ocgn-20211231

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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

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FORM 10-K

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(Mark One)

For the fiscal year ended December 31, 2021

Commission File Number 001-36751

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OCUGEN, INC.

(Exact Name of Registrant as Specified in its Charter)

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263 Great Valley Parkway

Malvern,Pennsylvania19355

(Address of principal executive offices, including zip code)

(484) 328-4701

(Registrant’s telephone number, including area code)

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Securities registered pursuant to Section 12(b) of the Act:

Title of each class Tradingsymbol(s) Name of each exchangeon which registered

Common Stock OCGN The Nasdaq Stock Market LLC(The Nasdaq Capital Market)

Securities registered pursuant to section 12(g) of the Act: None

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Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act.

Yes ☒ No ☐

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act.

Yes ☐ No ☒

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 ☒ No ☐

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 ☒ No ☐

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.

Large accelerated filer ☒ Accelerated filer ☐

Non-accelerated filer ☐ Smaller 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 13(a) of the Exchange 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. ☒

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

As of June 30, 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 $1.6 billion, based upon the closing price of the registrant's common stock on June 30, 2021.

As of February 21, 2022, there were 199,488,183 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 2022 annual meeting of stockholders to be filed no later than 120 days after the end of the registrant’s fiscal year ended December 31, 2021.

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FORWARD LOOKING STATEMENTS

Part I

Item 1. Business 1

Item 1A. Risk Factors 37

Item 1B. Unresolved Staff Comments 85

Item 2. Properties 86

Item 3. Legal Proceedings 86

Item 4. Mine Safety Disclosures 86

Part II

Item 7A. Quantitative and Qualitative Disclosure About Market Risk 99

Item 8. Financial Statements and Supplementary Data 99

Item 9A. Controls and Procedures 99

Item 9B. Other Information 100

Part III

Item 10. Directors, Executive Officers, and Corporate Governance 101

Item 11. Executive Compensation 101

Item 14. Principle Accountant Fees and Services 101

Part IV

Item 15. Exhibits and Financial Statement Schedules 102

Signatures

Consolidated Financial Statements F-1

Unless the context otherwise requires, references to the “Company,” “we,” “our,” or “us” in this report refer to Ocugen, Inc. and its subsidiaries, and references to “OpCo” refer to Ocugen OpCo, Inc., the Company’s wholly owned 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,” 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 funding to continue to advance our 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 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; including the extent to which developments with respect to the COVID-19 pandemic will affect the regulatory pathway available for COVID-19 vaccines in the United States, Canada, or other jurisdictions;

•the performance of third-parties upon which we depend, including contract development and manufacturing organizations ("CDMOs"), suppliers, 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;

•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") compliance, and other relevant regulatory 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.

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 ® 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 or trademarks, as applicable. All tradenames, trademarks, and service marks 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. Business.

OVERVIEW

We are a clinical-stage biopharmaceutical company focused on developing gene therapies to 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 co-developing COVAXIN with Bharat Biotech for the U.S. and 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"), 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, 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 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 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 trial 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 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-

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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 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 designed to fulfill unmet medical needs in the area of retinal diseases, including inherited retinal diseases ("IRDs"), such as RP and LCA, and dry AMD. Our modifier gene therapy platform is based on 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 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 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 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 four Orphan Drug Designations ("ODDs") from the FDA 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 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 ("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 currently evaluating options to initiate OCU400 clinical trials in 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. We are currently executing pre-IND studies consistent with FDA discussions to support a Phase 1/2 clinical trial.

Novel Biologic Therapy for Retinal Diseases

Our pipeline also includes our biologic product candidate, OCU200, a novel fusion protein designed to treat severely sight-threatening diseases such as DME, DR, and wet AMD. We are currently establishing a cGMP process for the production of clinical trial materials and executing pre-IND studies consistent with FDA discussions to support a Phase 1/2a clinical trial.

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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 save lives from COVID-19 and cure blindness diseases. Key elements of the strategy we employ to accomplish this mission include:

•Advancing 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 through 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 severely sight-threatening diseases such as DME, DR, and Wet AMD. We are currently executing pre-IND studies consistent with FDA discussions to support a Phase 1/2a clinical trial.

•Expanding and exploring partnerships with current and future key collaborators and commercial partners to maximize patient access, global reach, and the value of our product candidates, as well as to expand our product candidate pipeline. We intend to explore strategic licensing, acquisition, and collaboration opportunities with qualified partners to maximize the benefit of our product candidates on patients globally and to expand our product candidate pipeline to support our future growth.

COMPETITIVE STRENGTHS

Our key competitive strengths include:

•Experienced Management Team and Esteemed Scientific Advisory Boards. Our management team and key advisors have extensive experience with a proven track record of success in developing, launching, and managing the life cycle of many vaccines and biopharmaceuticals at leading pharmaceutical 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 the 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 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 product candidate pipeline is summarized in the following chart:

COVID-19 VACCINE PRODUCT CANDIDATE

COVAXIN is a whole-virion inactivated COVID-19 vaccine candidate being developed for the prevention of COVID-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 was granted an EUL by the WHO in November 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 Bharat Biotech.

Overview 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 highly transmissible disease that spreads 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 South 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 the other variants of 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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(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 common approach to vaccine design. COVAXIN is designed to utilize the whole-virion inactivated SARS-CoV-2 virus to trigger the immune 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 six 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 with funding from the National Institutes of Health ("NIH") and is the first adjuvant in an authorized or approved vaccine against an infectious disease to activate toll-like receptor 7/8. In addition, the alum in the adjuvant stimulates the immune system to search for an invading pathogen. Molecules that activate toll-like receptor 7/8 provide a powerful stimulation of the immune system.

The rise of COVID-19 genetic variants has raised concerns that these variants may be able to escape neutralization by vaccines. The data from clinical trials conducted in India suggest that COVAXIN elicits a broad-spectrum immune response (including spike and nucleocapsid proteins) and induces both humoral and cellular responses. In addition, COVAXIN is designed to generate 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 currently authorized or approved messenger RNA ("mRNA") and adenovirus-based vaccines. The beneficial characteristics of COVAXIN are described in the figure below (Figure 1).

Figure 1: Beneficial characteristics of COVAXIN.

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 COVAXIN is inactivated using β-propiolactone treatment at a low temperature. As an inactivated virus vaccine, we believe COVAXIN can use all the proteins in the virus to elicit an immune response, rather than

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targeting the spike protein alone. We believe an inactivated whole-virion vaccine can produce a more robust response that can elicit memory and cross-react with mutated strains. Once vaccinated with COVAXIN, the immune system can respond to a live infection of SARS-CoV-2. COVAXIN is intended for administration into the deltoid muscle of the 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.

Phase 1 and Phase 2 clinical trials were conducted by Bharat Biotech in India to evaluate the safety and immunogenicity of COVAXIN. These clinical trials reported a favorable safety profile and strong Immunoglobulin G ("IgG") responses against the spike protein, the receptor-binding domain, and the nucleocapsid protein of SARS-CoV-2 along with strong cellular responses (Figure 2). Strong cellular responses are necessary for memory and long-term durability of vaccines.

Figure 2: Demonstration of broad-spectrum response of COVAXIN.

Figure 2 demonstrates the SARS-CoV-2 virus. COVAXIN demonstrates a strong IgG response against the spike protein, the receptor-binding domain, and the nucleocapsid protein of the SARS-CoV-2 virus. Current mRNA and adenovirus-based vaccines only elicit responses against the spike protein.

A Phase 3, randomized, placebo-controlled clinical trial was conducted in India by Bharat Biotech to evaluate 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 95% 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 protection against the 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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Figure 3: Composition of COVID-19 variants in symptomatic infections identified in the adult Phase 3 clinical trial in India.

Figure 3 displays the COVID-19 variants that caused symptomatic infections in the adult Phase 3 clinical trial conducted by Bharat Biotech in India. The majority of the cases were identified to be the Delta variant (B.1.617.2), followed by undisclosed variants, the Kappa variant (B.1.617.1), and the Alpha 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 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 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 the neutralizing antibody responses against the wild-type strain in the pediatric population ages two to 18 years were comparable 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 antibody titers against the spike protein, the receptor-binding domain, the nucleocapsid protein, and wild-type neutralizing antibodies. Among the 526 study subjects in the pediatric 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 production of the inactivated polio vaccine for the past 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 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 under the Minister of Health's Interim Order. Our submission was recommended and accepted under the Interim

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Order and transitioned to a NDS. The submission was conducted through our Canadian subsidiary, 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 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 and OCU410 using our modifier gene therapy platform to fulfill unmet medical needs in the area of retinal diseases, including IRDs, such as RP and LCA, and dry AMD. Our modifier gene therapy platform is a cutting-edge technology licensed from SERI, an affiliate of Harvard Medical School, and involves the targeted 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 genetically diverse IRDs and 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 replacement therapies have shown tremendous promise in rare retinal diseases, they are highly specific and cannot improve a multitude of disease-causing genetic defects. Our modifier gene therapy platform has the potential to restore retinal integrity and function across a range of genetically diverse IRDs and other degenerative retinal diseases providing us with significant potential long-term value.

Our 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 NR2E3, a member of the NHR family, is a dual activator and repressor that, with other transcription factors, modulates cell fate and differentiation of rod and 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 rescues degenerating retina by resetting the homeostatic state of key gene networks in the presence of a primary mutation.

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 from degeneration in patients with IRDs and improve patients' vision. It was also demonstrated preclinically that RORA offers a protective allele in AMD where the loss of photoreceptor cells leads to blindness. NR2E3 regulates 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.

Results of Preclinical Studies Support the Potential Efficacy of NR2E3 Modifier Gene Therapy

The efficacy of Nr2e3 was evaluated in five unique mouse models of IRDs in which treatment with the adeno-associated viral ("AAV")8-Nr2e3 gene by subretinal injection effectively rescued multiple genetically diverse IRDs by protecting photoreceptors from further damage after disease onset. These models represent a heterogeneous group of diseases in humans and are relevant in establishing the modifier role of NR2E3. The five 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 Nr2e3rd7/J ("rd7"). rd1 is rod cGMP-specific 3', 5'-cyclic PDE6β 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. This preclinical data was published in Nature Gene Therapy.

This study showed that the administration of AAV8-Nr2e3 therapy improved clinical, histological, functional, and molecular disease outcomes in each of the five models of 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 single 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 4, Figure 6,and Figure 8) and advanced stages (Figure 5, Figure 7,and Figure 9) of IRDs and serve as a broad-spectrum gene therapy to reduce retinal degeneration.

Figure 4:AAV8-Nr2e3 early-stage outer nuclear layer ("ONL") rescue in IRD mouse models.

Figure 4 displays the cell layer numbers of the ONL from AAV8-Nr2e3 treated and untreated mice in different early-stage IRD models. These ONL photoreceptors induce phototransduction in the retina and thereby initiate the vision process. The normal mouse retina is comprised of 10 to 12 layers of rod and cone photoreceptor nuclei in the ONL. rd1 retinas showed a profound rescue of photoreceptor cells (six to eight layers of ONL) compared to the untreated eyes. Rho−/−, 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 that an increase of even 20% is significant. We believe Nr2e3 therapy has great promise in potentially restoring retinal development.

Figure 5:AAV8-Nr2e3 advanced stage ONL rescue in IRD mouse models.

Figure 5 displays the cell layer numbers of the ONL from AAV8-Nr2e3 treated and untreated mice in different advanced stage IRD models. Improvement varied from ~30 to 80% of the retina in the Rho−/−, RhoP23H, and rd16 AAV8-Nr2e3 treated mice, depending on distribution efficiency throughout the retina. Approximately three to five layers of ONL cells were preserved in Nr2e3 treated mice compared with untreated mice that show less than or equal to one layer of ONL remaining.

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Figure 6: Fundus imaging of AAV8-Nr2e3 early-stage rescues in IRD mouse models.

Figure 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.

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.

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.

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 cells in the eye. IRD disease 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 treated 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.

Analysis A within Figure 10 above displays the evaluation ofscotopic and photopic ERG B-wave amplitudes, which were evaluated at post-natal day 30 (B6 and rd1) or post-natal day 90 to 120 (Rho−/−, RhoP23H, and rd16) in AAV8-Nr2e3 treated and untreated mice. Analysis B above displays the percent increase in ERG B-wave responses in the treated IRD models.

Results of Preclinical Studies Support the Safety of NR2E3

The safety of Nr2e3 was evaluated in healthy mice following subretinal administration. B6 mice were treated with AAV8-Nr2e3-green fluorescent protein ("GFP") fusion construct at post-natal day zero and evaluated after both seven days and one month for any toxic effect as well as expression of Nr2e3-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 11). Also, there was no difference in retinal anatomy as indicated by fundus, histology (the cell layers), expression of opsin and rhodopsin proteins (immunohistochemistry), and retinal function (as indicated by ERG recording) between treated and untreated mice (Figure 11).

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Expression of enhanced GFP-Nr2e3 fusion protein was observed at post-natal day 30 in treated animals. In this Study, overexpression of the Nr2e3 protein following subretinal injection of AAV8-Nr2e3 was well-tolerated.

Figure 11: Overexpression of AAV8-Nr2e3 has no detrimental effects on the retina.

The analysis in Figure 11 above utilized a population size of five mice and displays the B6 control AAV8-Nr2e3 treated mice showing no abnormalities. Analysis A above displays the following: fundus, H/E staining, blue opsin, green opsin, and rhodopsin labeling of photoreceptor cells. Analysis B above displays the ERG response of the B6 control in both treated and untreated mice. The mice were injected at post-natal day zero and tissue was collected at post-natal day 30. Analysis C above displays the GFP label of AAV8-Nr2e3-GFP injected at post-natal zero with GFP expression assessed at both post-natal day seven and post-natal day 30.

Overview of IRDs 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 sustained restoration of normal retinal function for a mutated gene, but such therapies can only address one gene at a time, limiting their potential therapeutic use. Developing a custom gene therapy for each of the more than 175 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. For example, the genetic mutations of approximately 40% of RP patients remain unknown with few or no known therapeutic 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 and LCA.

RP is a group of rare, genetic disorders that involve a breakdown and loss of cells in the retina that affects approximately one in every 4,000 individuals. Common 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 two million individuals worldwide. 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 gene-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.

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Similar to RP, no or minimal treatment options are available for a large number of other retinal degenerative diseases, including dry AMD and LCA. AMD is attributed to the thinning of the macula of the retina, which 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.

OCU400 for IRDs

OCU400 is our first product candidate being developed with our modifier gene therapy platform. OCU400 is a 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 AAV8 vector that has the potential to be used as a gene therapeutic not only for the treatment of retinal diseases associated with mutations in genes such as NR2E3, RHO, CEP290, and PDE6ß, but also other gene mutations associated with IRDs, including 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 four ODDs from the FDA for the 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 NR2E3 and RHO disease genotypes, which 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.

OCU410 for the Treatment of Dry AMD

OCU410 is a modifier gene therapy product candidate being developed for the treatment of dry AMD. OCU410 utilizes an AAV delivery platform for the retinal delivery of the RORA gene. Various genetic 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. We are currently executing pre-IND studies consistent with FDA discussions to support a Phase 1/2 clinical trial for OCU410.

NOVEL BIOLOGIC PRODUCT CANDIDATE FOR RETINAL DISEASES

OCU200 is our novel biologic product candidate in preclinical development. OCU200 is a novel fusion protein designed to treat severely sight-threatening diseases like DR, DME, and wet AMD. We are currently establishing a cGMP process for the production of clinical trial materials and executing 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 can block blood vessels in the retina and cut off the blood supply, leading to damage to the blood vessels in the retina. DR is classified as two subtypes: non-proliferative DR and proliferative DR. Non-proliferative DR is the early-stage in which blood vessels are not able to grow, blood vessel walls weaken, and nerve fibers in the retina may swell. Proliferative DR is the advanced stage in which damaged blood vessels are closed off, leading to growth of new abnormal blood vessels in the retina. This growth of new abnormal blood vessels in the retina can lead to scar tissue, which can result in the detachment of the retina from the back of the eye.

Complications from DR could lead to DME. In DME, bulges can protrude from the vessel walls, leading to the leakage of fluid and blood into the retina. This leakage results in swelling, or “edema,” in the macula, which is a part of the retina. DME may occur at any stage of DR, but is more likely to occur later as the disease progresses. DME is the most common reason for vision loss for patients with DR.

DR and 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. The number of people affected by DR and DME is expected to 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-vascular endothelial growth factor ("VEGF") therapy, and corticosteroids, which are sub-optimally active in these patients. Anti-VEGF therapy does not work effectively in approximately 50% of DME patients.

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 corticosteroid therapy. The development of a therapeutic which targets multiple causative pathways of DR and DME, such as angiogenesis, oxidation, and inflammation, would offer a potential treatment option for all of these patients. We believe that OCU200 possesses 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. Most AMD cases begin as dry AMD and may progress towards the advanced “wet” form, which is characterized by penetration of abnormal blood vessels in the retina that 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 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 macula. Wet AMD affects approximately 10-15% of AMD patients, but progresses more rapidly and is known to be responsible for approximately 90% of acute blindness.

AMD is a leading cause of blindness in people over the age of 65 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 million patients in the United States have some form of AMD of which, approximately 1.1 million, or 10%, suffer from wet AMD. Approximately 0.2 million new cases of wet AMD are diagnosed each year in the United States.

Current FDA approved therapeutics for wet AMD include intravitreal injection of either ranibizumab or aflibercept, which target VEGF. Though treatments have been effective in mitigating the disease symptoms, clinical studies suggest substantial limitations remain. For example, a significant percentage of people do not respond to therapy and experience continuous deterioration of their vision. Additionally, the repeated use of anti-VEGF therapy becomes less effective over time. Between 30-50% of people affected by wet AMD continue to have fluid remain in the middle of the eye, also called the subretinal space, even after one to two years of treatment.

Given the above limitations of these existing treatments, we believe that a substantial unmet medical need 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 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 specifically focusing on non-responders to currently available treatment options.

OCU200 demonstrated potential therapeutic benefit in different animal models of neovascularization. In an animal model for DME and DR (oxygen-induced retinopathy in mice), OCU200, 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 (laser induced choroidal neovascularization 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 leaky blood vessels and subsequent disease symptoms (Figure 12).

Figure 12:OCU200 demonstrated efficacy in animal models for DR, DME, and Wet AMD.

COMPETITION

The biopharmaceutical industry is characterized by rapidly advancing technologies as well as a strong emphasis on intellectual 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 from major pharmaceutical companies, specialty pharmaceutical companies, biotechnology companies, 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 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.

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, Inc., IVERIC bio, Inc., MeiraGTx Holdings plc, Nanoscope Therapeutics, Inc., ProQR Therapeutics N.V., REGENXBIO Inc., Novartis AG, and Spark Therapeutics, Inc. Spark Therapeutics, Inc.'s product Luxturna, which is currently the only gene therapy approved to treat IRDs in the United States, addresses only RPE65 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 F. Hoffmann-La Roche 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 have marketed anti-VEGF products.

Many of our competitors, either alone or with strategic partners, may have significantly greater financial resources to support research and development, manufacturing, preclinical 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, licensing or acquiring technologies necessary for our programs, and in our commercialization efforts if our product candidates are authorized or approved. 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.

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 our manufacturing processes for both the clinical and commercial supply of our product candidates. We collaborate with our manufacturing partners to understand and establish controls for critical process parameters and critical quality attributes. Our in-house expertise includes personnel with extensive product development and commercialization experience who actively manage our manufacturing partners that produce products in our product candidate pipeline, including active involvement in the 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.

Clinical and Commercial Supply of COVAXIN

Pursuant to the Covaxin Agreement with Bharat Biotech, we obtained an exclusive 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 process of transferring to us certain proprietary technology owned or controlled by Bharat Biotech that is necessary for the commercial manufacture and supply 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. We 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 Commercial 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 COVAXIN 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 consolidated financial statements included elsewhere in this Annual Report on Form 10-K.

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Clinical and Commercial Supply of OCU400 and OCU410

We are party to a co-development and commercialization agreement with CanSinoBIO with respect to the development and commercialization of OCU400 and OCU410 (the "CanSinoBIO Agreement"). The CanSinoBIO Agreement was originally entered into in September 2019 with respect to OCU400 and was subsequently amended in September 2021 to include OCU410. Pursuant to the CanSinoBIO Agreement, we 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 license to develop, manufacture, and commercialize OCU400 and OCU410 in and for China, Hong Kong, Macau, and Taiwan (the “CanSinoBIO Territory”), and we maintain exclusive development, manufacturing, and commercialization rights with respect to OCU400 and OCU410 outside the CanSinoBIO Territory (the “Company Territory”).

We work with CanSinoBIO for the process development, manufacturing, testing, and release of drug products for use in pre-IND studies and clinical trials. We perform discovery and analytical 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, see “—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 the first product manufactured in the manufacturing 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 the consolidated financial statements included elsewhere in this Annual Report on Form 10-K.

LICENSE AND DEVELOPMENT AGREEMENTS

We are party to license and development agreements under which we license or co-own patents, patent applications, technical information, and other intellectual property for our product candidates: COVAXIN, OCU400, OCU410, 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, we 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 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 perfection and maintenance of the patents for OCU200.

The CU Agreement requires the payment for certain regulatory milestones aggregating to $1.5 million, an 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.

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 our product candidates. We intend to maintain and defend our intellectual property rights to protect our technology, inventions, processes, and improvements that are commercially important to the development of our business. There is no guarantee that any of our current or future intellectual property will advance the commercial success of our product 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 February 15, 2022, our patent portfolio included a total of eight issued patents in the United States, 38 issued or registered patents in foreign countries, three pending patent applications in the United States, and seven pending patent applications in foreign countries. Our issued or registered patents and pending patent applications include 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, methods of use, product candidates, and other proprietary technology. As of February 15, 2022, we had exclusive rights or owned rights to: (i) one issued U.S. patent, two pending U.S. patent applications, and three pending foreign patent applications related to OCU400; (ii) two pending U.S. patent applications 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. Our current portfolio of 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. 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 our 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.

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, discounts, 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.

FDA Regulation

In the United States, the FDA regulates biologics and drug products under the Federal Food, Drug, and Cosmetic Act ("FDCA") and its implementing regulations. In addition to the FDCA and its implementing regulations, biological products are regulated under the Public Health Service Act ("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") 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 U.S. clinical trial sites;

•approval by an Institutional Review Board ("IRB") for each clinical site, or centrally, before a clinical trial may be 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 biological product candidate for its intended use, performed in accordance with Good Clinical Practices ("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 in compliance with cGMP;

•submission to the FDA of a New Drug Application ("NDA"), in the case of a drug product candidate, or a BLA, in the case of a biological 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 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, and payment of user fees; and

•FDA review and approval of the NDA, or licensure of a BLA to permit commercial marketing for particular indications for 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 AWA, and other federal regulations and requirements. Prior to commencing the first clinical trial at a U.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. Some preclinical studies may continue even after the 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 may 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, 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 investigators. 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 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 its 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.

The FDA may also require, or companies may conduct, additional clinical trials for the same indication after a product is approved. These are 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.

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 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 is 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") 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 generally 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"), the FDA has set the review goal of completing its review of 90% of all applications for new molecular entities within 10 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 10 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 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 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"). 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.

For example, as a condition of approval of an NDA or BLA, the FDA may require post-marketing testing and surveillance to monitor the product’s safety or efficacy. In addition, holders of an 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 provide updated safety and efficacy information, 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 manufacturing facilities or at the facilities of third-party suppliers that may disrupt production or distribution or require substantial resources to correct and prevent recurrence of any deficiencies, and could result in fines or penalties by regulatory authorities. In addition, discovery of problems with a product or the failure to comply with applicable requirements may result in restrictions on a product, manufacturer, or holder of an approved BLA, including withdrawal or recall of the product from the market or other voluntary, FDA-initiated or judicial action, including warning letters, fines, injunctions, civil penalties, license revocations, seizure, total or partial suspension of production or criminal penalties, any of which could delay or prohibit further marketing. 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.

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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 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, reporting obligations, and restrictions on advertising and promotion. The EUA is only effective for the duration of the public health emergency. Although the criteria of an EUA differ from the criteria for approval of 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 guarantee that our product candidates will meet the criteria for 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 report 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 0.2 million individuals in the United States, or affecting more than 0.2 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 U.S. sales. ODD must be requested before submitting an 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 is considered by the FDA to be the same and is intended for the same indication. This hypothesis must be demonstrated to obtain ODD 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. 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 ODD generally is entitled to a seven-year exclusive marketing period in the 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 ODD exclusivity by means of greater effectiveness, greater safety, or providing a major contribution to patient care. ODD 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.

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 14 years from the product’s approval date. Subject to prior limitations, the period of 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 product 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 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 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" 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 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 10 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 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 extensive 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 quality-control to maintain compliance with 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. 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"), 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 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, refusal of orders under existing government contracts, exclusion from participation in federal and state healthcare programs, restitution, disgorgement, 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 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"). 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 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") 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 our 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" 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"), 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.

OCGN US Equity

OCGN · 10-K · period ended 2021-12-31

Item 1. Business.

OCGN US Equity☆

OCGN · 10-K · period ended 2021-12-31

Item 1. Business.

OCGN US Equity