate payable on U.S. Treasury securities in effect at the time of grant for a period that is commensurate with the assumed expected term.
Expected Dividends. The expected dividend yield is 0% because we have not historically paid, and do not expect for the foreseeable future to pay, a dividend on our common stock.
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Stock-based compensation expense was $0.9$7.0 million, $0.7 million, and $1.1$0.9 million for the years ended December 31, 2021, 2020, and 2019 and 2018, respectively. AtAs of December 31, 2019,2021, we had $0.9$12.6 million of unamortizedunrecognized stock-based compensation expense, related to unvested service-based stock options, which is expected to be recognized over a remaining weighted-average vesting period of 1.72.1 years.
Derivative liabilitiesResearch and Development and Clinical Trial Accruals
Our convertible notes contained bifurcated conversion features classifiedAs part of the process of preparing the consolidated financial statements included elsewhere in this Annual Report on Form 10-K, we are required to estimate and record expenses, for which a large portion are research and development expenses. Research and development expenses include, among other categories, development, clinical trials, patent costs, and regulatory compliance costs incurred with research organizations, contract manufacturers, and other third-party vendors. The estimation process involves identifying services that have been performed on our behalf by third-parties, estimating and accruing expenses in our consolidated financial statements based on the evaluation of the progress to completion of specific tasks and the facts and circumstances known to us at the time of the estimate, and assessing the accuracy of these estimates going forward to determine if adjustments are required. We periodically collaborate with the third-parties to assist in determining our estimates. Payments for these activities performed by third-parties are based on the terms of the individual arrangements with the third-parties, which may differ from the pattern of costs incurred, and are reflected in the consolidated financial statements as derivative liabilitiesprepaid or accrued research and development expense, as applicable. We believe our estimates and assumptions are reasonable under the conversion feature does not have a fixed conversion price and conversioncurrent conditions; however, actual results may differ from these estimates. Any changes to estimates will be settledrecorded in the period in which a variable number of shares. Our convertible notes also contain bifurcatedcircumstance causing a change in control features that were determinedestimate becomes known and the impact of any change in estimate could be material.
Series B Convertible Preferred Stock Issuance
On March 1, 2021, we entered into a preferred stock purchase agreement, pursuant to which we agreed to issue and sell 0.1 million shares of our Series B Convertible Preferred Stock, par value $0.01 per share (the "Series B Convertible Preferred Stock"), at a price per share equal to $109.60, to Bharat Biotech. On March 18, 2021, we issued the Series B Convertible Preferred Stock as an advance payment for the supply of COVAXIN to be redemption features and not clearly and closely relatedprovided by Bharat Biotech pursuant to a supply agreement with Bharat Biotech. The Series B Convertible Preferred Stock contains multiple conversion conditions, including our receipt of shipments by Bharat Biotech of the first 10.0 million doses of COVAXIN pursuant to the debt host.aforementioned supply agreement. We estimatedaccounted for the issuance of the Series B Convertible Preferred Stock in accordance with ASC 718 and recorded the fair value of $5.0 million within stockholders' equity during the embedded conversionyear ended December 31, 2021, with a corresponding short-term asset for the advanced payment for the doses of COVAXIN. We utilized the traded common stock price, adjusted by the Conversion Ratio (as defined in Note 9 in the notes to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K), to value the Series B Convertible Preferred Stock and changethe Finnerty model to estimate a 15% discount rate for the lack of marketability of the instrument. The valuation incorporates Level 3 inputs in control features at each issuance of convertible promissory notes and at the end of each reporting period using an income approach model. Inputs into this model includefair value hierarchy, including the expectedestimated time until conversion or change in controlthe instrument's liquidity and estimated volatility of our estimatescommon stock as of the probability of conversion or change in control occurring. There are no such derivatives valued asgrant date. As of December 31, 2021, we had not yet received shipments from Bharat Biotech of doses of COVAXIN, and as such, the amount remains recorded as a short-term asset for the advance payment for the doses of COVAXIN. See Note 9 in the notes to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K for additional information.
Accounting for the Warrant Exchange
On October 4, 2019, due to either the payment or conversion of the related notes.
Wewe issued warrants to purchase our common stock and we account for our warrants in accordance with FASB ASC Topic 815-40, Derivatives and Hedging — Contracts in Entity’s Own Equity (“ASC 815-40”), which isstock: the authoritative guidance on accounting for derivative financial instruments indexed to and potentially settled in a company’s own stock. To determine whether a contract is considered indexed to the issuer’s own equity, we perform the following two-step analysis: (1) evaluate whether the contract contains any exercise contingencies and, if so, whether they disqualify the contract from being classified as equity, and (2) assess whether the settlement terms are consistent with equity classification.
We entered into a Securities Purchase Agreement with certain accredited investors, pursuant to which we issued three series of warrants, Series A Warrants, Series B Warrants, and Series C Warrants. TheOn April 22, 2020, we entered into Amendment and Exchange Agreements (each an "Exchange Agreement" and collectively, the "Exchange Agreements") with the Series A Warrants and Series C Warrants were determinedholders. Pursuant to meet the criteria for equity classification. UponExchange Agreements, among other things, the closingnumber of common stock issuable upon the exercise of the Merger,Series A Warrants was adjusted. Concurrently with the Exchange Agreements, the Series BA Warrants were recognizedholders exchanged the Series A Warrants for shares of common stock and promissory notes (the "Warrant Exchange Promissory Notes") (collectively, the "Warrant Exchange").
We accounted for the Warrant Exchange by recognizing the fair value of the consideration transferred in excess of the carrying value of the Series A Warrants as a derivative liability as they did not meet the criteria related to equity indexation. We classified the Series B Warrants on our consolidated balance sheet as a derivative liability which was recognized atreduction of additional paid-in capital. The fair value at each reporting period subsequent toof the initial issuance untilconsideration transferred was comprised of (i) the warrants were reclassified as equity in November 2019 following a final mark to market uponfair value of the completion of a reset period pursuant to whichcommon stock issued based on the number of shares of commonissued and our stock underlying the Series B Warrants was increased basedprice on the trading price for the common stock (the "Reset Period"). Changes indate of issuance and (ii) the fair value at issuance of derivatives were recognized as other income (expense) in the consolidated statements of operations and comprehensive loss.
We estimated theWarrant Exchange Promissory Notes based on Level 2 fair value inputs. The fair value of Series B Warrants using the Monte Carlo simulation model. Key fair value inputs included the starting stock price, expected stock price volatility during the Reset Period, and additional shares issued from escrow. Upon conclusionconsideration transferred was in excess of the Reset Period, we estimated the fair value of the Series BA Warrants immediately prior to the consideration transfer. The excess consideration was accounted for as a deemed dividend to the Series A Warrant holders and is reflected as an additional net loss attributed to common stockholders in the calculation of basic and diluted net loss per common share for the year ended December 31, 2020. The fair value of the Series A Warrants immediately prior to the consideration transfer was estimated using a Black-Scholes valuation model. The methodology for measuring fair value is sensitive to the expected stock volatility assumption input mentioned above. Inputs used in the valuation arewere unobservable and are were
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therefore classified as Level 3 fair value inputs. The use of different valuation techniques or assumptions could result in materially different fair value estimates. See Note 10 in the notes to the consolidated financial statements included elsewhere in this reportAnnual Report on Form 10-K for additional information.
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Results of Operations
Comparison of the Years Ended December 31, 2019 and 2018
The following table summarizes the results of our operations for the years ended December 31, 2019 and 2018 (in thousands):
Year Ended
December 31,
20192018Change
Operating expenses:
Research and development$8,086  $10,321  $(2,235) 
General and administrative6,077  5,819  258  
Total operating expenses14,163  16,140  (1,977) 
Loss from operations(14,163) (16,140) 1,977  
Other income (expense)
Change in fair value of derivative liabilities(3,187) 1,665  (4,852) 
Loss on debt conversion(341) —  (341) 
Interest income 19  (18) 
Interest expense(1,768) (3,751) 1,983  
Other income (expense)(785) (12) (773) 
Total other income (expense)(6,080) (2,079) (4,001) 
Net loss$(20,243) $(18,219) $(2,024) 
Research and development expense
Research and development expense decreased by $2.2 million for the year ended December 31, 2019 when compared to the year ended December 31, 2018 primarily as a result of a net decrease in program development and clinical trial activities of $1.8 million and a net decrease of $0.4 million in other costs.
Specifically, expenses related to OCU300 decreased in 2019 by $2.0 million primarily related to preclinical and manufacturing activities in 2018. This decrease was offset by (a) a $0.2 million increase in OCU400 preclinical activities and (b) a $0.1 million net increase in OCU200 preclinical and manufacturing activities.
The $0.4 million net decrease in other research and development costs is primarily related to (a) a $0.2 million decrease in employee-related expenses due to a decrease in headcount and (b) a $0.2 million decrease in license fees associated with a license milestone achieved during 2018.
General and administrative expense
General and administrative expenses increased by $0.3 million, for the year ended December 31, 2019 when compared to the year ended December 31, 2018. The increase was primarily due to a $0.7 million increase in professional and consulting fees and a $0.3 million increase in insurance costs, which was offset by a $0.6 million decrease in employee-related expenses due to a decrease in headcount.
Change in fair value of derivative liability
The change in fair value of derivative liability was a loss of $3.2 million for the year ended December 31, 2019 compared to a gain of $1.7 million related to a change in fair value of the derivatives related to the debt instruments for the year ended December 31, 2018. The loss for the year ended December 31, 2019 primarily relates to the remeasurement of the Series B Warrant liability.
Loss on debt conversion
The loss on debt conversion of $0.3 million primarily relates to 2019 conversions of all previously-issued convertible debt.
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Interest expense
Interest expense was $1.8 million for the year ended December 31, 2019 and $3.8 million for the year ended December 31, 2018. The decrease in interest expense was primarily due to the 2019 conversions of all previously-issued convertible debt.
Other expense
Other expense was $0.8 million the year ended December 31, 2019 compared to a de minimis amount for the year ended December 31, 2018. Other expense for the year ended December 31, 2019 primarily relates to equity issuance fees associated with the Series B Warrants, which were expensed as incurred.
Liquidity and Capital Resources
We have not generated any revenue to date and have primarily funded our operations to date through the sale and issuance of common stock and warrants to purchase common stock, proceeds from convertible notes payable, and debt. Specifically, since its inception and through December 31, 2019, we have raised an aggregate of $51.1 million to fund its operations, of which $39.5 million was from the sale of our common stock and warrants, $10.3 million was from the issuance of convertible notes, $1.1 million was from borrowings under the EB-5 Program, and $0.2 million from grant proceeds. As of December 31, 2019, we had $7.6 million in cash, cash equivalents and restricted cash.
Since our inception, we have devoted substantial resources to research and development and have incurred significant net losses and expect to continue to incur net losses for the foreseeable future. We incurred net losses of approximately $20.2 million and $18.2 million for the year ended December 31, 2019 and 2018, respectively. As of December 31, 2019, we had an accumulated deficit of $51.5 million. In addition, as of December 31, 2019, we had accounts payable and accrued expenses of $4.2 million and indebtedness of $1.1 million.
Although it is difficult to predict future liquidity requirements, we believe that we have sufficient cash and cash equivalents to fund our operations into mid-2020, during which time, we expect to continue our development efforts with respect to our product candidates. We will need to raise additional capital in the future to further the development and commercialization of our other product candidates. Until such time, if ever, that we generate product revenue, we expect to obtain additional financing through the issuance of our common stock, issuance of warrants to purchase company stock, through other equity or debt financings, licensing or sale of assets, or through collaborations or partnerships with other companies. We may not be able to raise additional capital on terms acceptable to us, or at all, and any failure to raise capital as and when needed could compromise our ability to execute on our business plan and cause us to delay or curtail our operations until such funding is received.
The following table shows a summary of our cash flows for the periods indicated (in thousands):
Year Ended
December 31,
20192018
Net cash used in operating activities$(16,893) $(11,631) 
Net cash used in investing activities(2,357) (77) 
Net cash provided by financing activities25,066  7,185  
Net increase (decrease) in cash, cash equivalents and restricted cash$5,816  $(4,523) 
Operating activities
Cash used in operating activities was $16.9 million for the year ended December 31, 2019 compared with $11.6 million for the year ended December 31, 2018. The increase in cash used in operating activities relates to additional cash used for working capital purposes during 2019, including a significant decrease in accounts payable.
Investing activities
Cash used in investing activities was $2.4 million for the year ended December 31, 2019 compared with $0.1 million for the year ended December 31, 2018. The $2.3 million increase in cash used is primarily related to costs associated with the Merger.
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Financing activities
Cash provided by financing activities was $25.1 million for the year ended December 31, 2019 compared to $7.2 million for the year ended December 31, 2018. This $17.9 million increase is primarily due to the $22.5 million of proceeds, which were issued in connection with the June 2019 common stock and warrant financing entered into by Former Ocugen and Histogenics with certain accredited investors for an aggregate purchase price of $25.0 million (the "Pre-Merger Financing"), $1.0 million from issuance of the stock subscription agreement, and $0.2 million from issuance of common stock for warrant exercises. These increases were partially offset by a payment of $5.3 million to settle the convertible debt and a decrease in net proceeds of $0.5 million from the issuance of convertible debt.
Indebtedness

In September 2016, pursuant to the U.S. Government’s Immigrant Investor Program, commonly known as the EB-5 program (the “EB-5 Program”), we entered into an arrangement to borrow up to $10.0 million from EB5 Life Sciences, L.P. (the “Lender”) in $0.5 million increments. Borrowings are at a fixed interest rate of 4.0% and are to be utilized in the clinical development, manufacturing, and commercialization of our products and for our general working capital needs. Outstanding borrowings pursuant to the EB-5 Program become due upon the seventh anniversary of the final disbursement. Amounts repaid cannot be re-borrowed. At December 31, 2019, there was $1.0 million of principal outstanding under the EB-5 program. Subsequent to December 31, 2019, we borrowed an additional $0.5 million under the arrangement.
Funding requirements
We expect to continue to incur significant expenses in connection with our ongoing activities, particularly as we continue research and development, including clinical development activities of our product candidates, increase our headcount and add operational, financial and information systems to execute our business plan, maintain, expand and protect our patent portfolio, contract to manufacture our product candidates, and operate as a public company.
Our future funding requirements, both near- and long-term, will depend on many factors, including, but not limited to:
the initiation, progress, timing, costs and results of clinical trials for our product candidates;
the outcome, timing and cost of the regulatory approval process for our product candidates by the FDA;
future costs of manufacturing and commercialization;
the cost of filing, prosecuting, defending and enforcing our patent claims and other intellectual property rights;
the cost of defending intellectual property disputes, including patent infringement actions brought by third parties against us;
the costs of expanding infrastructure and increasing headcount, as well as the higher corporate infrastructure costs associated with becoming a public company; and
the extent to which we in-license or acquire other products, product candidates or technologies.
We believe that the existing cash and cash equivalents will be sufficient to fund our operations into mid-2020, during which time we expect to continue our development efforts with respect to our product candidates. We have based this estimate on assumptions that may prove to be wrong, and we could utilize our available capital resources sooner than we expect. Substantial additional financing will be needed to fund our operations thereafter and to commercially develop any current or future product candidates. We currently do not have any commitments to obtain additional funds and may be unable to obtain sufficient funding in the future on acceptable terms, if at all. However, our management is currently evaluating different strategies to obtain the required funding for future operations. These strategies may include, but are not limited to: public and private placements of equity and/or debt, payments from potential strategic research and development, sale of assets, and licensing and/or collaboration arrangements with pharmaceutical companies or other institutions. There can be no assurance that these future funding efforts will be successful. If we cannot obtain the necessary funding, we will need to delay, scale back or eliminate some or all of our research and development programs; consider other various strategic alternatives, including a merger or sale; or cease operations. If we cannot expand our operations or otherwise capitalize on our business opportunities because we lack sufficient capital, our business, financial condition and results of operations could be materially adversely affected.
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Off-Balance Sheet Arrangements
We did not have off-balance sheet arrangements during the periods presented, and we do not currently have any off-balance sheet arrangements as defined in the rules and regulations of the SEC.
Recent Accounting Pronouncements
For a discussion of recent accounting pronouncements, see Note 2 in the notes to ourthe consolidated financial statements included elsewhere in this report.Annual Report on Form 10-K.
Other Company Information
JOBS Act
On April 5, 2012, the Jumpstart Our Business Startups Act (“JOBS Act”) was enacted. Section 107 of the JOBS Act permits an “emerging growth company” or a “smaller reporting company” to delay the adoption of new or revised accounting standards until those standards would otherwise apply to private companies. We plan to avail ourselves of this exemption from new or revised accounting standards as a smaller reporting company and, therefore, we may not be subject to the same new or revised accounting standards as other public companies that are not emerging growth companies or smaller reporting companies.
For so long as we are a “smaller reporting company,” we intend to rely on exemptions relating to: (1) providing an auditor’s attestation report on our system of internal control over financial reporting pursuant to Section 404(b) of the Sarbanes-Oxley Act and (2) complying with certain requirements that may be adopted by the Public Company Accounting Oversight Board.
Although we remain a smaller reporting company, as of December 31, 2019, we are no longer an emerging growth company.
Item 7A.    Quantitative and Qualitative Disclosures about Market Risk.
Not applicable.As of December 31, 2021, we are not subject to any material market risk, including interest rate risk and foreign currency exchange rate risk. We consider all highly liquid investments that have maturities of three months or less when acquired to be cash equivalents. Cash equivalents may include bank demand deposits, marketable securities with maturities of three months or less at purchase, and money market funds that invest primarily in certificates of deposit, commercial paper, and U.S. government and U.S. government agency obligations. Given the short-term nature of these investments, we believe there is no associated material interest rate risk. We additionally conduct business both domestically and internationally and are therefore subject to foreign currency exchange rates. Foreign currency exchange rates do not currently have a material impact on our business and therefore do not represent a material market risk. We additionally do not have material commodity price or equity price risks.
Item 8.    Financial Statements and Supplementary Data
The financial statements required by this item are set forth beginning at page F-1 of this report and are incorporated herein by reference. The reports of our Independent Registered Public Accounting Firm, Ernst & Young LLP, Public Company Accounting Oversight Board identification number 42, are also included therein.
Item 9.    Changes in and Disagreements with Accountants on Accounting and Financial Disclosure.
Not applicable.
Item 9A.    Controls and Procedures.
Evaluation of Disclosure Controls and Procedures
We have carried out an evaluation, under the supervision and with the participation of our management, including our principal executive officer and principal financial officer, of the effectiveness of the design and operation of our disclosure controls and procedures (as defined in Rules 13a-15(e) and 15d-15(e) under the Securities Exchange Act of 1934, as amended)amended (the “Exchange Act”"Exchange Act"),) as of December 31, 2019.2021. Based upon that evaluation, our principal executive officer and principal financial officer concluded that, as of the end of the period covered by this report, our disclosure controls and procedures are effective in ensuring that (a) the information required to be disclosed by us in the reports that we file or submit under the Exchange Act is recorded, processed, summarized, and reported within the time periods specified in the SEC’s rules and forms, and (b) such information is accumulated and communicated to our management, including our principal executive officer and principal financial officer, as appropriate to allow timely decisions regarding required disclosure. In designing and evaluating our disclosure controls and procedures, our management recognized that any controls and procedures, no matter how well designed and operated, can provide only reasonable assurance of achieving the desired control objectives, and our management necessarily was required to apply its judgment in evaluating the cost-benefit relationship of possible controls and procedures.
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Management’s Annual Report on Internal Control Over Financial Reporting
Our management is responsible for establishing and maintaining adequate internal control over financial reporting. Internal control over financial reporting is defined in Rule 13a-15(f) or 15d-15(f) under the Exchange Act as a process designed by, or under the supervision of, our principal executive officer and principal financial officer and effected by our Board of Directors, management, and other personnel, to provide reasonable assurance regarding the reliability of financial reporting and the
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preparation of our financial statements for external reporting purposes in conformity with generally accepted accounting principlesGAAP and includes those policies and procedures that:
pertain to the maintenance of records that in reasonable detail accurately and fairly reflect the transactions and dispositions of our assets;
provide reasonable assurance that transactions are recorded as necessary to permit preparation of financial statements in conformity with generally accepted accounting principles,GAAP, and that our receipts and expenditures are being made only in accordance with authorizations of our management and directors; and
provide reasonable assurance regarding prevention or timely detection of unauthorized acquisition, use, or disposition of our assets that could have a material effect on our consolidated financial statements.
Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. Projections of any evaluation of effectiveness to future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate.
Under the supervision of and with the participation of our Chief Executive Officer and Chief Financial Officer, our management assessed the effectiveness of our internal control over financial reporting as of December 31, 20192021 based on the criteria set forth by the Committee of Sponsoring Organizations of the Treadway Commission (COSO) in Internal Control-Integrated Framework (2013).of 2013. Based on this assessment, management concluded that our internal control over financial reporting was effective as of December 31, 2019.2021. Our independent registered public accounting firm, Ernst & Young LLP, has issued an audit report on our internal control over financial reporting, as stated in their report included with the consolidated financial statements included elsewhere in this Annual Report on Form 10-K.
Changes in Internal Control Over Financial Reporting
There have been no changes in our internal control over financial reporting during our most recent fiscal quarter that has materially affected, or is reasonably likely to materially affect, our internal control over financial reporting.
Item 9B.    Other Information.
Our Board of Directors has established Thursday, June 4, 2020 as the date of our 2020 Annual Meeting of Stockholders (the “2020 Annual Meeting”).
The 2020 Annual Meeting will be held at the offices of Pepper Hamilton LLP, 400 Berwyn Park, 899 Cassatt Road, Berwyn, PA 19312, at 8:00 a.m., local time. Stockholders of record at the close of business on Tuesday, April 14, 2020 will be entitled to vote at the 2020 Annual Meeting.
Because the date of the 2020 Annual Meeting has been advanced by more than 30 calendar days from the date of the preceding year’s annual meeting, in accordance with Rule 14a-5(f) under the Exchange Act, we are informing stockholders of certain dates related to the 2020 Annual Meeting.
Pursuant to Rule 14a-8 under the Exchange Act, a stockholder intending to present a proposal to be included in the proxy materials for the 2020 Annual Meeting must deliver a proposal in writing to our principal executive offices no later than a reasonable time before we begin printing and mailing the proxy materials for the 2020 Annual Meeting. According to our bylaws, a stockholder must provide notice to the our corporate secretary of proposals intended to be presented at, but not included in the proxy materials for, the 2020 Annual Meeting, including director nominations for election to our Board of Directors, in a timely manner. Under our bylaws, in order to be timely, in the event that the date of the annual meeting is advanced more than 30 days prior to or delayed more than 30 days after the anniversary of the preceding year’s annual meeting, notice by the stockholder must be delivered to us by the close of business on the later of (x) the 90th day prior to such annual meeting or (y) the 10th day following the day on which public announcement of the date of such meeting is first made.
As such, the new deadline for submission of proposals to be included in the proxy materials or otherwise to be considered at the 2020 Annual Meeting is the close of business on Monday, April 6, 2020, which we consider a reasonable time before we will begin printing and mailing proxy materials and is the 10th day following the date of filing of this Annual Report. ProposalsNone.
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should be addressed to: Corporate Secretary, Ocugen, Inc., 5 Great Valley Parkway, Suite 160, Malvern, PA 19355. Any such proposal must (i) meet the requirements set forth in the rules and regulations of the SEC in order to be eligible for inclusion in the proxy materials for the 2020 Annual Meeting and (ii) contain the information specified in, and otherwise comply with, our bylaws. We may omit any proposal from the proxy materials that does not comply with the SEC’s rules.
Because of the uncertainties surrounding the impact of the COVID-19 pandemic, we are planning for the possibility that the 2020 Annual Meeting may be held solely by means of remote communication. If we take this step, we will announce the decision to do so in advance of the 2020 Annual Meeting, and details on how to participate in the webcast will be set forth in a press release issued by us and available at www.ocugen.com.
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PART III
Item 10.    Directors, Executive Officers, and Corporate Governance.
The information required by this Item is incorporated by reference from the discussion responsive thereto contained in the Proxy Statement for our 20202022 Annual Meeting of Stockholders, which we intend to file with the SEC within 120 days of the end of the fiscal year to which this Annual Report on Form 10-K relates.
Item 11.     Executive Compensation.
The information required by this Item is incorporated by reference from the discussion responsive thereto contained in the Proxy Statement for our 20202022 Annual Meeting of Stockholders, which we intend to file with the SEC within 120 days of the end of the fiscal year to which this Annual Report on Form 10-K relates.
Item 12.    Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters.
The information required by this Item is incorporated by reference from the discussion responsive thereto contained in the Proxy Statement for our 20202022 Annual Meeting of Stockholders, which we intend to file with the SEC within 120 days of the end of the fiscal year to which this Annual Report on Form 10-K relates.
Item 13.    Certain Relationships and Related Transactions, and Director Independence.
The information required by this Item is incorporated by reference from the discussion responsive thereto contained in the Proxy Statement for our 20202022 Annual Meeting of Stockholders, which we intend to file with the SEC within 120 days of the end of the fiscal year to which this Annual Report on Form 10-K relates.
Item 14.    Principle Accountant Fees and Services.
The information required by this Item is incorporated by reference from the discussion responsive thereto contained in the Proxy Statement for our 20202022 Annual Meeting of Stockholders, which we intend to file with the SEC within 120 days of the end of the fiscal year to which this Annual Report on Form 10-K relates.
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PART IV
Item 15.    Exhibits,Exhibit and Financial StatementsStatement Schedules.
The financial statements, financial statement schedules, and exhibits filed as part of this Annual Report on Form 10-K are as follows:
(a)(1) Financial Statements
See “Index to Consolidated Financial Statements” beginning on page F-1 of this report.
(a)(2) Financial Statement Schedules
Financial statement schedules have been omitted because the required information is not present, not present in amounts sufficient to require submission of the schedules, or because the required information is provided in the financial statements or notes thereto.
(a)(3) Exhibits
The exhibits required to be filed as part of this report are listed in the Exhibit Index attached hereto and are incorporated herein by reference.
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EXHIBIT INDEX
ExhibitDescription
2.1
2.2
3.1
3.2
3.3
3.4
3.5
4.1* 3.6
3.7
4.1*
4.2
4.3 
4.4 4.3*
4.5 10.1+
4.6 
4.7 
4.8 
10.1 
10.2# 


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ExhibitDescription
10.3# 
10.4# 
10.5# 
10.6# 
10.7# 
10.8# 
10.9# 
10.10# 
10.11# 
10.12# 
10.13# 
10.14 


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ExhibitDescription
10.15# 
10.16# 
10.17 
10.18# 
10.19# 
10.20# 
10.21 
10.22 
10.23 
10.24 
10.25+ 
10.26+ 10.2+
10.27+ 10.3+
10.28+ 10.4+
Ocugen, Inc. 2019 Equity Incentive Plan (filed as Appendix A to the Registrant's Proxy Statement on Schedule 14A as filed on November 8, 2019, and incorporated herein by reference)
10.29*+ 10.5+
10.30*+ 10.6+


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ExhibitDescription
Description
10.7+
10.31# 10.8+
10.9+
10.10+
10.11
10.12
10.13#
10.32# 10.14#
10.33 10.15
10.34# 10.16#
10.35# 
10.36 10.17#
10.37 10.18
10.38 10.19#
10.39 10.20
10.40 10.21
10.41 10.22
10.42 
10.43 
10.44 10.23
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ExhibitDescription
10.45# 
10.24#


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Exhibit10.25#Description
10.26+
10.46+ 
10.47+ 10.27+
10.28+
10.48+ 21.1*
10.49+ 
21.1* 
23.1*
31.1*
31.2*
32.1*
101.INS*Inline XBRL Instance Document
101.SCH*Inline XBRL Taxonomy Extension Schema Document
101.CAL*Inline XBRL Taxonomy Extension Calculation Linkbase Document
101.DEF*Inline XBRL Taxonomy Extension Definition Linkbase Document
101.LAB*Inline XBRL Taxonomy Extension Label Linkbase Document
101.PRE*Inline XBRL Taxonomy Extension Presentation Linkbase Document
104The cover page from this Annual Report on Form 10-K, formatted in Inline XBRL
____________________________________________
*    Filed herewith.
#    Portions of this exhibit have been omitted pursuant to Item 601(b)(10)(iv) of Regulations S-K.
+    Indicates a management contract or compensatory plan or arrangement.

Item 16.    10-K Summary
Not applicable.
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SIGNATURES
Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto duly authorized.
Ocugen, Inc.
Dated: March 27, 2020February 28, 2022/s/ Shankar Musunuri, Ph.D., MBA
Shankar Musunuri, Ph.D., MBA
Chief Executive Officer & Chairman
(Principal Executive Officer)
Dated: March 27, 2020February 28, 2022/s/ Sanjay Subramanian
Sanjay Subramanian
Chief Financial Officer and Head of Corporate Development
(Principal Financial Officer and Principal Accounting Officer)
Pursuant to the requirementrequirements of the Securities Exchange Act of 1934, as amended, this Annual Report on Form 10-Kreport has been signed below by the following persons on behalf of the registrant and in the capacities heldand on the dates indicated.
SignatureTitleDate
/s/
/s/ Shankar MusunuriChairman, Chief Executive Officer, and DirectorMarch 27, 2020February 28, 2022
Shankar Musunuri(Principal Executive Officer)
/s/ Sanjay SubramanianChief Financial Officer and Head of Corporate DevelopmentMarch 27, 2020February 28, 2022
Sanjay Subramanian(Principal Financial and Principal Accounting Officer)
/s/ Ramesh KumarDirectorMarch 27, 2020February 28, 2022
Ramesh Kumar
/s/ Junge ZhangDirectorMarch 27, 2020February 28, 2022
Junge Zhang
/s/ Uday KompellaDirectorFebruary 28, 2022
Uday Kompella
/s/ Manish PottiDirectorMarch 27, 2020February 28, 2022
Manish Potti
/s/ Uday B. KompellaKirsten CastilloDirectorMarch 27, 2020February 28, 2022
Uday B. KompellaKirsten Castillo
/s/ Frank LeoPrabhavathi FernandesDirectorMarch 27, 2020February 28, 2022
Frank Leo
/s/ Suha TaspolatogluDirectorMarch 27, 2020
Suha TaspolatogluPrabhavathi Fernandes

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INDEX TO CONSOLIDATED FINANCIAL STATEMENTS
OCUGEN, INC.
Page
Consolidated Financial Statements



F-1

Report of Independent Registered Public Accounting Firm
To the Stockholders and the Board of Directors of Ocugen, Inc.
Opinion on the Financial Statements
We have audited the accompanying consolidated balance sheets of Ocugen, Inc. (the Company) as of December 31, 20192021 and 2018,2020, the related consolidated statements of operations and comprehensive loss, stockholders’ equity (deficit) and cash flows for each of the three years thenin the period ended December 31, 2021 and the related notes (collectively referred to as the “consolidated financial statements”). In our opinion, the consolidated financial statements present fairly, in all material respects, the financial position of the Company at December 31, 20192021 and 2018,2020, and the results of its operations and its cash flows for each of the three years thenin the period ended December 31, 2021, in conformity with U.S. generally accepted accounting principles.
We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the Company’s internal control over financial reporting as of December 31, 2021, based on criteria established in Internal Control — Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 framework), and our report dated February 28, 2022 expressed an unqualified opinion thereon.
The Company’s Ability to Continue as a Going Concern
The accompanying consolidated financial statements have been prepared assuming that the Company will continue as a going concern. As discussed in Note 1 to the financial statements, the Company has suffered recurring losses from operations and has stated that substantial doubt exists about the Company’s ability to continue as a going concern. Management’s evaluation of the events and conditions and management’s plans regarding these matters are also described in Note 1. The consolidated financial statements do not include any adjustments that might result from the outcome of this uncertainty.
Basis for Opinion
These consolidated financial statements are the responsibility of the Company’s management. Our responsibility is to express an opinion on the Company’s financial statements based on our audits. We are a public accounting firm registered with the Public Company Accounting Oversight Board (United States) (PCAOB)PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the Securities and Exchange Commission and the PCAOB.
We conducted our audits in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable assurance about whether the financial statements are free of material misstatement, whether due to error or fraud. The Company is not required to have, nor were we engaged to perform, an audit of its internal control over financial reporting. As part of our audits we are required to obtain an understanding of internal control over financial reporting but not for the purpose of expressing an opinion on the effectiveness of the Company’s internal control over financial reporting. Accordingly, we express no such opinion.
Our audits included performing procedures to assess the risks of material misstatement of the consolidated financial statements, whether due to error or fraud, and performing procedures that respond to those risks. Such procedures included examining, on a test basis, evidence regarding the amounts and disclosures in the consolidated financial statements. Our audits also included evaluating the accounting principles used and significant estimates made by management, as well as evaluating the overall presentation of the consolidated financial statements. We believe that our audits provide a reasonable basis for our opinion.
Critical Audit Matter
The critical audit matter communicated below is a matter arising from the current period audit of the consolidated financial statements that was communicated or required to be communicated to the audit committee and that: (1) relates to accounts or disclosures that are material to the consolidated financial statements and (2) involved our especially challenging, subjective, or complex judgments. The communication of the critical audit matter does not alter in any way our opinion on the consolidated financial statements, taken as a whole, and we are not, by communicating the critical audit matter below, providing a separate opinion on the critical audit matter or on the accounts or disclosures to which it relates.

F-2

Accounting for convertible preferred stock
Description of the Matter
As discussed in Note 9 of the consolidated financial statements, the Company issued Series B convertible preferred stock ("convertible preferred stock") in March 2021 to Bharat Biotech as an advance payment for the supply of COVAXIN. The Company accounts for convertible preferred stock as a liability or as an equity instrument depending on the specific terms of the preferred stock purchase agreement. The Company accounted for the convertible preferred stock as an equity instrument within stockholder's equity at its fair value and recognized a corresponding short-term asset for the advance payment.

Auditing the accounting conclusions for the convertible preferred stock was complex and required significant auditor judgement to evaluate the classification of the preferred stock on the balance sheet. In particular, the accounting for convertible preferred stock involved an assessment of its terms, including the settlement provisions, to determine if the convertible preferred stock should be classified as an equity instrument or liability.
How We Addressed the Matter in Our AuditTo test the accounting for convertible preferred stock, our audit procedures included, among others, inspecting the preferred stock purchase agreement, including the form of preferred stock, settlement provisions, and testing the Company's technical accounting analysis of the preferred stock purchase agreement and application of the relevant accounting guidance. This also included the involvement of subject matter resources to assist in evaluating management's conclusion on the interpretation and application of the relevant accounting literature.
/s/ Ernst & Young LLP
We have served as the Company’s auditor since 2018.
Philadelphia, Pennsylvania
March 27, 2020February 28, 2022

F-3
F-2

Report of Independent Registered Public Accounting Firm
To the Stockholders and the Board of Directors of Ocugen, Inc.
Opinion on Internal Control Over Financial Reporting
We have audited Ocugen, Inc.’s internal control over financial reporting as of December 31, 2021, based on criteria established in Internal Control — Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 framework) (the COSO criteria). In our opinion, Ocugen, Inc. (the Company) maintained, in all material respects, effective internal control over financial reporting as of December 31, 2021, based on the COSO criteria.
We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the consolidated balance sheets of the Company as of December 31, 2021 and 2020, and the related consolidated statements of operations, comprehensive income, stockholders’ equity (deficit) and cash flows for each of the three years in the period ended December 31, 2021, and the related notes and our report dated February 28, 2022 expressed an unqualified opinion thereon.
Basis for Opinion
The Company’s management is responsible for maintaining effective internal control over financial reporting and for its assessment of the effectiveness of internal control over financial reporting included in the accompanying Management’s Annual Report on Internal Control Over Financial Reporting. Our responsibility is to express an opinion on the Company’s internal control over financial reporting based on our audit. We are a public accounting firm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the Securities and Exchange Commission and the PCAOB.
We conducted our audit in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable assurance about whether effective internal control over financial reporting was maintained in all material respects.
Our audit included obtaining an understanding of internal control over financial reporting, assessing the risk that a material weakness exists, testing and evaluating the design and operating effectiveness of internal control based on the assessed risk, and performing such other procedures as we considered necessary in the circumstances. We believe that our audit provides a reasonable basis for our opinion.
Definition and Limitations of Internal Control Over Financial Reporting
A company’s internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles. A company’s internal control over financial reporting includes those policies and procedures that (1) pertain to the maintenance of records that, in reasonable detail, accurately and fairly reflect the transactions and dispositions of the assets of the company; (2) provide reasonable assurance that transactions are recorded as necessary to permit preparation of the financial statements in accordance with generally accepted accounting principles, and that receipts and expenditures of the company are being made only in accordance with authorizations of management and directors of the company; and (3) provide reasonable assurance regarding prevention or timely detection of unauthorized acquisition, use, or disposition of the company’s assets that could have a material effect on the financial statements.
Because of its inherent limitations, internal control over financial reporting may not prevent or detect material misstatements. Also, projections of any evaluation of effectiveness to future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate.
/s/ Ernst & Young LLP
Philadelphia, Pennsylvania
February 28, 2022

F-4

OCUGEN, INC.
CONSOLIDATED BALANCE SHEETS
December 31,
2019
December 31,
2018
Assets
Current assets
Cash and cash equivalents$7,444,052  $1,628,136  
Prepaid expenses and other current assets1,322,167  313,499  
Asset held for sale7,000,000  —  
Total current assets15,766,219  1,941,635  
Property and equipment, net222,464  245,788  
Restricted cash151,016  150,477  
Other assets667,747  116,333  
Total assets$16,807,446  $2,454,233  
Liabilities and stockholders’ equity (deficit)
Current liabilities
Accounts payable$1,895,613  $3,277,525  
Accrued expenses2,270,045  1,402,750  
Short-term debt, net—  7,483,847  
Derivative liabilities—  1,741,222  
Operating lease obligation172,310  —  
Other current liabilities205,991  204,242  
Total current liabilities4,543,959  14,109,586  
Non-current liabilities
Operating lease obligation, less current portion163,198  —  
Long term debt, net1,072,123  1,016,727  
Other non-current liabilities9,755  37,459  
Total non-current liabilities1,245,076  1,054,186  
Total liabilities5,789,035  15,163,772  
Commitments and contingencies (Note 9)
Stockholders’ equity (deficit)
Convertible preferred stock, $0.01 par value, 10,000,000 shares authorized, 7 and 0 issued and outstanding, respectively—  —  
Common stock, $0.01 par value, 200,000,000 authorized, 52,746,728 and 4,960,552 shares issued, respectively; 52,625,228 and 4,960,552 shares outstanding, respectively527,467  49,606  
Treasury Stock, at cost 121,500 and 0 shares, respectively(47,864) —  
Accumulated other comprehensive income—  451  
Additional paid-in capital62,018,632  18,477,598  
Accumulated deficit(51,479,824) (31,237,194) 
Total stockholders’ equity (deficit)11,018,411  (12,709,539) 
Total liabilities and stockholders’ equity (deficit)$16,807,446  $2,454,233  
(in thousands, except share and per share amounts)

As of December 31,
20212020
Assets
Current assets
Cash and cash equivalents$94,958 $24,039 
Advance for COVAXIN supply4,988 — 
Prepaid expenses and other current assets2,700 1,839 
Total current assets102,646 25,878 
Property and equipment, net1,164 633 
Restricted cash151 151 
Other assets1,800 714 
Total assets$105,761 $27,376 
Liabilities and stockholders’ equity
Current liabilities
Accounts payable$2,312 $395 
Accrued expenses and other current liabilities4,325 2,941 
Short-term debt, net— 234 
Operating lease obligations363 44 
Total current liabilities7,000 3,614 
Non-current liabilities
Operating lease obligations, less current portion1,231 389 
Long term debt, net1,712 1,823 
Total non-current liabilities2,943 2,212 
Total liabilities9,943 5,826 
Commitments and contingencies (Note 14)00
Stockholders’ equity
Convertible preferred stock; $0.01 par value; 10,000,000 shares authorized at December 31, 2021 and 2020
Series A; 7 issued and outstanding at December 31, 2021 and 2020— — 
Series B; 54,745 and 0 issued and outstanding at December 31, 2021 and 2020, respectively— 
Common stock; $0.01 par value; 295,000,000 and 200,000,000 authorized; 199,502,183 and 184,133,384 shares issued, and 199,380,683 and 184,011,884 shares outstanding at December 31, 2021 and 2020, respectively1,995 1,841 
Treasury Stock, at cost, 121,500 shares at December 31, 2021 and 2020(48)(48)
Additional paid-in capital225,537 93,059 
Accumulated deficit(131,667)(73,302)
Total stockholders’ equity95,818 21,550 
Total liabilities and stockholders’ equity$105,761 $27,376 
See accompanying notes to consolidated financial statements.

F-3F-5

OCUGEN, INC.
CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS
Year ended December 31,
20192018
Operating expenses:
Research and development$8,085,522  $10,321,397  
General and administrative6,077,097  5,819,111  
Total operating expenses14,162,619  16,140,508  
Loss from operations(14,162,619) (16,140,508) 
Other income (expense)
Change in fair value of derivative liabilities(3,187,380) 1,664,689  
Loss on debt conversion(341,136) —  
Interest income1,214  19,213  
Interest expense(1,767,836) (3,750,630) 
Other income (expense)(784,873) (12,428) 
Total other income (expense)(6,080,011) (2,079,156) 
Net loss$(20,242,630) $(18,219,664) 
Other comprehensive income (loss)
Foreign currency translation adjustment(451) 451  
Comprehensive loss$(20,243,081) $(18,219,213) 
Net loss per share of common stock—basic and diluted$(1.46) $(3.67) 
Weighted average common shares outstanding—basic and diluted13,893,819  4,960,552  
(in thousands, except share and per share amounts)

Year ended December 31,
202120202019
Revenues
Collaboration revenue$— $43 $— 
Total revenues— 43 — 
Operating expenses
Research and development35,108 6,354 8,086 
In-process research and development— 7,000 — 
General and administrative22,920 7,974 6,077 
Total operating expenses58,028 21,328 14,163 
Loss from operations(58,028)(21,285)(14,163)
Other income (expense)
Change in fair value of derivative liabilities— — (3,187)
Loss on debt conversion— — (341)
Interest expense(79)(721)(1,768)
Other income (expense)(310)184 (784)
Total other income (expense)(389)(537)(6,080)
Loss before income taxes(58,417)(21,822)(20,243)
Income tax benefit(52)— — 
Net loss and comprehensive income$(58,365)$(21,822)$(20,243)
Deemed dividend related to Warrant Exchange— (12,546)— 
Net loss to common stockholders$(58,365)$(34,368)$(20,243)
Shares used in calculating net loss per share attributable to common stockholders — basic and diluted195,013,043 112,236,110 13,893,819 
Net loss per share attributable to common stockholders — basic and diluted$(0.30)$(0.31)$(1.46)
See accompanying notes to consolidated financial statements.

F-4F-6

OCUGEN, INC.
CONSOLIDATED STATEMENTS OF STOCKHOLDERS’ EQUITY (DEFICIT)
Common StockTreasury StockAdditional
Paid-in
Capital
Accumulated
Other
Comprehensive
Income
Accumulated
Deficit
Total
SharesAmount
Balance at December 31, 20174,960,552  $49,606  $—  $17,402,911  $—  $(13,017,530) $4,434,987  
Foreign currency translation adjustment—  —  —  —  451  —  451  
Stock-based compensation expense—  —  —  1,074,687  —  —  1,074,687  
Net loss—  —  —  —  —  (18,219,664) (18,219,664) 
Balance at December 31, 20184,960,552  $49,606  $—  $18,477,598  $451  $(31,237,194) $(12,709,539) 
Issuance of common stock for Subscription Agreement80,569  806  —  999,194  —  —  1,000,000  
Conversion of debt1,125,673  11,256  —  13,968,532  —  —  13,979,788  
Issuance of common stock and warrants for Pre-Merger Financing4,385,964  43,860  —  13,106,596  —  —  13,150,456  
Issuance of stock for reverse asset acquisition, net of $2.6 million of costs1,651,748  16,517  —  3,549,271  —  —  3,565,788  
Reclassification of Series B Warrants from liability to equity—  —  —  11,255,740  —  —  11,255,740  
Issuance of common stock for warrant exercises, net40,542,222  405,422  —  (222,388) —  —  183,034  
Repurchase of treasury stock—  —  (47,864) —  —  —  (47,864) 
Foreign currency translation—  —  —  —  (451) —  (451) 
Stock-based compensation expense—  —  —  884,089  —  —  884,089  
Net loss—  —  —  —  —  (20,242,630) (20,242,630) 
Balance at December 31, 201952,746,728  $527,467  $(47,864) $62,018,632  $—  $(51,479,824) $11,018,411  
(in thousands, except share amounts)

Series A Convertible Preferred StockSeries B Convertible Preferred StockCommon StockTreasury StockAdditional
Paid in Capital
Accumulated
Deficit
Total
SharesAmountSharesAmountSharesAmount
Balance at December 31, 2018 $  $ 4,960,552 $50 $ $18,478 $(31,237)$(12,709)
Stock-based compensation expense— — — — — — — 884 — 884 
Issuance of common stock for subscription agreement— — — — 80,569 — 999 — 1,000 
Conversion of debt— — — — 1,125,673 11 — 13,969 — 13,980 
Issuance of common stock and warrants for Pre-Merger Financing— — — — 4,385,964 44 — 13,106 — 13,150 
Issuance of stock for reverse asset acquisition, net— — — 1,651,748 17 — 3,549 — 3,566 
Reclassification of Series B Warrants from liability to equity— — — — — — — 11,256 — 11,256 
Issuance of common stock for warrant exercises, net— — — — 40,542,222 405 — (222)— 183 
Repurchase of treasury stock— — — — — — (48)— — (48)
Net loss— — — — — — — — (20,243)(20,243)
Balance at December 31, 20197 $  $ 52,746,728 $528 $(48)$62,019 $(51,480)$11,019 
Stock-based compensation expense— — — — — — — 660 — 660 
Warrant Exchange— — — — 21,920,820 219 — (5,197)— (4,978)
Issuance of common stock for subscription agreements and warrant exercises— — — — 1,328,405 13 — 319 — 332 
At-the-market common stock issuance, net— — — — 108,137,431 1,081 — 35,258 — 36,339 
Net loss— — — — — — — — (21,822)(21,822)
Balance at December 31, 20207 $  $ 184,133,384 $1,841 $(48)$93,059 $(73,302)$21,550 
See accompanying notes to consolidated financial statements.





F-5
F-7


OCUGEN, INC.
CONSOLIDATED STATEMENTS OF STOCKHOLDERS’ EQUITY (DEFICIT) (CONTINUED)
(in thousands, except share amounts)
Series A Convertible Preferred StockSeries B Convertible Preferred StockCommon StockTreasury StockAdditional
Paid in Capital
Accumulated
Deficit
Total
SharesAmountSharesAmountSharesAmount
Balance at December 31, 20207 $  $ 184,133,384 $1,841 $(48)$93,059 $(73,302)$21,550 
Stock-based compensation expense— — — — — — — 6,958 — 6,958 
Issuance of common stock for option and warrant exercises— — — — 1,381,799 14 — 1,248 — 1,262 
At-the-market common stock issuance, net— — — — 987,000 10 — 4,839 — 4,849 
Registered direct offering common stock issuance, net— — — — 13,000,000 130 — 114,480 — 114,610 
Series B Convertible Preferred Stock issuance, net— — 54,745 — — — 4,953 — 4,954 
Net loss— — — — — — — — (58,365)(58,365)
Balance at December 31, 20217 $ 54,745 $1 199,502,183 $1,995 $(48)$225,537 $(131,667)$95,818 
See accompanying notes to consolidated financial statements.

F-8

OCUGEN, INC.
CONSOLIDATED STATEMENTS OF CASH FLOWS
Year ended December 31,
20192018
Cash flows from operating activities
Net loss$(20,242,630) $(18,219,664) 
Adjustments to reconcile net loss to net cash used in operating activities:
Depreciation expense60,608  49,623  
Non-cash interest expense1,733,521  3,750,630  
Non-cash lease expense250,361  —  
Change in fair value of derivative liability3,187,380  (1,664,689) 
Stock-based compensation expense884,089  1,074,687  
Conversion of convertible notes341,136  —  
Other non-cash4,803  —  
Changes in assets and liabilities:
Prepaid expenses and other current assets(1,007,367) (201,861) 
Accounts payable and accrued expenses(1,628,621) 3,633,394  
Deferred rent—  1,540  
Other assets(227,172) (54,203) 
Lease obligations(249,389) —  
Net cash used in operating activities(16,893,281) (11,630,543) 
Cash flows from investing activities
Purchase of property, plant and equipment(29,446) (77,414) 
Payment of asset acquisition costs(2,327,273) —  
Net cash used in investing activities(2,356,719) (77,414) 
Cash flows from financing activities
Proceeds from sale of common stock for pre-merger financing22,546,353  —  
Proceeds from stock subscription1,000,000  —  
Purchases of treasury stock(47,864) —  
Issuance of common stock for warrant exercises183,034  —  
Repayments of debt(5,290,000) —  
Proceeds from issuance of debt6,800,000  7,300,400  
Payment of debt issuance costs(99,202) (103,925) 
Payments on financing leases(25,866) (11,928) 
Net cash provided by financing activities25,066,455  7,184,547  
Effect of changes in exchange rate on cash—  451  
Net increase (decrease) in cash, cash equivalents and restricted cash5,816,455  (4,522,959) 
Cash, cash equivalents and restricted cash at beginning of period1,778,613  6,301,572  
Cash, cash equivalents and restricted cash at end of period$7,595,068  $1,778,613  
Supplemental disclosure of non-cash investing and financing transactions:
Purchase of fixed assets by entering into capital lease (Note 9)$—  $63,817  
Conversion of convertible notes (Note 7)$13,979,788  $—  
Equity issuance costs (Note 3)$1,150,000  $—  
Right-of-use asset related to operating leases$470,356  $—  
Reverse asset acquisition costs (Note 3)$2,252,795  $—  
(in thousands)
Year ended December 31,
202120202019
Cash flows from operating activities
Net loss$(58,365)$(21,822)$(20,243)
Adjustments to reconcile net loss to net cash used in operating activities:
Depreciation and amortization expense229 102 61 
Non-cash interest expense78 721 1,734 
Non-cash lease expense360 189 250 
In-process research and development expense— 7,000 — 
Change in fair value of derivative liability— — 3,187 
Stock-based compensation expense6,958 660 884 
Loss on debt conversion— — 341 
Income tax benefit(52)— — 
Gain on forgiveness of PPP Note(426)— — 
Impairment on note receivable761 — — 
Other non-cash26 (349)
Changes in assets and liabilities:
Prepaid expenses and other current assets(742)(370)(1,007)
Accounts payable and accrued expenses3,498 (541)(1,629)
Other assets100 (104)(227)
Lease obligations(366)(195)(249)
Net cash used in operating activities(47,941)(14,709)(16,893)
Cash flows from investing activities
Purchase of property and equipment(939)(307)(30)
Payments for asset acquisitions(127)— (2,327)
Issuance of note receivable(750)— — 
Net cash used in investing activities(1,816)(307)(2,357)
Cash flows from financing activities
Proceeds from issuance of common stock129,211 37,822 1,183 
Payment of equity issuance costs(8,525)(1,477)— 
Purchases of treasury stock— — (48)
Proceeds from Pre-Merger Financing— — 22,546 
Proceeds from issuance of debt— 921 6,800 
Payments of debt issuance costs— (6)(99)
Repayments of debt— (5,625)(5,290)
Financing lease principal payments(10)(24)(26)
Net cash provided by financing activities120,676 31,611 25,066 
Net increase in cash, cash equivalents, and restricted cash70,919 16,595 5,816 
Cash, cash equivalents, and restricted cash at beginning of period24,190 7,595 1,779 
Cash, cash equivalents, and restricted cash at end of period$95,109 $24,190 $7,595 
See accompanying notes to consolidated financial statements.


F-6
F-9

OCUGEN, INC.
CONSOLIDATED STATEMENTS OF CASH FLOWS (CONTINUED)
(in thousands)
Year ended December 31,
202120202019
Supplemental disclosure of non-cash investing and financing transactions:
Exercise of warrants$603 $— $— 
Series B Convertible Preferred Stock issuance$4,988 $— $— 
Forgiveness of PPP Note$426 $— $— 
Purchase of property and equipment$16 $214 $— 
Right-of-use assets related to operating leases$1,226 $180 $470 
Issuance of Warrant Exchange Promissory Notes$— $5,625 $— 
Obligation settled with common stock$— $331 $— 
Conversion of convertible notes$— $— $13,980 
Equity issuance costs$— $$1,150 
Reverse asset acquisition costs$— $— $2,253 
See accompanying notes to consolidated financial statements.

F-10

OCUGEN, INC.
NOTES TO CONSOLIDATED FINANCIAL STATEMENTS
1.    Nature of Business
Ocugen, Inc. (formerly known as Histogenics Corporation), together with its wholly owned subsidiaries (“Ocugen” or the “Company”), is a clinical-stage biopharmaceutical company focused on discovering, developing and commercializing transformativegene therapies to treat the whole eye.cure blindness diseases and developing a vaccine to save lives from COVID-19. The Company is locatedheadquartered in Malvern, Pennsylvania.Pennsylvania, and manages its business as 1 operating segment.
Ocugen hasCOVID-19 Vaccine Candidate
In February 2021, the Company entered into a late-stage, Phase 3 program, OCU300,Co-Development, Supply and Commercialization Agreement with Bharat Biotech International Limited ("Bharat Biotech"), pursuant to which has received Orphan Drug Designationthe Company obtained an exclusive right and license under certain of Bharat Biotech’s intellectual property rights, with the right to grant sublicenses, to develop, manufacture, and commercialize COVAXIN for the prevention of COVID-19 caused by SARS-CoV-2 in the United States, its territories, and possessions. In June 2021, the Company entered into an amendment to the Co-Development, Supply and Commercialization Agreement (as so amended, the "Covaxin Agreement") pursuant to which the parties agreed to expand the Company's rights to develop, manufacture, and commercialize COVAXIN to include Canada in addition to the United States, its territories, and possessions (the "Ocugen Covaxin Territory").
COVAXIN is a whole-virion inactivated COVID-19 vaccine candidate and is formulated with the inactivated SARS-CoV-2 virus, an antigen, and an adjuvant. COVAXIN requires a 2-dose vaccination regimen given 28 days apart and is stored in standard vaccine storage conditions (2-8°C). COVAXIN was granted an Emergency Use Listing by the World Health Organization in November 2021. Over 295 million doses globally have been administered to date.
The Company is pursuing Biologics License Application ("ODD"BLA") fromapproval for COVAXIN in the United States based upon the recommendation of the U.S. Food and Drug Administration ("FDA"). OCU300In October 2021, the Company submitted an Investigational New Drug ("IND") application to the FDA to initiate a Phase 2/3 immuno-bridging and broadening clinical trial evaluating COVAXIN for adults ages 18 years and older. The clinical trial is designed to evaluate whether the immune response experienced in participants in a small molecule therapeutic currently incompleted Phase 3 clinical developmenttrial in India is similar to a demographically representative, adult population in the United States. In November 2021, the Company was notified that the FDA issued a clinical hold on its IND application. In December 2021, the FDA sent the Company a letter setting forth the reasons for patients with ocular rednessthe clinical hold and discomfort stemming from ocular graft-versus-host disease (“oGVHD”). Ocugenspecific guidance on steps that must be taken to have the clinical hold lifted. The Company provided the FDA responses to their comments and the FDA lifted its clinical hold in February 2022. The Company plans to initiate the Phase 2/3 immuno-bridging and broadening clinical trial for COVAXIN as soon as the Company is able to. The Company also plans to initiate a safety-bridging clinical trial in the first half of 2022, subject to discussions with the FDA. Subject to the foregoing, the Company anticipates submitting a BLA with the FDA near the end of 2022. In November 2021, the Company also submitted a request to the FDA for Emergency Use Authorization ("EUA") for COVAXIN for pediatric use in ages two to 18 years in the United States. The EUA submission was based on the results of a Phase 2/3 immuno-bridging pediatric clinical trial conducted by Bharat Biotech in India. The Company's EUA submission is currently under review by the FDA. In February 2022, Delta and only companyOmicron neutralization results along with a safety database of more than 36 million teenagers who had been vaccinated with COVAXIN were submitted to receive ODDthe FDA to support the Company's EUA submission.
The Company is also pursuing approval for COVAXIN in Canada. In July 2021, the Company completed its rolling submission to Health Canada for COVAXIN. The rolling submission process, which permits companies to submit safety and efficacy data and information as they become available, was recommended and accepted under the Minister of Health’s Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 and transitioned to a New Drug Submission ("NDS") for COVID-19. The submission was conducted through the Company's Canadian subsidiary, Vaccigen Ltd. The Company is in discussions with Health Canada regarding its NDS submission for COVAXIN. In December 2021, the Company was provided with a Notice of Deficiency ("NOD") from Health Canada regarding its NDS submission. Health Canada requested further analyses of the COVAXIN preclinical and clinical data, as well as additional information regarding chemistry, manufacturing, and controls ("CMC"). The Company has responded to and provided proposed resolutions for the treatmentdeficiencies included in the NOD. The Company's responses are currently under review by Health Canada.
The Company is evaluating its commercialization strategy for COVAXIN in the United States and Canada, if authorized or approved in either jurisdiction. In June 2021, the Company selected Jubilant HollisterStier as its manufacturing partner for COVAXIN to prepare for the potential commercial manufacturing for the Ocugen Covaxin Territory. The Company expects to
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enter into a master services agreement with oGVHDJubilant HollisterStier for the commercial manufacture of COVAXIN. The technology transfer process from Bharat Biotech to Jubilant HollisterStier for drug product manufacturing has been initiated.
In September 2021, the Company entered into a Development and isCommercial Supply Agreement (the “Supply Agreement”) with Bharat Biotech, pursuant to which Bharat Biotech will supply the only company conducting Phase 3 studies in this patient population. OCU300 is formulated usingCompany with clinical trial materials and commercial supplies of COVAXIN finished drug product prior to the Company’s proprietary nanoemulsioncompletion of a technology OcuNanoE—Ocugen’s ONE Platform™ (“OcuNanoE™”).transfer. Following the completion of a technology transfer, Bharat Biotech will supply COVAXIN drug product components and continue to supply finished drug product as necessary for the commercial manufacture and supply of COVAXIN subsequent to a regulatory authorization or approval.
OcugenModifier Gene Therapy Platform
The Company is developing a modifier gene therapy platform fordesigned to fulfill unmet medical needs in the area of retinal diseases, including inherited retinal diseases (“IRDs”("IRDs"), such as retinitis pigmentosa ("RP") and Leber congenital amaurosis ("LCA"), and dry age-related macular degeneration ("AMD"). Ocugen’sThe Company's modifier gene therapy platform is novel in that it targets nuclear hormone receptors (“NHRs”based on Nuclear Hormone Receptors ("NHRs"), which have the potential to restore homeostasis, to the retina and may target multiple genes that are associated with a range of IRDs. Unlike single-gene replacement therapies, which only target one genetic mutation,basic biological processes in the Company believes that itsretina. The modifier gene therapy platform, through its targetinguse of NHRs, may impactrepresents a novel approach that has the potential to address multiple retinal diseases caused by mutations in multiple genes with one product; and potentially address complex diseases, such as dry AMD, that are associatedpotentially caused by imbalances in multiple gene networks.
The Company believes that OCU400, its first product candidate being developed with its modifier gene therapy platform, has the potential to be broadly effective in restoring retinal integrity and function across a range of genetically diverse diseases. Ocugen’s first gene therapy candidate,IRDs, including RP and LCA. OCU400 has received ODD4 Orphan Drug Designations from the FDA for the treatment of certain disease genotypes: nuclear receptor subfamily 2 group E member 3 ("NR2E3(")NR2E3"mutation-associated retinal diseases and), centrosomal protein 290 ("CEP290("CEP290"), rhodopsin ("RHO"), and phosphodiesterase 6B ("PDE6ß") mutation-associated inherited retinal diseases. Ocugen’sdegenerations. In November 2021, the Company submitted an IND application to the FDA for OCU400 for the treatment of the NR2E3 and RHO disease genotypes. The Company's IND application was accepted by the FDA in December 2021. The Company has initiated a Phase 1/2 clinical trial in the United States for the treatment of these disease genotypes and the first patient is expected to be dosed in the first half of 2022. This Phase 1/2 clinical trial is a multicenter, open-label, dose ranging study to assess the safety of unilateral subretinal administration of OCU400 in subjects with NR2E3-related RP. OCU400 has additionally received Orphan Medicinal Product Designation from the European Commission, based on the recommendation of the European Medicines Agency, for RP and LCA. The Company believes OCU400 has the potential for broad spectrum applications to treat many IRDs. The Company is currently evaluating options to initiate OCU400 clinical trials in Europe.
The Company's second gene therapy product candidate, OCU410, is targetedbeing developed to utilize the nuclear receptor genes RAR-related orphan receptor A ("RORA") for the treatment of dry age-related macular degeneration (“AMD”) andAMD. The Company is currently in preclinical development. Currently, there are no FDA-approved therapiesexecuting pre-IND studies consistent with FDA discussions to treat this disease.support a Phase 1/2 clinical trial. The Company has engaged CanSino Biologics, Inc. ("CanSinoBIO") to manufacture clinical supplies and be responsible for the CMC development for OCU400 and OCU410. See Note 3 for additional information about the Company's collaboration with CanSinoBIO.
Ocugen isNovel Biologic Therapy for Retinal Diseases
The Company's pipeline also developingincludes a biologic product candidate, OCU200, a novel fusion protein for the treatment of wet AMD, diabetic retinopathy (“DR”) anddesigned to treat severely sight-threatening diseases such as diabetic macular edema, (“DME”), whichdiabetic retinopathy, and wet AMD. The Company is in preclinical development. Ocugen expectscurrently establishing a current Good Manufacturing Practice process for the production of clinical trial materials and executing pre-IND studies consistent with FDA discussions to initiatesupport a Phase 1/22a clinical trial fortrial. The Company has completed the technology transfer of manufacturing processes to its contract development and manufacturing organization that will manufacture OCU200 within the next two years. Ocugen plans to expand the therapeutic applications of OCU200 beyond DME, DR and wet AMD to potentially include macular edema following retinal vein occlusion (“RVO”) and myopic choroidal neovascularization (“mCNV”).
Merger with Histogenics
On September 27, 2019, the Company completed its reverse merger with Ocugen, OpCo Inc. (formerly known as Ocugen, Inc. (“Former Ocugen”)) in accordance with the terms of the Agreement and Plan of Merger and Reorganization, dated as of April 5, 2019, by and among Histogenics, Former Ocugen and Restore Merger Sub, Inc., a wholly owned subsidiary of Histogenics (“Merger Sub”), as amended (the “Merger Agreement”), pursuant to which Merger Sub merged with and into Former Ocugen, with Former Ocugen surviving as a wholly owned subsidiary of Histogenics (the “Merger”). Immediately after completion of the Merger, Histogenics changed its name to Ocugen, Inc. and the business conducted by Ocugen, Inc. became the business conducted by Former Ocugen. Former Ocugen is deemed to be the accounting acquirer. Accordingly, the historical financial statements of Former Ocugen became the Company’s historical financial statements, including the comparative prior periods. See Note 3 for additional information.
Reverse Stock Split
In connection with, and immediately prior to the completion of the Merger, Histogenics effected a reverse stock split of the common stock, at a ratio of 1-for-60 (the ‘‘Reverse Stock Split’’). Under the terms of the Merger Agreement, the Company issued common stock to Former Ocugen’s stockholders at an exchange rate of 0.4794 shares of common stock, after taking into account the Reverse Stock Split, for each share of Former Ocugen’s common stock outstanding immediately prior to the Merger.
The capital structure, including the number of shares of common stock issued appearing in the consolidated balance sheets for the periods presented, reflects that of Ocugen. All references in the consolidated financial statements to the number of shares and per-share amounts of common stock have been retroactively restated to reflect the exchange rate.
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clinical supplies.
Going Concern
The Company has incurred recurring net losses and negative cash flows from operations since inception and has funded its operating lossesoperations to date through the sale of common stock, warrants to purchase common stock, the issuance of convertible notes, debt, and debt.grant proceeds. The Company incurred net losses of approximately $20.2$58.4 million, $21.8 million, and $18.2$20.2 million for the yearyears ended December 31, 2021, 2020, and 2019, and 2018, respectively, andrespectively. As of December 31, 2021, the Company had an accumulated deficit of $51.5$131.7 million as of December 31, 2019. As of December 31, 2019, the Company hadand cash, cash equivalents, and restricted cash totaling $7.6$95.1 million.
The Company has a limited operating history and its prospects areis subject to risks, expenses, and uncertainties frequently encountered by companies in its industry. The Company intends to continue its research, development, and developmentcommercialization efforts for its product candidates, which will
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require significant additional funding. If the Company is unable to obtain additional financing in the future or its research, development, and developmentcommercialization efforts require higher than anticipated capital, there may be a negative impact on the financial viability of the Company. The Company plans to increase working capital by raising additional capital through public and private placements of equity and/or debt, payments from potential strategic research and development arrangements, salesales of assets, andgovernment grants, licensing and/or collaboration arrangements with pharmaceutical companies or other institutions.institutions, or other funding from the government or other third parties. Such financing may not be available at all, or on terms that are favorable to the Company. While management of the Company believes that it has a plan to fund ongoing operations, its plan may not be successfully implemented. Failure to generate sufficient cash flows from operations, raise additional capital, through one or more financings, or appropriately manage certain discretionary spending could have a material adverse effect on the Company’s ability to achieve its intended business objectives.
As a result of these factors, together with the anticipated increase in spending that will be necessary to continue to research, develop, and commercialize the Company’s products,product candidates and the uncertainty of futures revenues associated with COVAXIN, there is substantial doubt about the Company’s ability to continue as a going concern within one year after the date that these audited consolidated financial statements are issued. The audited consolidated financial statements do not contain any adjustments that might result from the resolution of any of the above uncertainties.
2.    Summary of Significant Accounting Policies
Basis of Presentation and Consolidation
The accompanying consolidated financial statements included herein have been prepared in conformity with accounting principles generally accepted in the United States (“GAAP”("GAAP") and under the rules and regulations of the U.S. Securities and Exchange Commission ("SEC"). The consolidated financial statements include the accounts of Ocugen Inc. and its wholly owned subsidiaries. All intercompany balances and transactions have been eliminated in consolidation. Certain prior year amounts have been reclassified to conform with current year presentation.
Foreign Currency Translation and Transactions
The assets and liabilities of the Company’s foreign subsidiary are translated into U.S. dollars based on exchange rates in effect at the end of each period. Revenues and expenses are translated at average exchange rates during the periods. Currency transaction gains or losses are included in other expenses. Gains or losses from balance sheet translation are included in accumulated other comprehensive income.
Use of Estimates
In preparing the consolidated financial statements in conformity with GAAP, management is required to make estimates and assumptions that affect the reported amounts of assets and liabilities and disclosure of contingent assets and liabilities at the date of the financial statements, as well as the reported amounts of expenses during the reporting period. Due to the inherent uncertainty involved in making estimates, actual results reported in future periods may be affected by changes in these estimates. On an ongoing basis, the Company evaluates its estimates and assumptions. These estimates and assumptions include those used in the estimation ofaccounting for research and development contracts, including clinical trial accruals, debt and equity instruments (including derivative liabilities), asset held for sale, and the valuationcollectibility of share-based payment arrangements, warrants,the note receivable.
Segment Information
As of December 31, 2021, the Company viewed its operations and embedded conversion featuresmanaged its business as 1 operating segment consistent with how the Company's chief operating decision-maker, the Company's Chief Executive Officer, makes decisions regarding resource allocation and assessing performance. As of December 31, 2021, substantially all of the Company's assets were located in the United States.
Cash, Cash Equivalents, and Restricted Cash
The Company considers all highly liquid investments that have maturities of three months or less when acquired to be cash equivalents. Cash equivalents may include bank demand deposits, marketable securities with maturities of three months or less at purchase, and money market funds that invest primarily in certificates of deposit, commercial paper, and U.S. government and U.S. government agency obligations. The Company’s restricted cash balance consists of cash held to collateralize a corporate credit card account.
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The following table provides a reconciliation of cash, cash equivalents, and restricted cash in the consolidated balance sheets to the total amount shown in the consolidated statements of cash flows (in thousands):
As of December 31,
20212020
Cash and cash equivalents$94,958 $24,039 
Restricted cash151 151 
Total cash, cash equivalents, and restricted cash$95,109 $24,190 
Collaboration Arrangements
The Company assesses whether collaboration agreements are subject to Financial Accounting Standards Board ("FASB") Accounting Standards Codification ("ASC") Topic 808, Collaborative Arrangements ("ASC 808"), based on whether they involve joint operating activities and whether both parties have active participation in the arrangement and are exposed to significant risks and rewards. To the extent that the arrangement falls within the scope of ASC 808, the Company assesses whether the payments between the Company and the collaboration partner are subject to other accounting literature. If payments from the collaboration partner represent consideration from a customer, the Company accounts for those payments within the scope of FASB ASC Topic 606, Revenue from Contracts with Customers. However, if the Company concludes that its collaboration partner is not a customer, the Company will record royalty payments received as collaboration revenue in the period in which the underlying sale occurs and record expenses and expense reimbursements as either research and development expense or general and administrative expense, or a reduction thereof, based on the convertible notes.underlying nature of the expense or expense reimbursement. During the year ended December 31, 2020, the Company recorded collaboration revenue from an agreement accounted for as a collaborative arrangement within the scope of ASC 808. No collaboration revenue was recorded during the years ended December 31, 2021 and 2019.
Asset Held for Sale
An asset is considered to be held for sale when all ofDuring 2019, the following criteria are met: (i) management commits to a plan to sell the asset; (ii) it is unlikely that the disposal plan will be significantly modified or discontinued; (iii) the asset is available for immediate sale in its present condition; (iv) actions required to complete the sale of the asset have been initiated; (v) sale of the asset is probable and the completed sale is expected to occur within one year; and (vi) the asset is actively being marketed for sale at a price that is reasonable given its current market value.
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A long-lived asset classified as held for sale is measured at the lower of its carrying amount or fair value less cost to sell. If the long-lived asset is newly acquired, the carrying amount of the long-lived asset is established based on its fair value less cost to sell at the acquisition date. A long-lived asset is not depreciated or amortized while it is classified as held for sale, and an impairment loss would be recognized to the extent the carrying amount exceeds the asset's fair value less cost to sell.
As of December 31, 2019, OcugenCompany had an intangible asset held for sale acquired from Histogenics with athat was carried at its original fair value less cost to sell of $7.0 million. See Note 3The Company concluded during the year ended December 31, 2020 that a sale of the intangible asset was no longer probable to be completed within one year from the date the intangible asset was initially recorded as held for sale. As such, the carrying value of the intangible asset was reduced to zero with the corresponding charge of $7.0 million recognized as in-process research and development expense in the consolidated statements of operations and comprehensive loss during the year ended December 31, 2020 as the in-process research and development did not have an alternative future use.
Property and Equipment, Net
The Company's property and equipment currently includes furniture and fixtures, machinery and equipment, leasehold improvements, and construction in progress. Property and equipment is recorded at historical cost. Significant additions or improvements are capitalized, and expenditures for repairs and maintenance are charged to expense as incurred. Gains and losses on disposal of assets are included in the consolidated statements of operations and comprehensive loss. Depreciation is calculated using the straight-line method and is recognized over the expected useful life of the underlying asset. Construction in progress is not depreciated until such time that the asset is completed and placed into service. Once placed into service, the asset is depreciated over its expected useful life.
Expected useful lives by major asset category are as follows:
Furniture and fixtures3 to 7 years
Machinery and equipment5 to 7 years
Leasehold improvementsLower of the expected useful life or remaining lease term
Leases
The Company determines if an arrangement is a lease at inception. This determination generally depends on whether the arrangement conveys to the Company the right to control the use of an explicitly or implicitly identified fixed asset for a period of time in exchange for consideration. Control of an underlying asset is conveyed to the Company if the Company obtains the rights to direct the use of and to obtain substantially all of the economic benefits from using the underlying asset. The
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Company's current and historical lease agreements include lease and non-lease components, which the Company has elected not to account for separately for all classes of underlying assets. Lease expense for variable lease components is recognized when the obligation is probable.
Operating leases are included in other assets and operating lease obligations in the Company’s consolidated balance sheets. Operating lease right-of-use assets and liabilities are recognized at the commencement date based on the present value of lease payments over the lease term. Operating lease payments are recognized as lease expense on a straight-line basis over the lease term and recognized as research and development expense or general and administrative expense based on the underlying nature of the expense. The Company currently leases real estate classified as operating leases. FASB ASC Topic 842, Leases ("ASC 842") requires a lessee to discount its unpaid lease payments using the interest rate implicit in the lease or, if that rate cannot be readily determined, its incremental borrowing rate. The implicit interest rate was not readily determinable in the Company’s current and historical operating leases. As such, the incremental borrowing rate was used based on the information available at the commencement date in determining the present value of lease payments.
The lease term for the Company’s leases includes the non-cancellable period of the lease plus any additional information.periods covered by either an option to extend (or not to terminate) the lease that the Company is reasonably certain to exercise, or an option to extend (or not to terminate) the lease controlled by the lessor.
Lease payments included in the measurement of the lease liability are comprised of fixed payments, variable payments that depend on index or rate, and amounts probable to be payable under the exercise of an option to purchase the underlying asset if reasonably certain.
Variable payments not dependent on an index or rate associated with the Company’s leases are recognized when the event, activity, or circumstance is probable. Variable payments include the Company's proportionate share of certain utilities and other operating expenses and are presented as operating expenses in the Company’s consolidated statements of operations and comprehensive loss in the same line item as expense arising from fixed lease payments.
Exit and Disposal Activities
The Company records liabilities for one-time termination benefits in accordance with FASB ASC Topic 420, Exit and Disposal Cost Obligations ("ASC 420"). In accordance with ASC 420, an arrangement for one-time termination benefits exists at the date the plan of the termination meets the following criteria: (i) management commits to a plan of termination; (ii) the plan identifies the impacted employees and expected completion date; (iii) the plan identifies the terms of the benefits arrangement; (iv) it is unlikely significant changes to the plan will be made or the plan will be withdrawn; and (v) the plan has been communicated to employees. Costs for one-time termination benefits in which the employee is required to render service until termination in order to receive the benefits, are recognized ratably over the future service period.
The Company records liabilities for employee termination benefits covered by ongoing benefit arrangements in accordance with FASB ASC Topic 712, Compensation—Nonretirement Postemployment Benefits ("ASC 712"). In accordance with ASC 712, costs for termination benefits under ongoing benefits arrangements are recognized when management has committed to a plan of termination and the costs are probable and estimable.
Severance-related charges, once incurred, are recognized as either research and development expense or general and administrative expense within the consolidated statements of operations and comprehensive loss depending on the job function of the former employee.
Fair Value Measurements
The companyCompany follows the provisions of the Financial Accounting Standards Board’s (“FASB”) Accounting Standards Codification (“ASC”)FASB ASC Topic 820, Fair Value Measurements (“("ASC 820”820"), which defines fair value as used in numerous accounting pronouncements, establishes a framework for measuring fair value and expands disclosure of fair measurements.
The estimated fair value of certain financial instruments, cash and cash equivalents, accounts payable, and accrued expenses are carried at historical cost basis, which approximates their fair values because of the short-term nature of these instruments. As of December 31, 2019 and 2018, the Company believes the fair value of the EB-5 note approximates its carrying value.
ASC 820 defines fair value as the exchange price that would be received for an asset or paid to transfer a liability (an exit price) in the principal or most advantageous market for the asset or liability in an orderly transaction between market participants on the measurement date. ASC 820 also establishes a fair value hierarchy, which requires an entity to maximize the use of observable inputs and minimize the use of unobservable inputs when measuring fair value. ASC 820 describes three levels of inputs that may be used to measure fair value:
Level 1 — quoted prices in active markets for identical assets or liabilities
Level 2 — quoted prices for similar assets and liabilities in active markets or inputs that are observable
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Level 3 — inputs that are unobservable (for example cash flow modeling inputs based on assumptions)
The company had derivativecarrying value of certain financial instruments, including cash and cash equivalents, accounts payable, and accrued expenses approximate their fair values due to the short-term nature of these instruments. As of December 31, 2021, the Company has concluded that werethe fair valued on a recurring basisvalue of the borrowings under the EB-5 Loan Agreement (as defined in Note 8), using Level 3 inputs.2 inputs, approximate their carrying value. See Note 8 for additional information.
Financial Instruments Indexed to and Potentially Settled in Common StockDerivatives
The Company accounts fordoes not have derivative hedging instruments used to mitigate risk. The Company evaluates all financial instruments to determine if such instruments are derivatives or contain features that qualify as embedded derivatives in accordance with FASB ASC Topic 815, Derivatives and Hedging ("ASC 815"). Additionally, the Company assesses warrants to purchase common stock to determine liability versus stockholders' equity classification in accordance with ASC 815 and FASB ASC Topic 815-40,480, Derivatives and Hedging — Contracts in Entity’s OwnDistinguishing Liabilities from Equity (“ASC 815-40”), which is the authoritative guidance on accounting. For derivative instruments that are accounted for derivative financial instruments indexed to and potentially settled in a company’s own stock. To determine whether a contract is considered indexed to the issuer’s own equity, the Company performs a two-step analysis:
Step 1: Evaluate whether the contract contains any exercise contingencies and, if so, whether they disqualify the contract from being classified as equity, and
Step 2: Assess whether the settlement terms are consistent with equity classification.
The Company classifies theliabilities, including liability-designated warrants, onthe derivative instrument is initially recorded at its consolidated balance sheetsfair value as a derivative liability whichand is recognized at fair valuethen revalued at each reporting period subsequent to the initial issuance. Changesdate, with changes in the fair value of derivatives are recognizedreported as other income (expense) in the consolidated statements of operations and comprehensive loss. The classification of derivative instruments, including whether such instrument should be recorded as a liability or as stockholders' equity, is evaluated at the end of each reporting period.
Cash, Cash EquivalentsIn 2018 and Restricted Cash
The2019, the Company considers all highly liquid investments that have maturities of three months or less when acquired to be cash equivalents. Cash and cash equivalents include bank demand deposits, marketable securities with maturities of three months or less at purchase, and money market funds that invest primarily in certificates of deposit, commercial paper and United States government and United States government agency obligations. The Company’s restricted cash balance consists of cash held to collateralize a corporate credit card account.
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The following table provides a reconciliation of cash, cash equivalents, and restricted cashissued convertible notes in the consolidated balance sheets toaggregate principal amount of $8.8 million (the "Convertible Notes"). During the total amount shown in the consolidated statements of cash flows:
As of December 31,
20192018
Cash, cash equivalents and restricted cash reconciliation:
Cash and cash equivalents$7,444,052  $1,628,136  
Restricted cash151,016  150,477  
Total cash, cash equivalents and restricted cash$7,595,068  $1,778,613  

Property and Equipment, Net
Property and equipment is recorded at cost. Significant additions or improvements are capitalized, and expenditures for repairs and maintenance are charged to expense as incurred. Gains and losses on disposal of assets are included in the consolidated statements of operations and comprehensive loss. Depreciation is calculated using the straight-line method and is recognized over an expected useful life of 5 years for equipment and 7 years for furniture. The total accumulated depreciation and amortization for equipment and furniture as ofyear ended December 31, 2019, and 2018 was $0.1the Company issued 1.1 million shares of common stock at $8.69 per share to extinguish the Convertible Notes, resulting in a loss of $0.3 million and $0.1an increase of $13.0 million respectively.
Leases
in additional paid-in capital. The Convertible Notes contained embedded conversion and change-in-control features, which were recorded at fair value as derivative liabilities and revalued at each reporting date. The Company determines if an arrangement is a leaseadditionally had Series B Warrants (as defined in Note 10) that were classified as derivative liabilities at inception. This determination generally depends on whetherissuance and revalued each reporting period until they met the arrangement conveysderivative scope exception allowing for stockholders' equity classification. The change in fair value of derivative liabilities related to the CompanyConvertible Notes and the right to controlSeries B Warrants was $3.2 million during the use of an explicitly or implicitly identified fixed asset for a period of time in exchange for consideration. Control of an underlying asset is conveyed to the Company if the Company obtains the rights to direct the use of and to obtain substantially all of the economic benefits from using the underlying asset. The Company has lease agreements which include lease and non-lease components, which the Company has elected to account for as a single lease component for all classes of underlying assets. Lease expense for variable lease components are recognized when the obligation is probable.
Operating leases are included in other assets and lease obligations on the Company’s consolidated balance sheets. Operating lease right-of-use ("ROU") assets and liabilities are recognized at commencement date based on the present value of lease payments over the lease term. Operating lease payments are recognized as lease expenseyear ended December 31, 2019. There were no derivative instruments revalued on a straight-linerecurring basis overduring the lease term. years ended December 31, 2021 and 2020.
Stock-Based Compensation
The Company primarily leases buildings (real estate) which are classified as operating leases. ASC 842 requires a lessee to discount its unpaid lease payments using the interest rate implicit in the lease or, if that rate cannot be readily determined, its incremental borrowing rate. As an implicit interest rate is not readily determinable in the Company’s leases, the incremental borrowing rate is used based on the information available at commencement date in determining the present value of lease payments.
The lease term for all of the Company’s leases includes the non-cancellable period of the lease plus any additional periods covered by either a Company option to extend (or not to terminate) the lease that the Company is reasonably certain to exercise, or an option to extend (or not to terminate) the lease controlled by the lessor. Options for lease renewals have been excluded from the lease term (and lease liability) for the majority of the Company’s leases as the reasonably certain threshold is not met.
Lease payments included in the measurement of the lease liability are comprised of fixed payments, variable payments that depend on index or rate, and amounts probable to be payable under the exercise of the Company option to purchase the underlying asset if reasonably certain.
Variable lease payments not dependent on a rate or index associated with the Company’s leases are recognized when the event, activity, or circumstance in the lease agreement on which those payments are assessed as probable. Variable lease payments include the Company's proportionate share of utilities and other operating expenses and are presented as operating expenses in the Company’s income statement in the same line item as expense arising from fixed lease payments.
Stock-based compensation
Ocugen accounts for its stock-based compensation awards in accordance with FASB ASC Topic 718, Compensation—Stock Compensation (“("ASC 718”718"). The Company has issued stock-based compensation awards including stock options and restricted stock units ("RSUs"), and also accounts for certain issuances of preferred stock and warrants in accordance with ASC 718. ASC 718 requires all stock-based payments, to employees, including grants of employee stock options and restricted stock units and modifications to existing agreements,RSUs, to be recognized in the consolidated statements of operations
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and comprehensive loss based on their grant date fair values. OcugenThe Company uses the Black-Scholes option-pricing model to determine the fair value of options granted. Ocugen recognizedFor RSUs, the fair value of the RSUs is determined by the market price of a share of the Company's common stock on the grant date. The Company recognizes forfeitures as they occur.
Ocugen’s stock-based awards are subject to service-based vesting conditions. Compensation expense related to stock-based compensation awards to employees and directorsgranted with service-based vesting conditions is recognized on a straight-line basis based on the grant date fair value over the associated service period of the award, which is generally the vesting term. Stock-based compensation awards generally vest over a one to three year requisite service period and have a contractual term of 10 years. To the extent a stock-based compensation award is subject to performance-based vesting conditions, the amount of compensation expense recorded reflects an assessment of the probability of achieving the performance conditions. Compensation expense for stock-based compensation awards with performance-based vesting conditions is only recognized when the performance-based vesting condition is deemed probable to occur. Shares issued upon stock option exercise and RSU vesting are newly issued shares of common stock.
Estimating the fair value of stock options requires the input of subjective assumptions, including the expected lifeterm of the stock option, stock price volatility, the risk-free interest rate, and expected dividends. The assumptions used in Ocugen’sthe Company’s Black-Scholes option-pricing model represent management’s best estimates and involve a number of variables, uncertainties, and assumptions, and the application of management’s judgment, as they are inherently subjective. If any assumptions change, Ocugen’sthe Company’s stock-based compensation expense could be materially different in the future.
TheseThe assumptions used in Ocugen’s Black-Scholes option-pricing model for stock options are as follows:
Expected Term. Due to the historical lack of a public market for the trading of Ocugen common stock and the lack of sufficient company-specific historical data, the expected term of employee stock options subject to service-based vesting conditions is
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determined using the “simplified” method, as prescribed in Securities and Exchange Commission’sSEC’s Staff Accounting Bulletin No. 107, (“SAB No. 107”), whereby the expected lifeterm equals the arithmetic average of the vesting term and the original contractual term of the stock option. The expected term of non-employee options is equal to the contractual term.
Expected Volatility. The expected volatility is based on historical volatilities of Ocugen and similar entities within Ocugen’s industry for periods commensurate with the expected term assumption.
Risk-Free Interest Rate. The risk-free interest rate is based on the interest rate payable on U.S. Treasury securities in effect at the time of grant for a period that is commensurate with the assumed expected term.
Expected Dividends. The expected dividend yield is 0% because Ocugen has not historically paid, and does not expect for the foreseeable future to pay, a dividend on its common stock.
Income Taxes
The Company is a Delaware C-Corporation. The Company recognizesaccounts for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities for temporarythe expected future tax consequences of events that have been recognized in the financial statements or the Company’s tax returns. Under this method, deferred tax assets and liabilities are determined based on the differences between the consolidated financial reporting basisstatements and the tax basis of its assets and liabilities and the expected benefits of net operating loss carryforwards. The impact of changes inusing enacted tax rates and laws on deferred taxes, if any, is applied duringin effect for the yearsyear in which temporarythe differences are expected to be settled and is reflectedreverse. Changes in the financial statements in the period of enactment. The measurement of deferred tax assets is reduced, if necessary, if,and liabilities are recorded in the provision for income taxes. The Company assesses the likelihood that its deferred tax assets will be recovered from future taxable income and, to the extent it believes, based onupon the weight of theavailable evidence, that it is more likely than not that some,all or all,a portion of the deferred tax assets will not be realized. realized, a valuation allowance is established.
The Company’s policy isCompany accounts for uncertain tax positions recognized in the consolidated financial statements by prescribing a more-likely-than-not threshold for financial statement recognition and measurement of a tax position taken or expected to recognize interest and penalties accrued onbe taken in a tax return. The provision for income taxes includes the effects of any resulting tax reserves, or unrecognized tax benefits, as a component of income tax expense. No interest or penalty expense was recognized during the periods presented.
The Company has assessed and concluded that there are uncertain tax positions giving rise to the unrecognized tax benefits as of December 31, 2019. The Company’s conclusions regarding uncertain tax positions may be subject to review and adjustment at a later date based upon ongoing analysis of tax laws, regulations and interpretations thereof,considered appropriate as well as other factors. Generally, federal, state,the related net interest and local authorities may examine the Company’s tax returns for three years from the date of the filing and the current and prior three years remain subject to examination as of December 31, 2019.
Segment Information
The Company views its operations and manages its business as 1 operating segment, which is the development of innovative therapies to address the whole eye. As of December 31, 2019, substantially all of the Company’s assets were located in the United States.penalties.
Recently Adopted Accounting Standards
In February 2016,December 2019, the FASB issued Accounting Standards Update (“ASU”("ASU") No. 2016-02,2019-12, LeasesIncome Taxes (Topic 842) (“ASC 842”). In July 2018,740): Simplifying the FASB issued ASU No. 2018-10, Codification Improvements to Topic 842, Leases (“ASU 2018-10”), which provides narrow amendments to clarify how to apply certain aspects of the new lease standard, and ASU No. 2018-11, Leases
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(Topic 842)—Targeted Improvements (“ASU 2018-11”), which addressed implementation issues related to the new lease standard. These and certain other lease-related ASUs have generally been codified in ASC 842. ASC 842 supersedes the lease accounting requirements in ASC Topic 840, Leases (“ASC 840”). ASC 842 establishes a right-of-use model that requires a lessee to record a right-of-use (“ROU”) asset and a lease liability on the balance sheetAccounting for all leases. Under ASC 842, leases are classified as either finance or operating, with classification affecting the pattern of expense recognition in the income statement. The standard also requires disclosures to help investors and other financial statement users better understand the amount, timing and uncertainty of cash flows arising from leases.
The Company adopted ASC 842 on January 1, 2019 using the effective date transition method. Prior period results continue to be presented under ASC 840 based on the accounting standards originally in effect for such periods. The Company has elected certain practical expedients permitted under the transition guidance within ASC 842 to leases that commenced before January 1, 2019, including the package of practical expedients. The election of the package of practical expedients resulted in the Company not reassessing prior conclusions under ASC 840 related to lease identification, lease classification and initial direct costs for expired and existing leases prior to January 1, 2019. The adoption of ASU 2016-02 did not have a significant impact on the Company’s consolidated results of operations or cash flows. Upon adoption, the Company recognized an ROU asset and lease liability of $0.4 million and $0.4 million, respectively. See Note 9 for additional information.
Recent Accounting Pronouncements
In August 2018, the FASB issued ASU No. 2018-13, Fair Value Measurement (Topic 820): Disclosure Framework—Changes to the Disclosure Requirements for Fair Value MeasurementIncome Taxes. This standard modifiesremoves certain disclosure requirements on fair value measurementsexceptions for recognizing deferred taxes for investments, performing intraperiod allocations, and calculating income taxes in interim periods. This standard also adds guidance to reduce complexity in certain areas, including recognizing franchise tax, recognizing deferred taxes for tax basis of goodwill, allocating taxes to the members of a consolidated group, and recognizing the effect of enacted changes in tax laws or rates during an interim period. This standard was effective for the Company on January 1, 2020.2021. The adoption of this standard willdid not have a material impact on the Company's disclosures.consolidated financial statements.
Recent Accounting Pronouncements
In November 2021, the FASB issued ASU No. 2021-10, Government Assistance (Topic 832): Disclosures by Business Entities about Government Assistance. This standard has an effective and transition date of January 1, 2022. This standard increases the transparency of transactions with the government that are accounted for by applying a grant or contribution accounting model, and aims to reduce diversity that currently exists in the recognition, measurement, presentation, and disclosure of government assistance received by business entities due to the lack of specific authoritative guidance in GAAP. This standard requires an entity to provide information regarding the nature of the transaction with a government and the related accounting policy used to account for this transaction, the line item on the consolidated balance sheet and consolidated statement of operations and comprehensive loss that are affected by the transaction and the amounts applicable to each financial statement line item, and the significant terms and conditions of the transaction, including commitments and contingencies. The Company does not currently expect the adoption of this standard to have a material impact on the Company's consolidated financial statements.
In May 2021, the FASB issued ASU No. 2021-04, Earnings Per Share (Topic 260), Debt — Modifications and Extinguishments (Subtopic 470-50), Compensation — Stock Compensation (Topic 718), and Derivatives and Hedging — Contracts in Entity’s Own Equity (Subtopic 815-40). This standard will have an effective and transition date of January 1, 2022. This standard clarifies and reduces diversity in an issuer's accounting for modifications or exchanges of freestanding equity-classified written call options, including warrants, that remain equity-classified after modification or exchange. The standard requires an entity to treat a modification or an exchange of a freestanding equity-classified written call option that remains equity-classified after the modification or exchange as an exchange of the original instrument for a new instrument. The standard additionally provides guidance on measuring and recognizing the effect of a modification or an exchange. The
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Company does not currently expect the adoption of this standard to have a material impact on the Company's consolidated financial statements.
In August 2020, the FASB issued ASU No. 2020-06, Debt — Debt with Conversion and Other Options (Subtopic 470-20) and Derivatives and Hedging — Contracts in Entity's Own Equity (Subtopic 815-40). This standard will have an effective and transition date of January 1, 2024. Early adoption is currently permitted. This standard simplifies an issuer's accounting for convertible instruments by eliminating two of the three models that require separate accounting for embedded conversion features as well as simplifies the settlement assessment that entities are required to perform to determine whether a contract qualifies for equity classification. This standard also requires entities to use the if-converted method for all convertible instruments in the diluted earnings per share calculation and include the effect of potential share settlement (if the effect is more dilutive) for instruments that may be settled in cash or shares, except for certain liability-classified share-based payment awards. The standard requires new disclosures about events that occur during the reporting period and cause conversion contingencies to be met and about the fair value of a public business entity's convertible debt at the instrument level, among other things. The Company does not currently expect the adoption of this standard to have a material impact on the Company's consolidated financial statements.
In June 2016, the FASB issued ASU No. 2016-13, Financial Instruments—Instruments — Credit Losses (Topic 326): Measurement of Credit Losses on Financial Instruments. The FASB subsequently issued amendments to ASU No. 2016-13, which have the same effective date and transition date of January 1, 2023. These standards requireASU No. 2016-13, as amended, requires that credit losses be reported using an expected losses model rather than the incurred losses model that is currently used, and establishes additional disclosures related to credit risks. For available-for-sale debt securities with unrealized losses, these standards now require allowances to be recorded instead of reducing the amortized cost of the investment. These standards limit the amount of credit losses to be recognized for available-for-sale debt securities to the amount by which carrying value exceeds fair value and requires the reversal of previously recognized credit losses if fair value increases. The Company does not currently expect the adoption of these standardsthis standard to have a material impact on itsthe Company's consolidated financial statements.
3.Merger    License and Pre-Merger FinancingDevelopment Agreements
Pre-Merger Financing
In June 2019, Former OcugenCo-Development, Supply and Histogenics entered into a Securities PurchaseCommercialization Agreement (as amended, the “Financing SPA”) with certain accredited investors (the “Investors”). Pursuant to the Financing SPA, among other things, (i) immediately prior to the Merger, Former Ocugen issued 4.6 million shares of common stock to the Investors (the “Initial Shares” and, as converted pursuant to the exchange rate in the Merger into the right to receive approximately 2.2 million shares the Company’s common stock, the “Converted Initial Shares”), (ii) immediately prior to the Merger, Former Ocugen issued and deposited 4.6 million shares of common stock into escrow on behalf of the Investors (the “Additional Shares” and, as converted pursuant to the exchange rate in the Merger, into the right to receive approximately 2.2 million shares of the Company’s common stock, the “Converted Additional Shares”) and (iii) the Company agreed to issue, on the fifth trading day following the consummation of the Merger, three series of warrants to purchase shares of the Company’s common stock (the “Series A Warrants,” the “Series B Warrants” and the “Series C Warrants” and collectively, the “Pre-Merger Financing Warrants”) in exchange for an aggregate purchase price of $25.0 million (“Pre-Merger Financing”). See Note 10 for additional information on the Pre-Merger Financing Warrants.
On October 4, 2019, the Converted Additional Shares were released from escrow to the investors because, as determined at the close of business on October 2, 2019, 80% of the volume-weighted average trading price of a share of Ocugen’s common stock as quoted on Nasdaq for the first three trading days immediately following the closing date of the Pre-Merger Financing was lower than the price paid by the Investors for the Initial Shares.
Approximately $2.5 million of the $25.0 million Pre-Merger Financing was utilized to pay transaction costs related to the Merger and the Pre-Merger Financing in the form of equity. In addition, the Company utilized $5.3 million of the Pre-Merger
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Financing for the repayment of the Senior Secured Notes, as defined in Note 7. As a result, the Company received total net proceeds of $17.2 million from the Pre-Merger Financing.Bharat Biotech
The Company incurred $1.9entered into the Covaxin Agreement with Bharat Biotech to co-develop COVAXIN for the Ocugen Covaxin Territory. The Covaxin Agreement was originally entered into in February 2021 with respect to the U.S. market and was subsequently amended in June 2021 to add rights to the Canadian market. In consideration of the expansion of the Ocugen Covaxin Territory to include Canada, the Company paid Bharat Biotech a non-refundable, upfront payment of $15.0 million in equity issuance costs related to the Pre-Merger Financing, ofJune 2021, which $0.7 million was paidrecognized as research and development expense in cash and $1.2 million was paid with equity as of December 31, 2019. Approximately $1.1 million of equity issuance costs was allocated to the Series A Warrants and Series C Warrants and is included in additional paid-in capital. Approximately $0.8 million of issuance costs allocated to the Series B Warrant liability was expensed and is reflected in other income (expense) on the consolidated statements of operations and comprehensive loss forduring the year ended December 31, 2019.2021. The Company additionally agreed to pay Bharat Biotech $10.0 million within 30 days after the first commercial sale of COVAXIN in Canada. The Covaxin Agreement is a collaboration arrangement within the scope of ASC 808.
Merger with Histogenics
On September 27, 2019,Pursuant to the Covaxin Agreement, the Company completed the Merger in accordanceobtained an exclusive right and license under certain of Bharat Biotech’s intellectual property rights, with the terms of the Merger Agreement. The Merger was structured as a stock-for-stock transaction whereby all of Former Ocugen’s outstanding shares of common stock and securities convertible into or exercisable for Former Ocugen’s common stock were converted into the right to receive Histogenics’ common stockgrant sublicenses, to develop, manufacture, and securities convertible into or exercisable for Histogenics’ common stock. Immediately followingcommercialize COVAXIN in the Merger, the former equity holders of Former Ocugen owned 84.25%Covaxin Territory. In consideration of the outstanding capital stocklicense and other rights granted to the Company by Bharat Biotech, the parties agreed to share any Operating Profits (as defined in the Covaxin Agreement) generated from the commercialization of COVAXIN in the Ocugen Covaxin Territory, with the Company retaining 45% of such profits, and Bharat Biotech receiving the balance of such Operating Profits.
Under the Covaxin Agreement, the Company is collaborating with Bharat Biotech to develop COVAXIN for their respective territories. Except with respect to manufacturing rights under certain circumstances subsequently described, the Company has the exclusive right and is solely responsible for researching, developing, manufacturing, and commercializing COVAXIN for the Ocugen Covaxin Territory. Bharat Biotech is responsible for researching, developing, manufacturing, and commercializing COVAXIN outside of the Company, and the equity holders ofOcugen Covaxin Territory.
Bharat Biotech has agreed to provide to the Company immediately before the Merger owned 15.75% of the outstanding capital stock ofpreclinical and clinical data, and to transfer to the Company includingcertain proprietary technology owned or controlled by Bharat Biotech, that is necessary for the Initial Shares but excludingsuccessful commercial manufacture and supply of COVAXIN to support commercial sale in the Additional Shares and the Pre-Merger Financing Warrants pursuant to the Financing SPA.Ocugen Covaxin Territory, if authorized or approved.
In accordance with ASC Topic 805, Business Combinations (“ASC 805”),September 2021, the Company concluded that, while Histogenics is the legal acquirer, Former Ocugen is the accounting acquirer due to the fact that (i) Former Ocugen’s shareholders have the majority of the voting rights in Ocugen, (ii) Former Ocugen holds all of the board seats of the combined company and (iii) Former Ocugen management holds all key positions in the management of the combined company. The Company has further concluded that Histogenics does not meet the definition of a business under ASC 805 due to the fact that substantially all of the fair value of the gross assets disposed of is concentrated in a single identifiable asset or a group of similar identifiable assets. Therefore, the Merger was accounted for as a reverse asset acquisition. The Company incurred $4.9 million in transaction costs related to the Merger, of which $2.6 million was paid in cash and $2.3 million was paid with equity.
Assets and liabilities of Histogenics on September 27, 2019 were as follows (in thousands):
September 27,
2019
Cash and cash equivalents$302 
Asset held for sale7,000 
Accounts payable(1,106)
Net assets acquired$6,196 
Asset Held for Sale
In connection with the Merger, on May 8, 2019, Histogenics entered into an asset purchase agreement (the “Asset Purchase Agreement”)the Supply Agreement with Medavate Corp., a Colorado corporation (“Medavate”),Bharat Biotech, pursuant to which Histogenics agreed to sell substantially all of its assets relating to its NeoCart® program, including, without limitation, intellectual property, business and license agreements andBharat Biotech will supply the Company with clinical trial data (the “Assets”) in return for a cash paymentmaterials and commercial supplies of $6.5 million. On September 26, 2019, the parties entered into an amendmentCOVAXIN finished drug product prior to the Asset Purchase Agreement wherebycompletion of a technology transfer. Following the closing date was amended to October 4, 2019. On October 4, 2019, the parties entered intocompletion of a second amendment (the “Second Amendment”) to the Asset Purchase Agreement whereby the purchase price was increased to $7.0 million under the Asset Purchase Agreement and the closing date of the Asset Purchase Agreement was revised from October 4, 2019 to two business days after Medavate obtains financing in an amount no less than the purchase price (the “Closing Date”). The Second Amendment further provides that if the Closing Date does not occur on or prior to October 31, 2019, Ocugen may choose to terminate the Asset Purchase Agreement without recourse and, if Ocugen does not terminate the Asset Purchase Agreement, the purchase price shall increase 10% per month (or any portion thereof) between October 31, 2019 and the Closing Date. The Closing Date did not occur as of December 31, 2019, Ocugen has not terminated the Asset Purchase Agreement and as of December 31, 2019, the purchase price has increased to $8.5 million.
The NeoCart® asset qualified as held for sale as of the date of the reverse asset acquisition and is carried at its original fair value less cost to sell on the consolidated balance sheet as of December 31, 2019. The NeoCart® asset held for sale was valued at thetechnology transfer, Bharat Biotech will supply COVAXIN
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acquisition date based ondrug product components and continue to supply finished drug product as necessary for commercial manufacture and supply of COVAXIN subsequent to a quoted priceregulatory authorization or approval. The technology transfer process from Bharat Biotech to Jubilant HollisterStier for drug product manufacturing has been initiated. In March 2021, the Company issued shares of $7.0 million, which isSeries B Convertible Preferred Stock (as defined in Note 9) as an observable Level 2 fair value input. Subsequent increasesadvance payment for the supply of COVAXIN to be provided by Bharat Biotech under the Supply Agreement. See Note 9 for additional information about the Series B Convertible Preferred Stock issuance to Bharat Biotech.
The Covaxin Agreement continues in fair value are not recognized beyondeffect for the initial value atcommercial life of COVAXIN, subject to the timeearlier termination of the asset was classified as held for sale.Covaxin Agreement in accordance with its terms. The Covaxin Agreement also contains customary representations and warranties made by both parties and customary provisions relating to indemnification, limitation of liability, confidentiality, information and data sharing, and other matters. The Supply Agreement expires upon expiration of the Covaxin Agreement and may be earlier terminated by either party in the event of an uncured material breach or bankruptcy of the other party.
MEDINETLicense Agreement with The Schepens Eye Research Institute, Inc.
In December 2017, Histogenicsthe Company entered into an exclusive license agreement with The Schepens Eye Research Institute ("SERI"), which was amended in January 2021 (as so amended, the License"SERI Agreement"). The SERI Agreement gives the Company an exclusive, worldwide, sublicensable license to patent rights, biological materials, and Commercializationtechnical information for NHR genes Nuclear Receptor Subfamily 1 Group D Member 1 ("NR1D1"), NR2E3 (OCU400), RORA (OCU410), Nuclear Protein 1, Transcriptional Regulator ("NUPR1"), and Nuclear Receptor Subfamily 2 Group C Member 1 ("NR2C1"). The January 2021 amendment to the SERI Agreement (the “License Agreement”) with MEDINET Co., Ltd. (“MEDINET”)additionally granted the Company rights in co-owned intellectual property pursuant to grant MEDINET a license under certain patents, patent applications know-how, and technologyprovisional patent applications at the time of the amendment. Under the SERI Agreement, the Company may make, have made, use, offer to developsell, sell, and commercialize certain therapeuticimport licensed products, and must use commercially reasonable efforts to bring one or more licensed products to market as soon as reasonably practicable.
SERI maintains control of patent preparation, filing, prosecution, and maintenance. The Company is responsible for SERI’s out-of-pocket expenses related to the NeoCart® program. As consideration for the grantingfiling, prosecution, and maintenance of the license, MEDINET agreedlicensed patent rights. In the event that SERI decides to discontinue the prosecution or maintenance of the licensed patent rights, the Company has the right, but not the obligation, to file for, or continue to prosecute, maintain, or enforce such licensed patent rights. The Company has assumed prosecution of certain licensed patent rights under the SERI Agreement.
The SERI Agreement is a collaborative arrangement within the scope of ASC 808. The SERI Agreement requires the Company to pay Histogenics a non-refundable upfront cashlicensing fees for patent rights granted, an annual license maintenance fee, payment of $10.0certain regulatory and commercial milestones in the aggregate amount of $16.1 million, which was received in January 2018. Basedand low single-digit percentage royalties on annual net sales of products that fall under the licensed patent rights. The Company has made no milestone or royalty payments to date pursuant to the SERI Agreement.
The SERI Agreement will expire on the resultsexpiration date of the NeoCart® research, Histogenics suspendedlast to expire licensed patent rights, subject to the NeoCart® program. Subsequently, since MEDINET reliedearlier termination of the SERI Agreement in accordance with its terms. The Company may terminate the license upon 180 days’ prior written notice. SERI may immediately terminate the SERI Agreement if the Company ceases to carry on its business with respect to the NeoCart® productlicensed patent rights, fails to supply clinical trial patients, MEDINET suspended the developmentmake payments within thirty days of receiving a written notice of missed payment, fails to comply with its diligence obligations, defaults on its obligation to procure and maintain insurance, one of its clinical trial. Asofficers is convicted of December 31, 2019, the contract with MEDINET was wholly unperformed. As a result of the expected sale of the NeoCart® asset, the Company does not expect to retain any future obligationsfelony related to the MEDINET agreement.
4. Net Loss Per Sharelicensed products, the Company breaches any material obligation of Common Stock
The following table sets forth the computation of basicagreement and diluted earnings per share fordoes not cure such breach within 90 days, or if the years ended December 31, 2019 and 2018:
Year ended December 31,
20192018
Net loss—basic and diluted$(20,242,630) $(18,219,664) 
Shares used in calculating net loss per common share—basic and diluted13,893,819  4,960,552  
Net loss per common share—basic and diluted$(1.46) $(3.67) 
The following potentially dilutive securities have been excluded from the computation of diluted weighted average shares outstanding, as their inclusion would have been antidilutive:
Year ended December 31,
20192018
Options to purchase common stock731,189  632,752  
Warrants870,020  870,020  
Series A Warrants8,771,928  —  
Series B Warrants1,000  —  
Series C Warrants1,000  —  
Total10,375,137  1,502,772  


5. License and Collaboration AgreementsCompany becomes bankrupt or insolvent.
Co-Development and Commercialization Agreement with CanSino BiologicsCanSinoBIO
On September 27, 2019, OcugenThe Company entered into a co-development and commercialization agreement (the “CanSinoBIO Agreement”) with CanSino Biologics Inc. (“CanSinoBIO”)CanSinoBIO with respect to the development and commercialization of the Company's modifier gene therapy product candidate, OCU400.candidates, OCU400 and OCU410. The co-development and commercialization agreement was originally entered into in September 2019 with regards to OCU400, and was subsequently amended in September 2021 (as so amended, the "CanSinoBIO Agreement"), to include OCU410 to the Company's existing collaboration with CanSinoBIO.
Pursuant to the CanSinoBIO Agreement, the Company and CanSinoBIO will collaborate on the development of OCU400 and OCU410. CanSinoBIO will be responsible for all the costs for chemistry, manufacturing and controlCMC development and manufacture of clinical supplies of OCU400 for all territories. CanSinoBIO willsuch products and be solely responsible for allthe costs associated with such activities. CanSinoBIO has an exclusive license to develop, manufacture, and expenses of its development activitiescommercialize OCU400 and OCU410 in and for China, Hong Kong, Macau, and Taiwan (the "CanSinoBIO Territory"), and Ocugen will be responsible for all coststhe Company maintains exclusive development, manufacturing, and expenses of its development activities for any global locationcommercialization rights with respect to OCU400 and OCU410 outside the CanSinoBIO Territory (the "Ocugen"Company Territory").
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CanSinoBIO will pay to Ocugenthe Company an annual royalty between mid tomid- and high-single digits based on net sales of productsNet Sales (as defined in the CanSinoBIO Territory,Agreement) of OCU400 and OcugenOCU410 in the CanSinoBIO Territory. The Company will pay to CanSinoBIO an annual royalty between low tolow- and mid-single digits based on net salesNet Sales of productsOCU400 and OCU410 in the OcugenCompany Territory.
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Unless earlier terminated earlier,in accordance with its terms, the CanSinoBIO Agreement will continue in force on a country-by-country and product-by-product basis until the later of (a) the expiration of the last valid claim of the Company's patent rights of Ocugen covering such productOCU400 and OCU410 and (b) the tenth (10th)(10th) anniversary of the first commercial sale of such productOCU410 in such country. The CanSinoBIO Agreement will also terminate contemporaneously upon the termination of the Exclusive LicenseSERI Agreement, dated December 19, 2017, between Ocugen and Schepens Eye Research Institute, Inc.provided that CanSinoBIO is not in breach or default of the CanSinoBIO Agreement. The CanSinoBIO Agreement may be terminated by either party in its entirety upon (a) a material or persistent breach of the CanSinoBIO Agreement by the other party, (b) a challenge by the other party or any of its affiliates of any intellectual property controlled by the terminating party, or (c) bankruptcy or insolvency of the other party. Within forty-five (45) days after such termination, CanSinoBIO shall provide Ocugen with a statement of the CanSinoBIO development costs and, within one (1) year after receipt of such report, Ocugen shall reimburse CanSinoBIO all such CanSinoBIO development costs.
License Agreement with the Schepens Eye Research Institute
In 2017, the Company entered into a license agreement with The Schepens Eye Research Institute (“SERI”), which granted the Company an exclusive license to develop, commercialize, and continue to secure patents for OCU400 and OCU410. This agreement is accounted for as a collaborative arrangement. In connection with acquiring the license, the Company was required to pay a license fee of $0.1 million, which was recognized in 2017. The Company will also be required to reimburse SERI for all future patent costs related to this licensed technology.
The Company is obligated to pay SERI up to $6.0 million upon the achievement of certain development and regulatory milestones. The Company is also obligated to pay SERI up to $10.1 million upon the achievement of certain commercial milestones. The Company will also pay SERI royalties in the low single digits based on net sales. NaN milestones or royalties were paid or incurred through December 31, 2019, as the Company has not achieved any milestones, net sales or sublicensing under this agreement. The Company may cancel the license agreement at any time with 180 days’ written notice.
In 2017, the Company also entered into a Sponsored Research Agreement with SERI under which the Company recognized approximately $0.6 million and $0.5 million as research and development expense for the year ended December 31, 2019 and 2018, respectively, for work performed under this agreement.
License Agreement with the University of Illinois
In 2016, the Company entered into a license agreement with the University of Illinois at Chicago (“UIC”), which granted the Company an exclusive license to develop, commercialize and continue to secure patents for OCU300 and OCU310. In connection with acquiring the license for OCU300 and OCU310, the Company was required to pay a signing fee of $15,000.
The Company is required to pay royalties in the low single digits to low teens to UIC based on net sales and sublicense revenues generated by OCU300 and OCU310. The Company is also required to pay minimum annual royalties to UIC, beginning with an annual payment of $20,000 on the third anniversary of the effective date of the agreement, and increasing gradually to $50,000 by the sixth anniversary and continuing through the term of the agreement. The Company is also obligated to pay UIC up to $1.3 million upon the achievement of certain development and regulatory milestones.
During 2018, the Company incurred $0.3 million in milestone payments due to achieving a milestone associated with dosing the first patient in a Phase 3 clinical trial. The Company has not achieved any other milestones, net sales or sublicensing for OCU300 or OCU310. The Company may cancel the license agreement at any time with 90 days’ written notice.
License Agreement with the University of Colorado
In March 2014, the Company entered into a patentan exclusive license agreement with the University of Colorado (“CU”("CU"), which grantedwas amended in January 2017 and clarified by a letter of understanding in November 2017 (as so amended and clarified, the "CU Agreement"). The CU Agreement gives the Company an exclusive, worldwide, sublicensable license to develop and commercialize, and continue to secure patents for OCU200 includingto make, have made, use, import, offer to sell, sell, have sold, and practice the ability to enforce any rights against infringement.licensed products in all therapeutic applications. Under the agreement,CU Agreement, the Company must use commercially reasonable efforts to develop, manufacture, sublicense, market, and sell the licensed products, and has assumed primary responsibility for preparing, filing, and prosecuting broad patent claims for OCU200 for CU's benefit. Further, the Company assumed primary responsibility for all patent activities, including all costs associated with the perfection and maintenance of the patents for OCU200.
Pursuant toThe CU Agreement requires the termspayment of the agreement, in exchange for the licensed patents, the Company issued CU 0.1 million shares of the Company’s common stock. The agreement with CU, as amended in January 2017, obligates the Company to pay certain development and regulatory milestone fees of upmilestones aggregating to $1.5 million, royalties inan annual minimum payment that began the third year after the effective date, low single digitssingle-digit percentage earned royalties on net sales, and royalties in the mid-teens on sublicense income of OCU200. The Company has made no milestone or royalty payments to date pursuant to the CU Agreement.
The agreement with CU calls for minimum annual royalty payments of $20,000, startingAgreement will expire on the third anniversarylater of the expiration date of the last to expire licensed patent or the end of any relevant statutory or regulatory exclusivity period. The Company may terminate the CU Agreement upon 60 days’ prior written notice. CU may terminate the CU Agreement upon 60 days’ notice if the Company fails to make payments within 60 days of such payment’s due date, breach and do not cure any diligence obligation, provide any materially false report, or otherwise materially breach and do not cure any material provision of the CU Agreement.
4.    Notes Receivable
On April 13, 2021, the Company received a promissory note in the principal amount of $0.8 million from a company in connection with a potential collaboration. The promissory note bore interest at a rate per annum of 5% and the outstanding principal balance of the promissory note plus any accrued and unpaid interest thereon was payable in full on April 13, 2022 (the "Maturity Date"). Effective July 2021, the Company accepted an amended and restated promissory note (as so amended and restated, the "Promissory Note") pursuant to which the parties agreed to extend the Maturity Date of the Promissory Note to June 30, 2022 and increase the interest rate per annum to 9% with quarterly interest payments. The Promissory Note may be prepaid in whole or in part at any time, together with accrued and unpaid interest. The Promissory Note contains customary covenants and events of default, including, among others, failure to make payment, breach of agreement, and on each annual anniversary thereafter,bankruptcy.
The Company evaluated the probability of collecting the full principal and after sales commence, increasing toaccrued interest balance under the terms of the Promissory Note and determined that collection was not probable. During the year ended December 31, 2021, the Company wrote off the full principal and accrued interest balance of the Promissory Note and recorded the write-off as a percentage rate inloss within other income (expense) within the mid-consolidated statements of operations and comprehensive loss.
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5.    Property and Equipment
The following table provides a summary of the major components of property and equipment as reflected on the consolidated balance sheets (in thousands):
As of December 31,
20212020
Furniture and fixtures$284 $166 
Machinery and equipment855 452
Leasehold improvements167 177
Construction in progress232 — 
Financing lease right-of-use asset— 64
Total property and equipment1,538 859
Less: accumulated depreciation(374)(226)
Total property and equipment, net$1,164 $633 

The Company recognized depreciation expense of $0.2 million, $0.1 million, and $0.1 million during the years ended December 31, 2021, 2020, and 2019, respectively.
6.    Operating Leases
The Company has commitments under operating leases for its current headquarters as well as for additional office space. The Company's operating lease for its current headquarters includes the use of laboratory, office, and storage space located in Malvern, Pennsylvania (the "Lease Agreement"). The Lease Agreement was determined to have two lease components per ASC 842 with commencement dates in December 2020 and January 2021. The Lease Agreement has an initial term of seven years and the Company has the option to extend the Lease Agreement for 1 additional five-year term. The option for extension has been excluded from the lease term (and lease liability) for the Lease Agreement as it is not reasonably certain that the Company will exercise such option. The Company had a lease agreement for its former headquarters, which was terminated in January 2021 without penalty pursuant to the terms of the Lease Agreement. The termination was accounted for as a modification per ASC 842 as the contractual lease term of the former lease agreement was shortened. The Company also had a lease agreement for a former laboratory space, which was terminated in December 2020.
The components of lease expense were as follows (in thousands):
Year ended December 31,
202120202019
Operating lease cost$360 $189 $250 
Variable lease cost105 85 80 
Total lease cost$465 $274 $330 
Supplemental balance sheet information related to leases was as follows (in thousands):
As of December 31,
20212020
Right-of-use assets, net$1,587 $434 
Current lease obligations$363 $44 
Non-current lease obligations1,231 389 
Total lease liabilities$1,594 $433 
F-21

twentiesSupplemental information related to leases was as follows:
Year ended December 31,
202120202019
Weighted-average remaining lease terms — operating leases (years)5.36.92.0
Weighted-average discount rate — operating leases4.1 %4.6 %7.6 %
Future minimum operating lease base rent payments are approximately as follows (in thousands):
For the years ending December 31,Amount
2022$440 
2023261 
2024269 
2025277 
2026285 
Thereafter293 
Total$1,825 
Less: present value adjustment(231)
Present value of minimum lease payments$1,594 
In October 2021, the Company entered into a lease agreement for additional office space located in Malvern, Pennsylvania. The lease has an expected commencement date in the first half of 2022 and has an initial term of seven years. The aggregate estimated base rent payments due over the initial seven-year term is $3.8 million, which is excluded from the future minimum operating base rent payments above as the lease agreement has not yet commenced per ASC 842. Additionally, the Company will be responsible for the operating expenses and utilities associated with the leased premises. The Company has the option to extend the lease agreement for 2 additional five-year terms, provided the Company is not under an event of default pursuant to the terms of the previous year’s royalty payment paidlease agreement.
7.    Accrued Expenses and Other Current Liabilities
Accrued expenses and other current liabilities are as follows (in thousands):
As of December 31,
20212020
Research and development$866 $512 
Clinical703 117 
Professional fees747 405 
Employee-related1,716 963 
Severance-related (1)— 712 
Other293 232 
Total accrued expenses and other current liabilities$4,325 $2,941 
(1) In June 2020, the Company communicated notice to CU, through the term5 employees of the agreement. Future annual royalties will be recognizedtermination of their employment as a result of the discontinuation of a product candidate. This reduction represented one-third of the Company’s workforce at the time of communication. All terminations were “without cause” and each employee received termination benefits upon departure. The termination dates varied for each employee and ranged from June 30, 2020 to December 31, 2020.
F-22

The following table provides a summary of the severance-related charges and severance payments during the years ended December 31, 2021 and 2020 related to the June 2020 reduction in workforce (in thousands):
Amount
Accrued Severance at December 31, 2019$— 
Severance-related charges1,116 
Severance-related payments404 
Accrued Severance at December 31, 2020$712 
Severance-related charges— 
Severance-related payments712 
Accrued Severance at December 31, 2021$— 
As of December 31, 2021, the Company has satisfied its commitments under the separation agreements with the 5 former employees.
8.    Debt
The following table provides a summary of the carrying values for the components of debt as reflected on the consolidated balance sheets (in thousands):
As of December 31,
20212020
PPP Note$— $421 
EB-5 Loan Agreement1,712 1,636 
Total carrying value of debt, net$1,712 $2,057 
PPP Note
In April 2020, the Company was granted a loan from Silicon Valley Bank ("SVB"), in the years they are earned,amount of $0.4 million, pursuant to the Paycheck Protection Program (the “PPP”) of the Coronavirus Aid, Relief and Economic Security Act of 2020 (the “CARES Act”). Under the PPP, the loan was eligible for forgiveness to the extent the funds received were used for qualifying expenses as described by the CARES Act. The loan was in the form of a promissory note dated April 30, 2020 in favor of SVB (the "PPP Note"). The PPP Note had a maturity date of April 30, 2022 and bore interest at a rate of 1.0% per the license agreement.annum. The Company may canceldid not provide any collateral or guarantees for the license agreement atloan, nor did the Company pay any time with 60 days’ written notice.
6.Accrued Expenses
Accrued Expenses are as follows:
As of December 31,
20192018
Accrued expenses:
Research and development$271,322  $705,436  
Clinical421,788  469,473  
Consulting98,245  86,619  
Employee-related624,420  123,372  
Legal819,323  15,400  
Other34,947  2,450  
Total accrued expenses$2,270,045  $1,402,750  

7.Debtfacility charge to obtain the loan. The PPP Note provided for customary events of default, including, among others, failure to make payment, bankruptcy, breaches of representations, and material adverse events. In May 2021, the Company received notice from the Small Business Administration that the PPP Note was forgiven in its entirety, including both principal and accrued interest. The Company recognized a $0.4 million gain on loan extinguishment within other income (expense) for the forgiveness of the PPP Note within the consolidated statements of operations and comprehensive loss for the year ended December 31, 2021.
EB-5 Loan Agreement
In September 2016, pursuant to the U.S. government’s Immigrant Investor Program, commonly known as the EB-5 program, (the “EB-5 Program”), the Company entered into an arrangement (the “EB-5 Loan Agreement”) to borrow up to $10.0 million from EB5 Life Sciences, L.P. (the “Lender”("EB-5 Life Sciences") in $0.5 million increments. BorrowingBorrowings may be limited by the amount of funds raised by the LenderEB-5 Life Sciences and are subject to certain job creation requirements by the Company. Borrowings are at a fixed interest rate of 4.0% per annum and are to be utilized in the clinical development, manufacturing, and commercialization of the Company’s productsproduct candidates and for the general working capital needs of the Company. Outstanding borrowings pursuant to the EB-5 Program,Loan Agreement, including accrued interest, become due upon the seventh anniversary of the final disbursement. Amounts repaid cannot be re-borrowed. The EB-5 note isLoan Agreement borrowings are secured by substantially all assets of the Company, except for any patents, patent applications, pending patents, patent license, patent sublicense, trademarks, and other intellectual property rights.
In 2016,
F-23

Under the terms and conditions of the EB-5 Loan Agreement, the Company borrowed $1.0 million was borrowed by the Company.in 2016 and an additional $0.5 million in March 2020. Issuance costs for these borrowings totaled $0.1 million, which waswere recognized as a reduction to the loan balance and isare amortized to interest expense over the term of the loan. See Note 12
The carrying values of the EB-5 Loan Agreement borrowings as of December 31, 2021 and 2020 are summarized below (in thousands):
As of December 31,
20212020
Principal outstanding$1,500 $1,500 
Plus: accrued interest241 181 
Less: unamortized debt issuance costs(29)(45)
Carrying value$1,712 $1,636 
9.    Equity
COVAXIN Preferred Stock Purchase Agreement
On March 1, 2021, the Company entered into a preferred stock purchase agreement, pursuant to which the Company agreed to issue and sell 0.1 million shares of the Company’s Series B Convertible Preferred Stock, par value $0.01 per share (the "Series B Convertible Preferred Stock"), at a price per share equal to $109.60, to Bharat Biotech. On March 18, 2021, the Company issued the Series B Convertible Preferred Stock as an advance payment for information regarding events subsequentthe supply of COVAXIN to be provided by Bharat Biotech pursuant to the Supply Agreement. Subsequent to December 31, 2019.2021, the Company entered into supply commitments related to COVAXIN, which the advanced payment will be applied to.
As of December 31,
20192018
Principal outstanding$1,000,000  $1,000,000  
Plus: accrued interest127,777  87,222  
Less: unamortized debt issuance costs(55,654) (70,495) 
Carrying value of debt$1,072,123  $1,016,727  
Each share of Series B Convertible Preferred Stock is convertible, at the option of Bharat Biotech, into 10 shares of the Company’s common stock (the "Conversion Ratio") only after (i) the Company received stockholder approval to increase the number of authorized shares of common stock under its Sixth Amended and Restated Certificate of Incorporation and (ii) the Company’s receipt of shipments by Bharat Biotech of the first 10.0 million doses of COVAXIN manufactured by Bharat Biotech pursuant to the Supply Agreement, and further on the terms and subject to the conditions set forth in the Certificate of Designation of Preferences, Rights and Limitations of Series B Convertible Preferred Stock (the "Certificate of Designation"). In April 2021, the Company's stockholders approved an increase in the number of the Company's authorized shares of common stock from 200.0 million to 295.0 million. As of December 31, 2021, the conversion condition relating to the delivery of the first 10.0 million doses of COVAXIN had not been met. The conversion rate of the Series B Convertible Preferred Stock is subject to adjustment in the event of a stock dividend, stock split, reclassification, or similar event with respect to the Company’s common stock.
Bharat Biotech is entitled to receive dividends on the Series B Convertible NotesPreferred Stock equal (on an as-converted to common stock basis) to and in the same form as dividends actually paid on shares of common stock, when and if such dividends are paid. Except as provided by law and certain protective provisions set forth in the Certificate of Designation, the Series B Convertible Preferred Stock has no voting rights. Upon a liquidation or dissolution of the Company, holders of Series B Convertible Preferred Stock would be entitled to receive the same amount that a holder of common stock would receive if the Series B Convertible Preferred Stock were fully converted to common stock.
DuringThe Company accounted for the yearsissuance of the Series B Convertible Preferred Stock in accordance with ASC 718 and recorded its grant date fair value of $5.0 million within stockholders' equity during the year ended December 31, 2021, with a corresponding short-term asset for the advanced payment for the doses of COVAXIN. The Company utilized the traded common stock price, adjusted by the Conversion Ratio, to value the Series B Convertible Preferred Stock and the Finnerty model to estimate a 15% discount rate for the lack of marketability of the instrument. The valuation incorporates Level 3 inputs in the fair value hierarchy, including the estimated time until the instrument's liquidity and estimated volatility of the Company's common stock as of the grant date.
Registered Direct Offerings
On April 23, 2021, the Company entered into a securities purchase agreement with certain institutional investors pursuant to which the Company agreed to issue and sell in a registered direct offering (the "April 2021 Registered Direct Offering") an aggregate of 10.0 million shares of the Company's common stock at an offering price of $10.00 per share. The closing of the
F-24

April 2021 Registered Direct Offering occurred on April 27, 2021, and the Company received net proceeds of $93.4 million, after deducting equity issuance costs of $6.6 million.
On February 7, 2021, the Company entered into a securities purchase agreement with certain institutional investors pursuant to which the Company agreed to issue and sell in a registered direct offering (the "February 2021 Registered Direct Offering") an aggregate of 3.0 million shares of the Company's common stock at an offering price of $7.65 per share. The closing of the February 2021 Registered Direct Offering occurred on February 10, 2021, and the Company received net proceeds of $21.2 million, after, deducting equity issuance costs of $1.7 million.
At-the-Market Offerings
The Company commenced 3 separate at-the-market offerings ("ATMs") in May 2020, June 2020, and August 2020 (the "August 2020 ATM"). During the year ended December 31, 2021, the Company sold 1.0 million shares of common stock under the August 2020 ATM and received net proceeds of $4.8 million, after deducting equity issuance costs of $0.1 million. During the year ended December 31, 2020, the Company sold an aggregate of 108.1 million shares of common stock under the ATMs and received net proceeds of $36.3 million, after deducting equity issuance costs of $1.5 million.
Pre-Merger Financing
On September 27, 2019, the Company, which was formerly known as Histogenics Corporation ("Histogenics"), completed a reverse merger (the "Merger") with Ocugen OpCo, Inc. ("OpCo") in accordance with the terms of the Agreement and 2018,Plan of Merger and Reorganization, dated as of April 5, 2019, in which OpCo was deemed to be the accounting acquirer. In June 2019 prior to the Merger, OpCo and Histogenics entered into a Securities Purchase Agreement (as amended, the "Financing SPA") with certain accredited investors (the "Investors"). Pursuant to the Financing SPA, among other things, (i) immediately prior to the Merger, OpCo issued 2.2 million shares of common stock to the Investors, (ii) on October 4, 2019, the Company issued 2.2 million shares of the Company's common stock to the Investors and (iii) on October 4, 2019, the Company issued three series of warrants to purchase shares of the Company’s common stock (the “Series A Warrants,” the “Series B Warrants” and the “Series C Warrants” and collectively, the “SPA Warrants”) in exchange for an aggregate purchase price of $25.0 million (the "Pre-Merger Financing"). See Note 10 for additional information. In 2019, prior to the Pre-Merger Financing, the Company issued two senior secured convertible notes (the “Notes”"Senior Secured Convertible Notes") to new and existing stockholders in the Company, including Notes in the aggregate principal amount of $3.5 million to members of the Board of Directors. As of December 31, 2019, all Notes had been converted and were 0 longer outstanding.
F-16

At issuance, the following amounts were recorded:
Note Issuance DateNote
Principal
Amount
Fair Value of
Embedded Derivatives
Debt
Issuance
Costs
Carrying Value upon Issuance
January 2018$5,000,000  $(2,657,711) $(35,969) $2,306,320  
June 20181,000,000  (724,216) (3,000) 272,784  
November 20181,150,400  (21,127) (50,646) 1,078,627  
December 2018150,000  (2,857) (14,310) 132,833  
January 2019450,000  (182,882) (29,358) 237,760  
February 20191,000,000  (302,379) (55,875) 641,746  
Total$8,750,400  $(3,891,172) $(189,158) $4,670,070  

All Notes accrued interest at a rate of 5% per annum and had scheduled maturity dates on the eighteen month anniversary of the date of the issuance of the Notes (the “Maturity Date”). If prior to the Maturity Date, there was a consummation of the sale of all or substantially all of the assets of the Company, change in control or event of default, the Notes would become due and payable at an amount equal to 1.5 times the principal amount of the Notes together with all accrued interest (the “Change in Control Feature”).
If the Company received equity financing from the issuance of stock of the Company from an investor or group of investors in a transaction or series of related transactions above a certain amount of gross proceeds, the principal amount and all interest accrued but not paid through the closing date of the qualified equity financing was to automatically convert into the same class of equity securities as those issued in the qualified equity financing ("conversion feature").$5.3 million. The price per share varied among the Notes ranging from a 0% to 30% discount to the lowest price per share being paid by investors in the qualified equity financing.
The Company bifurcated the Conversion Feature for the January 2018, June 2018, January 2019, and February 2019 notes and classified it as a derivative liability because the Conversion Feature does not have a fixed conversion price and conversion will be settled in a variable number of shares of common stock. There was no bifurcated Conversion Feature for the November 2018 and December 2018 notes as there is no discount to the lowest equity price triggering conversion. The Company also bifurcated the Change in Control Feature for all of the Notes because it was determined to be a redemption feature not clearly and closely related to the debt host.
The fair value of both of the embedded features was accounted for as a derivative liability and was recorded as a discount on the Notes. Inputs used in valuation were unobservable and therefore considered Level 3 in the fair value hierarchy. The debt discount is accreted into interest expense over the expected time until conversion of the Notes. The accretion amounted to $0.6 million and $3.4 million, for the year ended December 31, 2019 and 2018, respectively.
The fair value of the embedded features was classified as a liability in the Company’s consolidated balance sheets at issuance, with subsequent changes in fair value during the year ended December 31, 2019 and 2018 recorded on the Company’s consolidated statements of operations and comprehensive loss as a change in fair value of derivative liabilities.
Amount
 Balance at January 1, 2018$— 
 Fair value of embedded derivatives at issuance3,405,911 
 Change in fair value of embedded derivatives(1,664,689)
 Balance at December 31, 2018$1,741,222 
 Fair value of embedded derivatives at issuance567,661 
 Change in fair value of embedded derivatives1,319,400 
 Conversion and extinguishment of debt(3,628,283)
 Balance at December 31, 2019$— 
F-17

The Company considered several possible outcomes in the likelihood and timing of a qualified equity financing and/or a change in control occurring that would trigger conversion or redemption and believes the amounts disclosed above based on inputs utilized in the valuation were the best estimates at each valuation date.
On April 5, 2019, Former Ocugen entered into a Stock Subscription Agreement (“Subscription Agreement”) with existing investors for the sale of 0.1 million shares of common stock for $1.0 million, or $12.41 per share including the sale of 40,286 shares of common stock for $0.5 million to a member of the Board of Directors. This capital raise triggered the conversion features on the convertible debt described above. The Notes were modified to change the discount percentage from the 0% discount per the terms of the November 2018 and December 2018 Notes and the 15% discount per the terms of the January 2019 and February 2019 Notes to 30% at the time of conversion. The Company issued 1.1 million shares of common stock at $8.69 per share on the date of conversion to extinguish the debt, which resulted in a loss of $0.3 million. This non-cash conversion also resulted in an increase of $13.0 million in additional paid-in capital, which was based on the principal balance outstanding and the unpaid interest upon conversion.
Convertible Promissory Notes
On April 4, 2019, the Company issued the convertible promissory note (the “Promissory Note”) to an existing stockholder for $0.9 million at an interest rate of 5% per annum. On May 16, 2019, the Promissory Note was converted into equity. Former Ocugen issued 0.1 million shares of common stock at the conversion date to extinguish the debt at $12.41 per share. This non-cash transaction resulted in an increase of $0.9 million in additional paid-in capital, which was based on the principal balance outstanding and the unpaid interest upon conversion.
Senior Secured Convertible Notes
On May 21, 2019, the Company issued senior secured convertible notes to certain investors for $2.4 million at an original issue discount of $0.5 million, and on June 28, 2019, the Company entered into an agreement to issue additional senior secured convertible notes to the investors for $2.9 million with an original issue discount of $0.4 million (together “Senior Secured Notes”). Immediately prior to the Merger completed on September 27, 2019, the investorsInvestors offset $5.3 million from the amount to be received under the Pre-Merger Financing and the Senior Secured Convertible Notes were deemed to have been repaid and cancelled. The accretion
10.Warrants
Canada Warrants
On July 15, 2021, the Company entered into a consulting agreement with an individual to provide services to the Company with regard to the Company's Canadian operations (the "Canada Consulting Agreement"). Compensation under the Canada Consulting Agreement includes, among other forms of compensation, the issuance of warrants to purchase up to 0.2 million shares of the original issue discountCompany's common stock (the "Canada Warrants") and cash payments of up to interest expense amounted$3.0 million upon the achievement of certain milestones related to $0.8COVAXIN. The Canada Consulting Agreement terminates on July 15, 2023, unless earlier terminated in accordance with its terms.
The Canada Warrants were issued on July 15, 2021 in a private placement transaction. The warrantholder has the right to exercise the Canada Warrants to purchase up to 0.2 million duringshares of the Company's common stock at an exercise price of $6.36 per share upon the achievement of certain milestones related to COVAXIN. The Canada Warrants terminate on July 15, 2031, unless earlier terminated in accordance with their terms. As of December 31, 2021, all of the Canada Warrants were outstanding and unvested. The Canada Warrants are accounted for in accordance with ASC 718.
SPA Warrants
On October 4, 2019, the Company issued the SPA Warrants as a component of the Pre-Merger Financing. During the year ended December 31, 2019.2019, the Company issued 8.8 million Series A Warrants, 20.6 million Series B Warrants, and 20.0 million Series C Warrants. During the year ended December 31, 2019, 20.6 million Series B Warrants and 20.0 million Series C Warrants were exercised.
The Series A Warrants and the Series C Warrants were classified as stockholders' equity at issuance. The Series B Warrants were classified as a liability as they did not meet the derivative scope exception to be accounted for within stockholders' equity.
F-25

The Series B Warrants were initially measured at fair value and marked to market each reporting period until November 2019 when the Series B Warrants were reassessed and determined to meet the derivative scope exception allowing for stockholders' equity classification. The Series B Warrants were marked to market a final time and the remaining liability balance was reclassified to equity. The change in derivative liability related to the Series B Warrants for the year ended December 31, 2019 was $1.9 million.
On April 22, 2020, the Company entered into a subscription agreement with an accredited investor for the sale of 1,000 shares of the Company's common stock in a private placement for an aggregate offering price of $395 (the "April 2020 Subscription Agreement"), which represented a dilutive issuance per the terms of the Series A Warrants as the sale price of the Company's common stock under the April 2020 Subscription Agreement was lower than the exercise price ("Dilutive Issuance"). The Dilutive Issuance resulted in adjustments to the number of issuable Series A Warrants and the exercise price of the Series A Warrants. Immediately prior to the Company entering into the April 2020 Subscription Agreement, 8.8 million Series A Warrants, 1,000 Series B Warrants, and 1,000 Series C Warrants were outstanding.
Contemporaneously with the April 2020 Subscription Agreement, the Company and OpCo entered into Amendment and Exchange Agreements (each an "Exchange Agreement" and collectively, the "Exchange Agreements") with the Investors. Pursuant to the Exchange Agreements, the Company, OpCo, and the Investors agreed, among other things, after giving effect to the dilutive issuance, to amend the Series A Warrants to provide for an adjustment to the number of common stock issuable upon the exercise of the Series A Warrants. Concurrently with such amendments, the Investors exchanged the Series A Warrants for (i) an aggregate of 21.9 million shares of common stock and (ii) a promissory notes of $5.6 million (the "Warrant Exchange Promissory Notes" and collectively with the common stock issued, the "Warrant Exchange"). The Warrant Exchange Promissory Notes were recorded at a fair value of $5.0 million. During the year ended December 31, 2020, the Company made payments to the Warrant Exchange Promissory Note holders of $5.6 million, causing the Warrant Exchange Promissory Notes to be repaid in full and no longer outstanding. Immediately following the consummation of the Warrant Exchange and the concurrent exercise of the remaining Series B Warrants and Series C Warrants, there were no SPA Warrants outstanding.
The Company accounted for the Warrant Exchange by recognizing the fair value of the consideration transferred in excess of the carrying value of the Series A Warrants as a reduction of additional paid-in capital. The fair value of the Series A Warrants immediately prior to the Warrant Exchange was $1.1 million, which was estimated using a Black-Scholes valuation model utilizing Level 3 inputs. The fair value of the consideration transferred to settle the Series A Warrants was approximately $13.6 million, comprised of $8.6 million in shares of common stock and the fair value of the Warrant Exchange Promissory Notes of $5.0 million. The fair value of consideration transferred to settle the Series A Warrants was in excess of the fair value of the Series A Warrants immediately prior to the Warrant Exchange by approximately $12.5 million. The excess consideration was accounted for as a deemed dividend to the Series A Warrant holders and was reflected as an additional net loss to common stockholders in the calculation of basic and diluted net loss per common share for the year ended December 31, 2020.
OpCo Warrants
Beginning in 2016, OpCo issued warrants to purchase the Company's common stock (the "OpCo Warrants"). As of December 31, 2021 and 2020, 0.6 million and 0.9 million OpCo Warrants were outstanding, respectively. As of December 31, 2021, the outstanding OpCo Warrants had a weighted-average exercise price of $6.23. The outstanding OpCo Warrants expire between 2026 and 2027.
8.11.    Stock-Based Compensation
Stock-based compensation expense for stock options granted areand RSUs is reflected in the consolidated statements of operations and comprehensive loss as follows:
Year Ended
December 31,
20192018
General and administrative$362,833  $515,160  
Research and development521,256  559,527  
Total$884,089  $1,074,687  
follows (in thousands):
Year ended December 31,
202120202019
General and administrative$4,909 $349 $363 
Research and development2,049 311 521 
Total$6,958 $660 $884 

Stock-based compensation expense during the year ended December 31, 2021 included $2.1 million of expense related to stock options with performance-based vesting conditions. There were no stock options with performance-based vesting conditions granted prior to 2021.

F-26

As of December 31, 2019,2021, the Company had $0.9$12.6 million of unrecognized stock-based compensation expense related to stock options outstanding under its equity plans.and RSUs outstanding. This expense is expected to be recognized over a weighted average period of 1.72.1 years as of December 31, 2019.2021.
Equity Plans
The Company maintains 2 equity compensation plans, the 2014 Ocugen OpCo, Inc. Stock Option Plan (the “2014 Plan”"2014 Plan") and the Ocugen, Inc. 2019 Equity Incentive Plan (the “2019 Plan”"2019 Plan", collectively with the 2014 Plan, the "Plans"), which replaced the Histogenics Corporation 2013 Equity Incentive Plan (the "2013 Plan").
On December 18, 2019, Ocugen’s stockholders approved the adoption of the 2019 Plan and the 2013 Plan was frozen. No additional awards have been or will be made under the 2013 Plan and any remaining authorized shares under the 2013 Plan will be recycled into the 2019 Plan. The 2019 Plan provides for the granting of up to 2.1 million equity awards in respect of
F-18

Ocugen’s common stock, inclusive of equity awards that were previously available for issuance under the 2013 Plan, as of December 31, 2019. Additionally, on the first business day of each fiscal year, commencing on January 1, 2020, pursuant to the "Evergreen" provision of the 2019 Plan, the aggregate number of shares that may be issued under the 2019 Plan shallwill automatically increase by a number equal to the lesser of 4.0%4% of the total number of shares of Company common stock outstanding on December 31st31st of the prior year, or a number of shares of Company common stock determined by the Board.
Board of Directors. As of December 31, 2019, an aggregate of 0.6 million and 0.1 million shares of Company common stock were issuable upon the exercise of outstanding stock options under2021, the 2014 Plan and the 2019 Plan authorize for the granting of up to 0.8 million and 11.5 million equity awards in respect to the Company's common stock, respectively. In addition to options and RSUs granted under the Plans, the Company has granted certain options and RSUs as material inducements to employment in accordance with Nasdaq Listing Rule 5635 (c)(4), which were granted outside of the Plans.
Stock Options to Purchase Common Stock
Weighted averageThe assumptions utilized in the fair value calculation for stock options to purchase common stock as of December 31, 2021, 2020, and 2019 and 2018 arewere as follows:
Year Ended
December 31,
20192018
Weighted average common stock price$1.04  $9.72  
Expected option term (years)6.06.0 – 10.0
Weighted average expected stock price volatility109%  85%  
Risk-free interest rate1.5% – 2.4%2.3% – 3.0%
Expected dividend rate—%  —%  
Year ended December 31,
202120202019
Weighted average expected option term (years)6.06.06.0
Range of expected stock price volatility109% – 116%110% – 117%89% – 110%
Weighted average expected stock price volatility111%112%109%
Range of risk-free interest rate0.4% – 1.4%0.3% – 1.7%1.5% – 2.4%
Expected dividend rate0%0%0%

The following table summarizes the stock option activity:
Number of SharesWeighted Average Exercise PriceWeighted Average Remaining Contractual Life (Years)Aggregate Intrinsic Value (In Thousands)
Options outstanding at December 31, 20204,224,433 $0.84 8.9$5,496 
Granted7,728,260 3.45 — 
Exercised(1,208,631)0.70 11,144 
Forfeited(657,895)4.79 1,277 
Options outstanding at December 31, 202110,086,167 $2.59 8.8$24,664 
Options exercisable at December 31, 20211,281,244 $2.92 8.1$2,990 
The stock option activity underabove includes 1.5 million of stock options with performance-based vesting conditions granted during the Plans:
Number of SharesWeighted Average Exercise PriceWeighted Average Remaining Contractual Life (Years)Aggregate Intrinsic Value
Options outstanding at December 31, 2018632,752  $5.93  7.9$4,801,696  
Granted238,761  $1.04  
Cancelled(140,324) $4.58  
Options outstanding at December 31, 2019731,189  $4.59  8.0$24,028  
Options exercisable at December 31, 2019385,841  $5.15  6.8$3,049  
year ended December 31, 2021, of which 0.9 million are not yet vested and exercisable as of December 31, 2021. The weighted average grant date fair value of stock options granted during the yearyears ended December 31, 2021, 2020, and 2019 were $2.87, $0.34, and 2018 was $0.84, and $7.97, respectively. respectively. The total fair value of stock options vested during the years ended December 31, 2021, 2020, and 2019 were $2.6 million, $0.5 million, and $1.0 million, respectively. During the year ended December 31, 2019 was $1.0 million.
9.Commitments
Operating Leases
The2021, the Company has commitments under operating leases for certain facilities used in its operations. The Company’s leases have initial lease terms rangingreceived $0.9 million of cash proceeds from onethe exercises of stock options. There were no stock option exercises prior to five years. Certain lease agreements contain provisions for future rent increases.
The components of lease expense were as follows:
Year Ended
December 31, 2019
Operating lease cost$250,361 
Variable lease cost79,700 
Total lease cost$330,061 
2021.
F-19F-27

Supplemental balance sheet information related to leases was as follows:
December 31, 2019
Right-of-use assets, net$344,574 
Current lease obligations172,310 
Non-current lease obligations163,198 
Total lease liabilities$335,508 
Supplemental information related to leases was as follows:
Year Ended
December 31, 2019
Weighted-average remaining lease terms—operating leases (years)2.0
Weighted-average discount rate—operating leases7.6 %
Future minimum operating minimum lease payments for all leases, exclusive of taxes and other carrying charges, are approximately as follows:
For the Years Ending December 31,Amount
2020$191,890  
2021160,909  
202211,354  
Total$364,153  
Less: present value adjustment(28,645) 
Present value of minimum lease payments$335,508  
The Company does not have any leases that have not yet commenced which are significant.
Financing Leases
In June 2018, the Company leased specialized research equipment under a lease classified as a financing lease. The leased equipment is included in property and equipment, net and is amortized on a straight-line basis over five years. Financing lease liabilities are included in other liabilities on the Company's consolidated balance sheets. The interest rate related to the lease obligation is 7.6% and the maturity date is July 2021.
Future minimum lease payments for all financing leases, exclusive of taxes and other carrying charges, are approximately as follows:
For the Years Ending December 31,Amount
2020$23,856  
20219,941  
Total$33,797  
Less: present value adjustment(1,851) 
Present value of minimum lease payments$31,946  
RSUs

10.Warrants
Pre-Merger Financing Warrants
On September 27, 2019, Ocugen completed the Merger with Former Ocugen. Immediately prior to the Merger, Ocugen and Former Ocugen completed a previously announced private placement transaction with certain Investors pursuant to the Financing SPA, whereby, among other things, (i) Former Ocugen issued to the Investors shares of Former Ocugen’s common stock, (ii) Former Ocugen issued and deposited additional shares of Former Ocugen’s common stock into escrow, and (iii) the
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Company agreed to issue on the fifth trading day following the consummation of the Merger, Series A Warrants, Series B Warrants, and Series C Warrants.
The Pre-Merger Financing Warrants are subject to blocker provisions which restrict the exercise of the Pre-Merger Financing Warrants if, as a result of such exercise, the holder, together with its affiliates would beneficially own in excess of 4.99% or 9.99% of the outstanding common stock, including the common shares issuable upon such exercise, as such percentage ownership is determined in accordance with the terms of the Pre-Merger Financing Warrants.
If Ocugen fails to issue to a holder of the Pre-Merger Financing Warrants the number of shares of common stock to which such holder is entitled upon such holder’s exercise of the such warrants, then Ocugen shall be obligated to pay the holder on each day while such failure is continuing an amount equal to 2.0% of the market value of the undelivered shares determined using any trading price of the common stock selected by the holder as in effect at any time during the period from delivery of the exercise notice until the applicable share delivery date, and if the holder purchases shares of common stock in connection with such failure, then Ocugen must, at the holder’s discretion, reimburse the holder for the cost of such shares or deliver the owed shares and reimburse the holder for the difference between the price such holder paid for such shares and the closing market price for shares of common stock on the date of exercise.
On November 5, 2019, the Company entered into an agreement with each Investor that amends the terms of each of the Pre-Merger Financing Warrants held by each such Investor (collectively, the “Warrant Amendments”). The terms of the Pre-Merger Financing Warrants and the Warrant Amendments are discussed below.
Series A Warrants
The Series A Warrants have an initial exercise price per share of $7.13, were exercisable upon issuance and have a term of 60 months from the date of issuance. The Series A Warrants are exercisable for up to 8.8 million shares of Ocugen common stock.
The Series A Warrants have an anti-dilution adjustment whereby if Ocugen issues or sells, enters into a definitive, binding agreement pursuant to which Ocugen is required to issue or sell or is deemed, pursuant to the provisions of the Series A Warrants, to have issued or sold, any common stock for a price per share lower than the exercise price then in effect (a “Dilutive Issuance”), subject to certain limited exceptions, then (i) the exercise price of the Series A Warrants shall be reduced to such lower price per share and (ii) the number of shares issuable upon exercise of the Series A Warrants shall be increased to the number of shares of common stock determined by multiplying (a) the exercise price in effect immediately prior to such Dilutive Issuance by (b) the number of shares of common stock issuable upon exercise of the Series A Warrants immediately prior to such Dilutive Issuance (without giving effect to any limitation on exercise contained therein), and dividing the product thereof by the exercise price resulting from such Dilutive Issuance.
Each Series A Warrant was amended pursuant to the Warrant Amendments such that an equity financing involving a research or non-profit foundation or organization qualified under Section 501(c) of the Internal Revenue Code of 1986, as amended, in an amount of gross proceeds not to exceed $10.0 million and closing on or prior to May 31, 2020, will be excluded from the anti-dilution adjustment, as set forth in the Series A Warrant.
Series B Warrants
The Series B Warrants have an exercise price of $0.01, were exercisable after the completion of a 10 trading-day period following the effectiveness of a registration statement covering the resale of common stock into which such warrants were exercisable and will expire on the date on which the Series B Warrants have been exercised in full (without giving effect to any limitation on exercise contained therein) and no shares remain issuable thereunder. The Series B Warrants were initially exercisable by a holder for 8.0 million shares of common stock.
Additionally, each Series B Warrant included a Reset Period pursuant to which the number of shares issuable upon exercise of the Series B Warrants shall be increased during certain Reset Periods (as defined in the Series B Warrants) pursuant to a formula based on the greater of (i) 80% of the arithmetic average of the two lowest dollar volume-weighted average prices of a share of Ocugen common stock on Nasdaq during the applicable Reset Period immediately preceding the applicable Reset Date to date and (ii) $1.00 (the “Reset Price”). Among other things, the Reset Period was triggered by the effectiveness of the registration statement covering the resale of the shares of common stock underlying the warrants (the "Registration Statement') which became effective on November 5, 2019. The Warrant Amendments provided that Series B Warrants would not be exercisable and the effectiveness of the Registration Statement would not trigger the Reset Period until the completion of a 10 trading-day period following the SEC’s declaring it effective. The Reset Period commenced on November 20, 2019. As the dollar volume-weighted average prices of Ocugen’s common stock on Nasdaq was under $1.00 for the first two trading days of
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the Reset Period, the Investors elected to advance the end of the Reset Period to November 21, 2019 and the number of shares issuable upon exercise of the Series B Warrants was increased based on a Reset Price of $1.00. This reset resulted in an aggregate of 12.6 million additional shares of common stock becoming issuable upon exercise of the Series B Warrants.
Series C Warrants
The Series C Warrants were exercisable upon issuance for up to 50.0 million shares of common stock at an initial exercise price of $7.13 per share. Each of the Series C Warrants was amended pursuant to the Warrant Amendments to permit the Investors, in lieu of making any cash payment otherwise contemplated to be made to the Company upon the exercise of the Series C Warrant, to elect instead to receive upon such exercise up to 20.0 million shares of common stock. Prior to the Warrant Amendments, the Series C Warrants had permitted the exercise without any cash payment of up to 50.0 million shares of common stock in the event that the volume weighted-average price of the common stock on Nasdaq was less than or equal to $1.20 per share on any five trading days following the issuance of the Series C Warrants. The Series C Warrants will expire upon the 45th trading day immediately following the earlier to occur of (i) the date the holder can sell all shares issuable upon exercise of the Series C Warrants pursuant to Rule 144 without restriction or limitation and without the requirement to be in compliance with Rule 144(c)(1) and (ii) October 4, 2020, provided that if such date falls on a day other than a business day or on which trading does not take place on Nasdaq (a “Holiday”), the next day that is not a Holiday.
The following table summarizes the activity ofRSU activity:
Number of SharesWeighted-
Average
Grant-Date
Fair Value
Aggregate Intrinsic Value (In Thousands)
RSUs outstanding at December 31, 2020— $— $— 
Granted204,901 6.87 1,483 
Forfeited(13,090)8.05 108 
RSUs outstanding at December 31, 2021191,811 $6.79 $873 
12.    Income Taxes
For the Pre-Merger Financing Warrants, including the effect of the Warrant Amendments:
Series A WarrantsSeries B WarrantsSeries C WarrantsTotal
Outstanding at January 1, 2019—  —  —  —  
Issued8,771,928  20,614,036  20,000,000  49,385,964  
Exercised—  (20,613,036) (19,999,000) (40,612,036) 
Outstanding at December 31, 20198,771,928  $1,000  1,000  8,773,928  
Exercise price$7.13  $0.01  $ 0.00  
Accounting for the Pre-Merger Financing Warrants
Although the Pre-Merger Financing Warrants were issued on October 4, 2019, the agreement for issuance of the Pre-Merger Financing Warrants was a firm commitment reached between Ocugen and the Investors as part of the Financing SPA upon the closing of the Merger. Therefore, for accounting purposes the issuance date was determined to be the date of the Merger. As of the date of the Merger, the Series A Warrants and Series C Warrants were classified as equity and the Series B Warrants were classified as a liability on the consolidated balance sheet.
The Series B Warrants were classified as a liability as they did not meet the derivative scope exception related to equity indexation because the Reset Date was triggered on the effective date of a Registration Statement and the timing of when a Registration Statement for the underlying shares is available is not an input in an option pricing model. Series B Warrants were classified as a derivative liability in the consolidated balance sheet measured at fair value on September 27, 2019 and marked to market at September 30, 2019. Upon the completion of the Reset Period, the Series B Warrants were reassessed and determined to meet the derivative scope exception allowing for equity classification. The Series B Warrants were marked to market a final time as a change in the fair value of a derivative liability and the remaining liability balance was reclassified to equity. Subsequent to the Reset Period, almost all of the Series B Warrants were exercised for shares of common stock.
The following table provides a roll-forward of the Series B Warrant liability:
Amount
Balance at January 1, 2019$— 
Fair value at issuance (September 27, 2019)9,387,760 
Change in fair value of embedded derivatives1,867,980 
Amount reclassified to equity(11,255,740)
Balance at December 31, 2019$— 
F-22

The fair value of the Series B Warrants upon issuance was calculated using a Monte Carlo simulation while estimating the stock price during the 45-day Reset Period, based on the terms described within the Financing SPA. Key fair value inputs included the starting stock price, expected stock volatility during the 45-day Reset Period, and additional shares issued from escrow. The methodology for measuring fair value was sensitive to the expected stock volatility assumption input mentioned above. The volatility used in the fair value estimate at issuance was 96.0%. Inputs used in the valuation are unobservable and are therefore classified as Level 3 fair value inputs. The fair value of the Series B Warrants upon the end of the Reset Period was based on a Black-Scholes valuation model, which is classified as Level 3 in the fair value hierarchy.
Accounting for the Warrant Amendments
The Company accounted for the Warrant Amendments as a modification by assessing whether the modification resulted in an incremental fair value of the warrants. An increase in fair value resulting from the modification may be recognized as expense in the consolidated statements of operations and comprehensive loss, whereas a decrease in fair value is not recognized. The Company determined that the modifications to the Series A Warrants and Series B Warrants were not substantive amendments that would result in an increase in fair value based on a qualitative assessment of the terms of the amendments. The Series C Warrants were determined to substantially modified. The Company estimated the fair value of the Series C Warrants immediately prior to and immediately after the modification and concluded that the fair value of the warrants decreased and therefore there was no incremental fair value to recognize resulting from the modification.
Former Ocugen Warrants
Prior to 2018, Former Ocugen issued warrants to investors ofyear ended December 31, 2021, the Company pursuantrecognized a deferred income tax benefit of $0.1 million due to a stockholders' agreement and to 2 employees of the Company pursuant to their respective employment agreements. As of December 31, 2019 and 2018, 0.9 million warrants to purchase common stock were outstanding and exercisable and had a weighted average exercise price of $5.67 per share. The warrants expire between 2025 and 2027.
11. Income Taxes
an asset acquisition. For the years ended December 31, 20192020 and 2018,2019, the Company did not recognize any current or deferred income tax expense or benefit due to the current and historical losses incurred by the Company.benefit. Losses before income taxes were $20.2$58.4 million, $21.8 million, and $18.2$20.2 million for the years ended December 31, 20192021, 2020, and 2018,2019 respectively, substantially all of which were incurred in the United States.
F-23The reconciliation of federal statutory income tax to the Company's provision for income taxes is as follows:
As of December 31,
202120202019
Expected provision at statutory rate21.0 %21.0 %21.0 %
State tax - net of federal benefit7.9 %7.5 %5.3 %
Tax credits3.2 %2.8 %3.2 %
Permanent differences(0.1)%(1.0)%(8.1)%
Other— %1.1 %2.9 %
Change in valuation allowance(31.9)%(31.4)%(24.3)%
Total provision for income taxes0.1 %— %— %

Deferred taxes are recognized for temporary differences between the basis of assets and liabilities for financial statement and income tax purposes. The significant components of the Company’s deferred tax assets and liabilities as of December 31, 2021 and 2020 are comprised of the following:following (in thousands):
As of December 31,
20212020
Deferred tax assets:
Net operating loss carryforwards$52,038 $35,714 
Capital loss carryforwards7,298 7,298 
Start-up costs11,235 11,235 
Accruals and reserves448 398 
Intellectual property amortization1,960 2,285 
Stock-based compensation expense2,064 1,290 
Tax credits4,350 2,541 
Lease liability461 125 
Total deferred tax assets79,854 60,886 
Valuation allowance(79,395)(60,761)
Deferred tax assets, net of allowance$459 $125 
Deferred tax liabilities:
Lease right-of-use assets(459)(125)
Net deferred tax assets$— $— 
As of December 31,
20192018
Deferred tax assets:
Net operating loss carryforwards$31,575,288  $6,864,360  
Capital loss carryforwards7,298,052  —  
Start-up costs11,234,751  —  
Accruals and reserves166,611  35,645  
Intellectual property amortization555,352  121,694  
Stock-based compensation expense1,123,100  993,234  
Convertible debt—  498,236  
Tax credits1,926,677  548,399  
Lease liability96,895  —  
Total deferred tax assets53,976,726  9,061,568  
Valuation allowance(53,877,168) (9,061,568) 
Deferred tax assets, net of allowance$99,558  $—  
Deferred tax liabilities:
Lease ROU asset(99,558) —  
Net deferred tax assets$—  $—  
F-28

The Company has evaluated the positive and negative evidence bearing upon its ability to realize its deferred tax assets. Management has considered the Company’s history of cumulative net losses, estimated future taxable income, and prudent and feasible tax planning strategies and has concluded that it is more likely than not that the Company will not realize the benefits of its deferred tax assets. Accordingly, a full valuation allowance has been established against these net deferred tax assets as of December 31, 2021 and 2020, respectively. The Company’s valuation allowance increased during 2021 by approximately $18.6 million primarily due to the generation of net operating losses and research and development and orphan drug credit carryforwards.
As of December 31, 20192021 and 2018,2020, the Company had U.S. federal net operating loss ("NOL") carryforwards of $113.6$184.4 million and $23.7$128.0 million, respectively, which may be available to offset future income tax liabilities. The Tax Cut and Jobs Act, which was enacted in December 2017, will generally allow federal losses generated after 2017 to be carried over indefinitely, but will generally limit the NOL deduction to the lesser of the NOL carryover or 80% of a corporation’s taxable income.income (subject to Section 382 of the Internal Revenue Code of 1986, as amended ("IRC")). In addition, there will be no carryback for losses generated after 2017. Losses generated prior to 2018 will generally be deductible to the extent of the lesser of a corporation’s NOL carryover or 100% of a corporation’s taxable income and will be available for twenty years from the period the loss was generated. The Company has federal NOLs generated after 2017 of $61.2$131.8 million, which do not expire. The federal NOLs generated prior to 2018 of $52.4$52.6 million will expire at various dates through 2037. In addition, the Company has a capital loss carryforward of $26.7 million which may be available to offset future capital gains and does not expire until 2024.
As of December 31, 20192021 and 2018,2020, the Company also had U.S. state NOL carryforwards of $112.4$183.1 million and $23.7$126.7 million, respectively, which may be available to offset future income tax liabilities and expire at various dates through 2039.2041.
As of December 31, 20192021 and 2018,2020, the Company hashad federal tax credit carryforwards of approximately $1.6$3.8 million and $0.8$2.2 million, respectively, which are available to offset future federal tax liabilities which expire at various dates through 2039.2041. As of December 31, 20192021 and 2018,2020, the Company hashad state tax credit carryforwards of approximately $0.4$0.7 million and $0.1$0.5 million, respectively, which are available to reduce future tax liabilities whichand expire at various dates through 2034.
The Company has recorded a full valuation allowance against its net deferred tax assets as of December 31, 2019 and 2018 because the Company has determined that is it more likely than not that these assets will not be fully realized due to the Company's history of operating losses and lack of available evidence supporting future taxable income. The Company experienced a net change in valuation allowance of $44.8 million during the year ended December 31, 2019, primarily related to the increase in NOL carryforwards. The increase in the federal and state NOL carryforwards during the year ended December 31, 2019 was primarily due to the acquired NOL carryforwards as a result of the Merger.

2036.
Under the provisions of the IRC, the NOL and tax credit carryforwards are subject to review and possible adjustment by the Internal Revenue Service and state tax authorities. Utilization of U.S. federal and state operating lossNOL and tax credit carryforwards may be subject to a substantial annual limitation under Section 382 and Section 383 of the Internal Revenue Code of 1986, as amended,IRC, and corresponding provisions of state law, due to ownership changes that have occurred previously or that could occur in the future. These ownership changes may limit the amount of NOL and tax credit carryforwards that can be utilized annually to offset future taxable income and tax liabilities, respectively. The Company acquired a significant amount of federal and state NOL carryforwards and federal and state tax credit carryforwards as a result of the Merger.
The Company
F-24

has not yet conducted a comprehensive study to assess whether a change of ownership has occurred, or whether there have been multiple ownership changes since its formation. Any limitation may result in expiration of a portion of the NOL carryforwardcarryforwards or tax credit carryforwards before utilization, which would be offset by a change in the Company's valuation allowance. Further, until a study is completed by the Company and any limitation is known, no amounts are being presented as an uncertain tax position.
The reconciliationCompany has not yet conducted a study of federal statutory income tax credit carryforwards. Such a study, once undertaken by the Company, may result in an adjustment to its tax credit carryforwards; however, until a study is completed and any adjustment is known, no amounts are being presented as an uncertain tax position. A full valuation allowance has been provided against the Company’s tax credits and, if an adjustment is required, this adjustment would be offset by an adjustment to the Company's provision for income taxesvaluation allowance. Thus, there would be no impact to the consolidated balance sheets or consolidated statements of operations and comprehensive loss if an adjustment is as follows:required.
As of December 31,
20192018
Expected provision at statutory rate21.0 %21.0 %
State tax - net of federal benefit5.3 %7.6 %
Research and development credits3.2 %2.1 %
Permanent differences(8.1)%(0.8)%
Other2.9 %0.0%
Change in valuation allowance(24.3)%(29.9)%
Total provision for income taxes— %— %
F-29

A reconciliation of the beginning and ending amount of unrecognized tax benefits is as follows:
Amount
Gross unrecognized tax benefits as of December 31, 2018$— 
Additions for tax positions taken in a prior year303,050 
Additions for tax positions taken in the current year— 
Reductions for tax positions taken in the prior year due to settlement— 
Reductions for tax positions taken in the prior year due to statutes lapsing— 
Gross unrecognized tax benefits as of December 31, 2019$303,050 
follows (in thousands):
Year ended December 31,
202120202019
Gross unrecognized tax benefits at beginning of year$303 $303 $— 
Additions for tax positions taken in a prior year— — 303 
Additions for tax positions taken in the current year— — — 
Reductions for tax positions taken in the prior year due to settlement— — — 
Reductions for tax positions taken in the prior year due to statutes lapsing— — — 
Gross unrecognized tax benefits at end of year$303 $303 $303 

The uncertain tax positions giving rise to the unrecognized tax benefits of $0.3 million at December 31, 20192021 relate to the timing of certain income and deductions for federal income tax purposes taken by Histogenics prior to the Merger. The reversal of unrecognized tax benefits would not have any impact on the effective tax rate in the future periods and is not expected to create cash tax liability.
The Company files tax returns as prescribed by the tax laws of the jurisdictions in which it operates. In a normal course of business, the Company is subject to examination by federal and state jurisdictions, where applicable. The Company’s tax years are still open under status from 20162018 to present.
13.    Net Loss per Share of Common Stock
12.The following table sets forth the computation of basic and diluted earnings per share for the years ended December 31, 2021, 2020, and 2019 (in thousands):
Year ended December 31,
202120202019
Net loss — basic and diluted$(58,365)$(21,822)$(20,243)
Deemed dividend related to Warrant Exchange— (12,546)— 
Net loss to common stockholders$(58,365)$(34,368)$(20,243)
Shares used in calculating net loss per share attributable to common stockholders — basic and diluted195,013,043 112,236,110 13,893,819 
Net loss per share attributable to common stockholders — basic and diluted$(0.30)$(0.31)$(1.46)
The following potentially dilutive securities have been excluded from the computation of diluted weighted-average shares outstanding, as their inclusion would have been antidilutive:
Year ended December 31,
202120202019
Options to purchase common stock10,086,167 4,224,433 731,189 
RSUs191,811 — — 
Warrants799,251 870,017 9,643,945 
Series A Convertible Preferred Stock (as converted to common stock)3,115 — — 
Series B Convertible Preferred Stock (as converted to common stock)547,450 — — 
Total11,627,794 5,094,450 10,375,134 

F-30

14.    Subsequent EventsCommitments and Contingencies
On March 26, 2020, theCommitments
The Company borrowed an additional $0.5 millionhas commitments under the termscertain license and conditions of the EB-5 Loan Agreement. Outstanding borrowings pursuant to the EB-5 Program, including accrued interest, become duedevelopment agreements, lease agreements, debt agreements, and consulting agreements. Commitments under certain license and development agreements include annual payments, payments upon the seventh anniversaryachievement of certain milestones, and royalty payments based on net sales of licensed products (see Note 3). Commitments under lease agreements are future minimum lease payments (see Note 6). Commitments under debt agreements are the final disbursement. Following this borrowing, totalfuture payment of principal outstandingand accrued interest under the EB-5 Loan Agreement (see Note 8). Commitments under consulting agreements include payments upon the achievement of certain milestones related to COVAXIN (see Note 10). Additionally, subsequent to December 31, 2021, the Company entered into supply commitments related to COVAXIN. See Note 15 for additional information.
Contingencies
On June 17, 2021, a securities class action lawsuit was filed against the Company and certain of its officers and directors in the U.S. District Court for the Eastern District of Pennsylvania (Case No. 2:21-cv-02725) that purported to state a claim for alleged violations of Sections 10(b) and 20(a) of the Securities Exchange Act of 1934 (the "Exchange Act") and Rule 10b-5 promulgated thereunder, based on statements made by the Company concerning the announcement of the Company's decision to pursue the submission of a BLA for COVAXIN for adults ages 18 years and older rather than pursuing EUA for the vaccine candidate. On July 16, 2021, a second securities class action was filed against the Company and certain of its officers and directors in the U.S. District Court for the Eastern District of Pennsylvania (Case No. 2:21-cv-03182) that also purported to state a claim for alleged violations of Sections 10(b) and 20(a) of the Exchange Act and Rule 10b-5 promulgated thereunder, based on the same statements as the first complaint. The complaints seek unspecified damages, interest, attorneys’ fees, and other costs.
On August 30, 2021, a stockholder derivative lawsuit was filed derivatively on behalf of the Company against certain of its officers and directors and the nominal defendant Ocugen in the U.S. District Court for the Eastern District of Pennsylvania (Case No. 2:21-cv-03876) that purported to state a claim for breach of fiduciary duty and contribution for violations of Sections 10(b) and 21(d) of the Exchange Act, based on facts and circumstances relating to the securities class action lawsuits and seeking contribution and indemnification in connection with claims asserted in the securities class action lawsuits. On September 22, 2021, a second stockholder derivative lawsuit was filed derivatively on behalf of the Company against certain of its officers and directors and the nominal defendant Ocugen in the U.S. District Court for the Eastern District of Pennsylvania (Case No. 2:21-cv-04169) that purported to state a claim for breach of fiduciary duties, unjust enrichment, abuse of control, waste of corporate assets, and contribution for violations of Sections 10(b) and 21(d) of the Exchange Act, based on the same allegations as the first complaint. The parties to both stockholder derivative lawsuits have stipulated to the consolidation of the two stockholder derivative lawsuits and also have submitted to the court in each action a proposed order requesting a stay of the litigation pending a decision on any motion to dismiss filed in the securities class action lawsuits, which remains pending before each court, and this status could change.
The Company believes that the lawsuits are without merit and intends to vigorously defend against them. At this time, no assessment can be made as to their likely outcome or whether the outcome will be material to the Company. No information is $1.5 million.available to indicate that it is probable that a loss has been incurred and can be reasonably estimated as of the date of the consolidated financial statements and, as such, no accrual for the loss has been recorded within the consolidated financial statements.
15.    Subsequent Events
Non-Binding Letter of Intent with Liminal Biosciences Inc.
On January 24, 2022, the Company entered into a non-binding letter of intent ("LOI") with Liminal Biosciences Inc. ("Liminal") for the acquisition of Liminal's manufacturing site in Belleville, Ontario for a combination of cash and warrants to purchase the Company's common stock. As consideration for entering into the LOI, the Company issued warrants to purchase 2.3 million shares of the Company's common stock at an exercise price of $3.76, subject to certain adjustments. The Liminal Warrants vest and become exercisable upon closing of the transactions contemplated by the LOI and terminate on the tenth
F-25F-31

anniversary of the issuance date, unless earlier terminated in accordance with their terms. The Liminal Warrants are cancellable by the Company in the event the transactions contemplated by the LOI are not consummated.
Completion of the transaction proposed in the LOI is subject to finalization of due diligence investigations by the parties, the negotiation and execution of definitive transaction agreements, and other customary closing conditions including certain funding requirements. The LOI may be terminated at any time by mutual written consent of the Company and Liminal, among the other termination provisions contained in the LOI.
COVAXIN Drug Product Components Purchase
In February 2022, the Company entered into a commitment to purchase $14.3 million of COVAXIN drug product components from Bharat Biotech to support the technology transfer from Bharat Biotech to Jubilant HollisterStier. The Company previously issued the Series B Convertible Preferred Stock in March 2021 as an advance payment of $6.0 million for the supply of COVAXIN to be provided by Bharat Biotech pursuant to the Supply Agreement, which will be applied to this commitment.
Public Offering of Common Stock
On February 22, 2022, the Company entered into an underwriting agreement (the “Underwriting Agreement”) with Cantor Fitzgerald & Co. (“Cantor”) pursuant to which the Company agreed to issue and sell 16.0 million shares of the Company’s common stock to Cantor at an offering price of $3.13 per share (the “Public Offering”). Pursuant to the terms of the Underwriting Agreement, the Company also granted Cantor a 30-day option to purchase up to an additional 2.4 million shares of the Company’s common stock at a price of $3.13 per share. The closing of the Public Offering occurred on February 25, 2022, and the Company received net proceeds of $49.8 million, after deducting the underwriting discounts and commissions and estimated offering expenses payable by the Company. The Public Offering was made pursuant to the Company’s Registration Statement on Form S-3ASR (File No. 333-254550), which was previously filed with the SEC and became automatically effective on March 22, 2021, as supplemented by a prospectus supplement, dated February 22, 2022.
F-32