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Item 1. Business

2021-03-01 compared with 2020-03-02 · 484 added, 414 removed, 264 unchanged (77% of the section changed)

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We have developed an extensive pipeline of therapies across multiple indications within these core focus areas.

We believe the historically unreliable and costly discovery and development process for new medicines is being replaced by the targeted engineering of biology at the genetic, molecular and cellular level.

We believe that our therapies differentiate us from our competition through a focus on advanced multigenic construction, unique delivery mechanisms, and controllable expression.

Our pipeline programs have the potential to help solve major outstanding technical and commercial challenges that continue to hinder the biopharmaceutical industry.

We believe that our array of technology platforms uniquely position us among other biotechnology companies to advance precision medicine.

We believe that our array of technology platforms uniquely positions us among other biotechnology companies to advance precision medicine.

Precision medicine is the practice of therapeutic product development that takes into account specific genetic variations within populations impacted by a disease to design targeted therapies to improve outcomes for a disease or patient population.

Our proprietary and complementary technology platforms provide a strong foundation to realize the core promise of precision medicine by supporting our efforts to construct powerful gene programs to drive efficacy, deliver these programs through viral, non-viral, and microbe-based approaches to drive lower costs, and control gene expression to drive safety.

Our therapeutic platforms, including UltraCAR-T, ActoBiotics, and AdenoVerse Immunotherapy, allow us to precisely control the level and physiological location of gene expression and modify biological molecules to control the function and output of living cells to treat underlying disease conditions.

We currently are advancing multiple product candidates through clinical trials, including UltraCAR-T therapies PRGN-3005, which targets the Mucin 16 antigen, or MUC16, on the cell surface of ovarian and other peritoneal cancers, and PRGN-3006, which targets the CD33 antigen on the cell surface of acute myeloid leukemia, or AML, blasts, as well as AG013 and AG019, which are based on our ActoBiotics platform and are being investigated for the treatment of oral mucositis, or OM, and recent-onset type 1 diabetes mellitus, or T1D, respectively.

In addition, we continue to rapidly advance earlier-stage preclinical programs across our core therapeutic areas.

Our therapeutic platforms, including UltraCAR-T, AdenoVerse immunotherapy, and ActoBiotics, are designed to allow us to precisely control the level and physiological location of gene expression and modify biological molecules to control the function and output of living cells to treat underlying disease conditions.

We are actively advancing our lead clinical programs, including:

PRGN-3005 and PRGN-3006, which are built on our UltraCAR-T platform;

PRGN-2009 and PRGN-2012, which are based on our AdenoVerse immunotherapy platform;

and AG019, which is built on our ActoBiotics platform.

In addition, we recently completed a Phase 1 study of INXN-4001, a non-viral triple-effector plasmid DNA, which is built on our UltraVector platform.

We have developed a proprietary electroporation device, UltraPorator, designed to further streamline and ensure the rapid and cost-effective manufacturing of UltraCAR-T therapies.

Our UltraPorator device received FDA clearance for manufacturing UltraCAR-T cells in clinical trials in October 2020, and we began dosing patients with UltraCAR-T cells manufactured with UltraPorator in our PRGN-3005 and PRGN-3006 clinical trials in November 2020.

We also have a robust pipeline of preclinical programs that we are pursuing in order to drive long-term value creation.

We exercise discipline in our portfolio management by systematically evaluating data from our preclinical programs in order to make rapid "go" and "no go" decisions.

Through this process, we believe we can more effectively allocate resources to programs that we believe show the most promise and advance such programs to clinical trials.

To guide our decision-making and operations, we have adopted the following tenets, which form the core of our operating ideology:

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• Rapid Execution .

Advance selected programs quickly to "go" and "no go" decisions and value inflection points.

Advance priority programs quickly to value inflection points.

• Strategic Partnerships .

Seek strategic partnerships to maximize value generation.

Our strategy is to use our discovery and clinical development infrastructure to continue advancement of our healthcare business with the goal of improving outcomes for patients with significant unmet medical needs.

Our strategy is to use our discovery and clinical development infrastructure to continue advancement of our clinical programs with the goal of improving outcomes for patients with significant unmet medical needs.

The key elements of our strategy include:

Advancing our lead programs and seeking opportunities to maximize their value.

We are actively advancing our lead programs, including:

PRGN-3005 and PRGN-3006, which are built on our UltraCAR-T platform;

AG019, which is built on our ActoBiotics platform;

and INXN-4001 non-viral triple effector plasmid DNA, which is built on our UltraVector platform.

PRGN-3005 is in a Phase 1 clinical trial for advanced ovarian cancer patients and PRGN-3006 is in a Phase 1/1b clinical trial for patients with relapsed or refractory AML or high-risk MDS.

The primary objective of the ongoing clinical studies is to determine the safety and maximum tolerated dose, or MTD, of PRGN-3005 and PRGN-3006.

AG019 is currently being studied in a Phase 1b/2a multi-center study conducted in participants with clinical recent-onset T1D.

INXN-4001 is being evaluated in a Phase 1 study to evaluate the safety of retrograde coronary sinus infusion of INXN-4001 in outpatient left ventricular assist device, or LVAD, recipients.

• Advancing our lead clinical stage programs and seeking opportunities to maximize their value.

We are actively advancing our lead programs that we believe have significant potential value.

We intend to efficiently pursue these programs toward clinical proof-of-concept and commercialization, whether independently or with collaborators.

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We exercise discipline in our portfolio management by systematically evaluating data from our preclinical programs in order to make rapid "go" and "no go" decisions.

Through this process, we can more effectively allocate resources to programs that we believe show the most promise and advance such programs to clinical trials.

Through this process, we believe we can more effectively allocate resources to programs that we believe show the most promise and advance such programs to clinical trials.

• Leveraging our technology and therapeutic platforms across indications.

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We continually assess the application of these technologies across therapeutic areas to determine where we can develop and provide unique solutions to challenges facing existing therapies.

In order to sharpen our focus on healthcare, solidify our capital position, and place our healthcare assets in the optimal position to succeed, in January 2020, we divested a number of our non-healthcare assets in two transactions to TS Biotechnology Holdings, LLC, or TS Biotechnology, a limited liability company managed by Third Security, LLC, or Third Security, which is a related party, and to Darling Ingredients, Inc., or Darling.

These sales are referred to collectively herein as the Transactions.

We also changed our company name to Precigen, Inc.

See "Non-Healthcare Assets and Transition to our Core Healthcare Business Model" below.

We have strategically focused our efforts on developing an innovative pipeline of therapies in immuno-oncology, infectious diseases, and autoimmune disorders based on our transformative UltraCAR-T, AdenoVerse immunotherapy, and ActoBiotics therapeutic platforms.

A core focus of our research and development programs has been an effort to address the drawbacks associated with conventional cell and gene therapy manufacturing approaches.

To this end, we are developing therapeutic candidates that reduce manufacturing risk by eliminating the need for centralized manufacturing and have invested in internal manufacturing capabilities to de-risk our clinical production.

Our Clinical Pipeline

Our Healthcare Subsidiaries

Our healthcare business is operated by our wholly owned subsidiaries PGEN Therapeutics, Inc., or PGEN or PGEN Therapeutics, Precigen ActoBio, Inc., or ActoBio, and Exemplar Genetics, Inc., or Exemplar, and also includes our majority ownership interest in Triple-Gene LLC, or Triple-Gene, as well as equity and royalty interests in therapeutics and therapeutic platforms from companies not controlled by us.

PGEN Therapeutics, Inc.

PGEN (formerly Precigen, Inc.) is a dedicated discovery and clinical stage biopharmaceutical company advancing the next generation of gene and cell therapies using precision technology to target urgent and intractable diseases in immuno-oncology, autoimmune disorders and infectious diseases.

PGEN operates as an innovation engine, progressing a preclinical and clinical pipeline of well-differentiated therapies toward clinical proof-of-concept and commercialization.

Our most advanced programs within PGEN include two therapies built on our UltraCAR-T platform, PRGN-3005, which is in a Phase 1 clinical trial for the treatment of advanced ovarian cancer, and PRGN-3006, which is in a Phase 1/1b clinical trial for the treatment of relapsed or refractory AML and higher-risk MDS.

In addition to our clinical programs, PGEN has a robust preclinical pipeline that includes PRGN-2009, an "off-the-shelf" therapy for human papillomavirus-positive, or HPV + , cancers developed using our AdenoVerse Immunotherapy platform, additional UltraCAR-T therapeutics for various cancers, additional "off-the-shelf" AdenoVerse Immunotherapeutics for infectious diseases, an AdenoVerse cytokine therapy for solid tumors, and PRGN-5001, a multifunctional therapeutic for solid tumors.

Precigen ActoBio, Inc.

ActoBio is pioneering a proprietary class of microbe-based biopharmaceuticals that enable expression and local delivery of disease-modifying therapeutics.

We refer to these microbe-based biopharmaceuticals as ActoBiotics.

Our ActoBiotics platform is a unique delivery platform precisely tailored for specific disease modification via local delivery directly to the relevant tissue.

ActoBiotics combine the advantages of highly selective protein-based therapeutic agents with local delivery by the well-characterized and food-grade bacterium Lactococcus lactis , or L.

ActoBiotics can be delivered orally in a capsule, through an oral rinse or in a topical solution.

We believe ActoBiotics have the potential to provide superior safety and efficacy via the sustained release of appropriate quantities of select therapeutic agents as compared to injectable biologics, while reducing the side effects commonly attributed to systemic delivery and corresponding peaks in concentration.

ActoBio, both independently and through a collaboration, has a clinical pipeline and a portfolio of candidates available for clinical development across a number of potential indications.

ActoBio's most advanced internal pipeline candidate, AG019, is currently in a Phase 1b/2a clinical trial for the treatment of recent onset T1D.

Another clinical candidate from ActoBio's platform, AG013, is being developed by our partner Oragenics, Inc., or Oragenics, a Florida corporation, and is in a Phase 2 clinical trial for the treatment of OM.

Triple-Gene LLC

Triple-Gene is a clinical stage gene therapy company focused on developing advanced treatments for complex cardiovascular diseases.

Triple-Gene's approach is to develop a holistic treatment for heart failure through improvements in angiogenesis, calcium homeostasis-associated cellular energetics, reductions in inflammatory signals, and the activation/recruitment of stem cells to support heart remodeling.

Triple-Gene's most advanced candidate, INXN-4001, a non-viral triple-effector plasmid designed for constitutive expression of human S100A1, SDF-1a, and VEGF-165 genes to address multiple pathways of heart failure, is currently in a Phase 1 clinical trial.

Exemplar Genetics, LLC

Exemplar is committed to enabling the study of life-threatening human diseases through the development of MiniSwine Yucatan miniature pig research models and services, as well as enabling the production of cells and organs in its genetically engineered swine for regenerative medicine applications.

Historically, researchers have lacked animal models that faithfully represent human diseases.

As a result, a sizeable barrier has blocked progress in the discovery of human disease mechanisms;

novel diagnostics, procedures, devices, prevention strategies and therapeutics;

and the ability to predict in humans the efficacy of those next-generation procedures, devices, and therapeutics.

Exemplar's MiniSwine models are genetically engineered to exhibit a wide variety of human disease states, which provides a more accurate platform to test the efficacy of new medications and devices.

Our Technology and Therapeutic Platforms

Our Technology Platforms

Our healthcare business is operated by our wholly owned subsidiaries PGEN Therapeutics, Inc., or PGEN Therapeutics, Precigen ActoBio, Inc., or ActoBio, and Exemplar Genetics, LLC, doing business as Precigen Exemplar, or Exemplar, and also includes our majority ownership interest in Triple-Gene LLC, doing business as Precigen Triple-Gene, or Triple-Gene, as well as equity and royalty interests in therapeutics and therapeutic platforms from companies not controlled by us.

PGEN Therapeutics

PGEN Therapeutics is a dedicated discovery and clinical stage biopharmaceutical company advancing the next generation of gene and cell therapies using precision technology to target urgent and intractable diseases in immuno-oncology, autoimmune disorders and infectious diseases.

PGEN Therapeutics operates as an innovation engine, progressing a preclinical and clinical pipeline of well-differentiated therapies toward clinical proof-of-concept and commercialization.

PGEN Therapeutics' Technology Platforms

We leverage a diverse portfolio of proprietary technology platforms to accelerate research and development efforts to deliver the promise of precision medicine.

Precigen's innovative technology platforms enable us to construct powerful, multigenic programs that we believe will drive efficacy, deliver multigenic constructs using viral, non-viral and microbe-based approaches that we believe will drive lower costs, and control expression of genes and performance of therapeutics in vivo for precise targeting of complex malignancies.

Precigen's innovative technology platforms enable us to construct powerful, multigenic programs that we believe will drive efficacy, deliver multigenic constructs using viral and non-viral approaches that we believe will drive lower costs, and control expression of genes and performance of therapeutics in vivo for precise targeting of complex malignancies.

The following discussion describes the technology platforms that we use for our approach to precision medicine.

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Expression of our membrane-bound interleukin-15, or mbIL15, gene improves functional characteristics of certain immune cells, including T cells, by enhancing their potential for expansion and persistence.

We deliver gene programs via viral, non-viral, and microbe-based approaches, including Sleeping Beauty , AttSite recombinases, gorilla adenoviral vectors, from our AdenoVerse library, and L.

We deliver gene programs via viral, non-viral, and microbe-based approaches, including Sleeping Beauty , AttSite recombinases, and gorilla adenoviral vectors, from our AdenoVerse library.

Sleeping Beauty is a non-viral transposon/transposase system licensed from the University of Texas MD Anderson Cancer Center that stably reprograms immune cells by inserting specific DNA sequences into the genome.

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This includes our gorilla adenovectors, which provide a potential competitive advantage in their large payload capacity, ability for repeat administrations and generation of robust antigen-specific immune responses.

lactis is a food-grade bacterium with a long history of safe use that we modify to deliver biologics at mucosal sites via oral administration.

The UltraPorator system includes proprietary hardware and software solutions and potentially represents major advancements over current electroporation devices by significantly reducing the processing time and contamination risk.

UltraPorator is designed for rapid and cost-effective manufacturing of UltraCAR-T therapies and has the potential to enable rapid manufacturing of a range of gene and cell therapies beyond UltraCAR-T.

The final component of our approach to precision medicine is our ability to control gene expression and regulation using the RheoSwitch, kill switches, and tissue-specific promoters.

The RheoSwitch Therapeutic System, our inducible gene switch system, is the most clinically advanced gene switch system and provides quantitative dose-proportionate regulation of the amount and timing of target protein expression in response to an orally available activator ligand, veledimex.

In addition, we have developed a suite of kill switches, which allow us to selectively eliminate cell therapies in vivo after their administration, to improve the safety profile of our cell therapies.

The RheoSwitch Therapeutic System, our inducible gene switch system, we believe is the most clinically advanced gene switch system and provides quantitative dose-proportionate regulation of the amount and timing of target protein expression in response to an orally available activator ligand, veledimex.

In addition, we have developed a suite of kill switches, which allow us to selectively eliminate cell therapies in vivo after their administration, to improve their safety profile.

We are developing tissue-specific promoters to only induce gene expression locally in cells or tissues of therapeutic interest.

We have leveraged our proprietary and complementary technology platforms discussed above and our expertise in immunology to develop key therapeutic platforms, including UltraCAR-T, AdenoVerse, and ActoBiotics, to address multiple pathways of complex disorders with significant unmet medical needs and to realize our core promise of precision medicine.

Our Therapeutic Platforms

We have leveraged our proprietary and complementary technology platforms discussed above and our expertise in immunology to develop key therapeutic platforms, including UltraCAR-T and AdenoVerse, to address multiple pathways of complex disorders with significant unmet medical needs and to realize our core promise of precision medicine.

PGEN Therapeutics' Therapeutic Platforms

Recent technological advances have revolutionized the field of immunotherapy for the treatment of cancer.

immunotherapy approaches, chimeric antigen receptor T, or CAR-T, cell therapies in particular have shown remarkable responses in cancer patients with hematological malignancies.

Of the many immunotherapy approaches, chimeric antigen receptor T, or CAR-T, cell therapies in particular have shown remarkable responses in cancer patients with hematological malignancies.

These therapies rely on the modification of T cells with chimeric antigen receptors to enable those T cells to bind to specific antigens on the patient's tumor cells and kill the tumor cells.

Concerns remain, however, regarding complex and lengthy manufacturing processes and the safety profile of CAR-T cell therapies.

Furthermore, conventional CAR-T cell therapies have faced a number of challenges in the treatment of solid tumors due to antigen heterogeneity, the suppressive nature of the tumor microenvironment and the limited persistence of CAR-T cells.

Furthermore, current autologous and allogeneic CAR-T cell therapies face challenges in the treatment of solid tumors due to rapid exhaustion and limited persistence of CAR-T cells.

Current approaches to CAR-T manufacturing require extensive ex vivo expansion following viral vector transduction to achieve clinically relevant cell numbers.

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Time is of the essence for advanced cancer patients and even modest delays in treatment can adversely affect outcomes.

Our UltraCAR-T platform is fundamentally differentiated from the competition and we believe it has the potential to address the shortcomings of current technologies and disrupt the CAR-T treatment landscape by increasing patient access through shortening manufacturing time from weeks to days, decreasing manufacturing-related costs, and improving outcomes.

Our UltraCAR-T platform is differentiated from the competition, and we believe it has the potential to address the shortcomings of current technologies and disrupt the CAR-T treatment landscape by increasing patient access through shortening manufacturing time from weeks to days, decreasing manufacturing-related costs, and improving outcomes.

We recently introduced our vision for a new UltraCAR-T library approach, which is intended to transform the personalized cell therapy landscape for cancer patients.

Our goal is to develop and validate a library of non-viral plasmids to target tumor-associated antigens.

Enabled by what we believe to be design and manufacturing advantages of UltraCAR-T, coupled with the capabilities of the UltraPorator system, we are working to empower cancer centers to deliver personalized, autologous UltraCAR-T treatment with overnight manufacturing to any cancer patient.

If our goal is realized, one or more non-viral plasmids could be selected based on the patient's cancer indication and biomarker profile from the library to build a personalized UltraCAR-T treatment.

After initial treatment, this approach has the potential to allow for redosing of UltraCAR-T targeting the same or new tumor-associated antigens based on the treatment response and the changes in antigen expression of the patient's tumor.

The key advantages of UltraCAR-T versus the traditional CAR-T approaches include:

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As a result of this optimization, our UltraCAR-T cells are precision-engineered to produce a homogeneous cell product that simultaneously co-expresses antigen-specific CAR, kill switch, and mbIL15 genes in any genetically modified UltraCAR-T cell.

This design differentiates our UltraCAR-T platform from our competition and reduces the developmental risk because product homogeneity is a critical consideration for later stages of clinical development and subsequent commercialization.

We utilize our protein engineering and immunology expertise to optimize antigen binding and signaling domains of each CAR based on the target antigen expression profile and cancer indication.

This design differentiates our UltraCAR-T platform from the approaches used by our competitors and, we believe, reduces the developmental risk as compared to those approaches because product homogeneity is a critical consideration for later stages of clinical development and subsequent commercialization.

We utilize our protein engineering and immunology expertise to optimize antigen binding, hinge, and signaling domains of each CAR based on the target antigen expression profile and cancer indication.

We have also included our proprietary kill switch technology in our UltraCAR-T cells to improve the safety profile.

Enhanced persistence and elimination of ex vivo expansion step due to expression of mbIL15

The key driver of improved UltraCAR-T cell performance is our proprietary cytokine mbIL15.

The expression of mbIL15 enhances in vivo expansion in the presence of tumor antigens and prevents T cell exhaustion to maintain a less differentiated, stem-cell like memory phenotype leading to longer persistence of UltraCAR-T cells.

This yields an enduring anti-tumor response that outlasts conventional CAR-T cells, which we believe is essential to successfully targeting solid tumors.

This design allows us to eliminate the need for any ex vivo expansion prior to administration, a requirement that is a major limitation of current CAR-T treatments.

The key driver of improved UltraCAR-T cell performance is mbIL15.

The expression of mbIL15 has been shown to enhance in vivo expansion of UltraCAR-T cells in the presence of tumor antigens and prevent T cell exhaustion to maintain a less differentiated, stem-cell like memory phenotype leading to longer persistence of UltraCAR-T cells.

This yields an enduring anti-tumor response that has been shown to outlast conventional CAR-T cells in preclinical studies, which we believe is essential to successfully targeting solid tumors.

This design allows us to eliminate the need for ex vivo expansion prior to administration, a requirement that is a major limitation of current CAR-T treatments.

Scalable, rapid, decentralized manufacturing process

Another key differentiator with the UltraCAR-T therapeutic platform is our decentralized and rapid proprietary manufacturing process, which allows us to manufacture overnight at a medical center's current good manufacturing practices, or cGMP, facility and reinfuse the patient the following day after gene transfer.

The decentralized nature of this process allows us to scale beyond the confines of a dedicated facility.

We are the first company to implement non-viral, decentralized, rapid manufacturing of CAR-T cells in the clinic and have validated our proprietary UltraCAR-T manufacturing process in practice by infusing patients one day after gene transfer at two different sites in our ongoing clinical trials.

Our UltraCAR-T manufacturing process provides a

significant potential competitive advantage in the timeline and cost required to manufacture and deliver CAR-T therapies to patients as compared to current treatment approaches that require large, centralized facilities to support manufacturing of a relatively small number of treatments.

Another key differentiator of the UltraCAR-T therapeutic platform is our rapid and decentralized proprietary manufacturing process, which allows us to manufacture UltraCAR-T cells overnight at a medical center's current good manufacturing practices, or cGMP, facility and reinfuse the patient the following day after gene transfer.

This process improves upon current approaches to CAR-T manufacturing, which require extensive ex vivo expansion following viral vector transduction to achieve clinically relevant cell numbers that we believe can result in the exhaustion of CAR-T cells prior to their administration, limiting their potential for persistence in patients.

The decentralized nature of the manufacturing process allows us to scale beyond the confines of a dedicated facility.

We are the first company to implement non-viral, rapid, decentralized manufacturing of CAR-T cells in the clinic and have validated our proprietary UltraCAR-T manufacturing process in practice by infusing patients one day after gene transfer at two different sites in our ongoing clinical trials.

We have developed a proprietary electroporation device, UltraPorator, designed to further streamline and ensure the rapid and cost-effective manufacturing of UltraCAR-T therapies.

The UltraPorator system, intended to be a viable scale-up and commercialization solution for decentralized UltraCAR-T manufacturing, includes proprietary hardware and software solutions and potentially represents major advancements over current electroporation devices by significantly reducing the processing time and contamination risk.

We believe our UltraCAR-T manufacturing process will provide a significant potential competitive advantage in the timeline and cost required to manufacture and deliver CAR-T therapies to patients as compared to current treatment approaches that require large, centralized facilities to support manufacturing of a relatively small number of treatments.

We believe development of rapid and successful overnight manufacturing of UltraCAR-T therapies at medical centers signifies a paradigm shift in CAR-T therapy by eliminating manufacturing and timing risks associated with conventional CAR-T therapies, and our intent is for it to take place directly in numerous treatment centers, which can improve the accessibility of our therapies for patients.

PGEN Therapeutics' most advanced programs based on the UltraCAR-T platform include PRGN-3005, which is in a Phase 1/1b clinical trial for patients with advanced ovarian, fallopian tube, or primary peritoneal cancer, and PRGN-3006, which is in a Phase 1/1b clinical trial for patients with relapsed or refractory acute myeloid leukemia, or AML, high-risk myelodysplastic syndromes, or MDS, and chronic myelomonocytic leukemia, or CMML.

PRGN-3005 is a first-in-class, investigational autologous CAR-T therapy that utilizes our UltraCAR-T platform to simultaneously express a CAR targeting the unshed portion of the Mucin 16 antigen, or MUC16, mbIL15, and kill switch genes.

MUC16 is an extremely large, type I transmembrane cell surface glycoprotein that plays a key role in the pathogenesis of ovarian cancer by promoting an increase in cell proliferation, metastasis, resistance to chemotherapy and immune system evasion by cancer cells.

MUC16 is overexpressed on more than 80 percent of ovarian tumors but has limited expression in healthy tissues, making it an attractive CAR-T target for ovarian cancer.

Other cancers with known overexpression of MUC16 include pancreatic, breast, endometrial, lung, and bladder cancers.

MUC16 undergoes proteolytic cleavage in the extracellular domain resulting in shedding of a large portion of extracellular domain, termed CA125, from the cell surface and leaving only a short, unshed extracellular domain tethered to the cell surface.

Therapies that target the region of MUC16 that is shed from the cell surface may have limited effectiveness due to their binding to CA125 in circulation which is not associated with tumor cells.

In order to eliminate binding to circulating CA125, we have designed our MUC16 CAR using an antigen binding domain that specifically binds the unshed portion of MUC16 and optimized its affinity to preferentially target PRGN-3005 to tumor cells.

PRGN-3005 is being evaluated for the treatment of advanced ovarian, fallopian tube, and primary peritoneal cancers.

Advanced ovarian cancer is often fatal, with Stage IV survival rates as low as 20 percent, and has limited treatment options.

Patients with ovarian cancer represent a large population, with approximately 300,000 patients diagnosed worldwide annually, including 22,000 in the United States alone.

In preclinical in vitro studies, PRGN-3005 UltraCAR-T cells have shown robust MUC16-specific cytotoxicity of ovarian cancer cell lines, a stem-cell like memory phenotype and significant improvement in their longevity even in the absence of exogenous cytokines as compared to conventional CAR-T cells.

PRGN-3005 UltraCAR-T cells have shown significantly superior anti-tumor response in mouse models of ovarian cancer compared to mice treated with a saline solution or conventional MUC16 CAR-T cells lacking mbIL15 expression.

Specifically, a single administration of PRGN-3005 one day after non-viral gene transfer showed significantly superior expansion and preferred memory phenotype of UltraCAR-T in vivo and significantly

superior efficacy compared to traditional CAR-T resulting in all PRGN-3005 treated mice becoming tumor-free.

Furthermore, rechallenging these tumor-free mice three months later with ovarian tumors for a second time (to simulate tumor relapse) led to the elimination of tumor burden without additional PRGN-3005 UltraCAR-T treatment.

These data demonstrated the potential of UltraCAR-T cells to persist long-term in vivo , prevent CAR-T cell exhaustion, and mount a durable anti-tumor response with the ability to continue to respond upon tumor rechallenge.

PRGN-3005 is currently being evaluated in a Phase 1/1b clinical trial.

The Phase 1 portion of the study is a dual-arm, non-randomized, open-label clinical trial in patients with advanced, recurrent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer.

Patients in this investigator-initiated Phase 1 dose escalation trial receive either intraperitoneal, or IP (Arm A), or intravenous, or IV (Arm B), administration of PRGN-3005 without prior lymphodepletion.

The primary objectives of the Phase 1 trial are to assess the safety and maximum tolerated dose, or MTD, of PRGN-3005.

For both routes of administration, PRGN-3005 will follow a 3+3 dose escalation pattern.

We are conducting this trial in collaboration with The University of Washington and The Fred Hutchinson Cancer Research Center, leaders in immunotherapy and CAR-T treatments.

We expect to enroll up to 71 patients total in this study.

In October 2020, we announced the FDA clearance of our UltraPorator system, a proprietary electroporation device and software solution for the scale-up of rapid and cost-effective manufacturing of UltraCAR-T therapies, as a manufacturing device for clinical trials of our investigational UltraCAR-T therapies in compliance with cGMP.

In November 2020, we announced that we have successfully dosed the first patient in the PRGN-3005 Phase 1 trial using UltraCAR-T cells manufactured using the UltraPorator system.

In December 2020, we presented preliminary data from the first six patients treated with PRGN-3005, who were treated at the two lowest dose levels in the IP arm without prior lymphodepletion.

The six patients were treated at either Dose Level 1 (>3x10 4 - ≤ 1 x 10 5 UltraCAR-T cells/kg;

N=3) or Dose Level 2 (>1x10 5 - ≤ 3 x 10 5 UltraCAR-T cells/kg;

Patients had received between 6 and 9 prior therapies before enrolling in the PRGN-3005 study.

Preliminary data from these patients showed that PRGN-3005 was well-tolerated, with no dose-limiting toxicities, or DLTs, neurotoxicities, or cytokine release syndromes reported.

PRGN-3005 UltraCAR-T cells showed encouraging expansion and persistence after low dose IP infusion without lymphodepletion across both dose levels.

In addition, 50 percent (3 out of 6) of the patients experienced regression in total target tumor burden and 33 percent (2 out of 6) patients achieved stable disease according to RECIST v1.1 criteria at their restaging evaluation.

In addition, we believe that our consistent ability to successfully manufacture UltraCAR-T cells at a medical center confirms the validity of our rapid, decentralized approach to manufacturing.

Enrollment is ongoing in the IP arm of the trial, and an expansion phase is planned at the MTD.

We have received clearance from the FDA to initiate dosing in the IV arm of the trial concurrently with the IP arm.

PRGN-3006 is a first-in-class, investigational autologous CAR-T therapy that utilizes our UltraCAR-T platform to express a CAR to target CD33, mbIL15 and a kill switch for better precision and control.

CD33, also known as Siglec-3, is a single pass transmembrane glycoprotein and a member of the sialic acid-binding immunoglobulin-like lectin super-family.

CD33 is an attractive target for immunotherapy because it is over-expressed on AML blasts and leukemic stem cells, or LSCs, but is not expressed on normal blood stem cells, also known as hematopoietic stem cells.

Approximately 85-90 percent of AML patients express CD33 on their tumor cells.

In addition to broad expression on AML blasts, CD33 is expressed on LSCs underlying AML.

LSCs are thought to be more resistant to chemotherapy treatment and to be capable of reinitiating the disease resulting in high relapse rates for AML.

In healthy subjects, CD33 is primarily expressed on normal myeloid precursors, colony-forming cells, monocytes, and maturing granulocytes.

Because CD33 is not expressed outside the hematopoietic system or on normal hematopoietic stem cells, it is an attractive target for treatment of AML.

AML is among the most common types of leukemia in adults with approximately 20,000 AML patients diagnosed in the United States annually.

AML is a heterogeneous disease with 50-70 percent relapse rates and rapid progression.

The prognosis for patients with AML is poor, with an average five-year survival rate of approximately 25 percent.

More than 10,000 cases of higher-risk MDS are diagnosed annually in the United States.

Due to the aggressive nature of AML progression, rapid availability of treatment is of even greater importance in this patient population, and our non-viral UltraCAR-T manufacturing process would represent a significant potential advantage over current approaches that require long lead times for manufacturing.

In preclinical studies, PRGN-3006 demonstrated robust expansion in the presence of CD33 antigen, lack of autonomous expansion in the absence of CD33 and prolonged persistence in the absence of exogenous cytokines.

PRGN-3006 exhibited target-specific killing of CD33 + tumor cells as well as a significant release of inflammatory cytokines such as IFNγ, upon co-culture with AML tumor cells.

PRGN-3006 cells were specifically eliminated by kill switch activator treatment, displaying functionality of the kill switch, which is intended to improve the safety profile of PRGN-3006.

In vivo , a single administration of PRGN-3006 UltraCAR-T cells only one day after gene transfer effectively eliminated the tumor burden and significantly improved overall survival of tumor bearing mice compared to CAR-T cells lacking mbIL15 expression (conventional CAR-T) in an aggressive xenograft model of AML.

PRGN-3006 demonstrated engraftment and significantly higher expansion and persistence in mice compared to conventional CAR-T cells, which lack mbIL15 expression.

PRGN-3006 is currently being evaluated in an investigator-initiated Phase 1/1b trial.

The Phase 1 portion of this study is a dual-arm, non-randomized, dose-escalation clinical trial where PRGN-3006 is delivered via intravenous infusion.

The patient population includes relapsed or refractory AML, higher-risk MDS, and CMML.

In the 3+3 dose escalation phase, patients will be treated in one of the two arms:

patients in Arm 1, or No Lymphodepletion arm, will receive UltraCAR-T cell infusion without prior lymphodepletion, and patients in Arm 2, or Lymphodepletion arm, will receive lymphodepleting chemotherapy prior to UltraCAR-T infusion.

Because our UltraCAR-T cells have the potential for enhanced in vivo expansion and persistence due to expression of mbIL15, we are evaluating the administration of PRGN-3006 in patients without prior lymphodepletion.

The primary objective of this trial is to assess the safety of PRGN-3006 and determine the MTD.

The Phase 1 trial is being conducted in collaboration with Moffitt Cancer Center, a pioneer in CAR-T clinical development.

In October 2020, we announced the FDA clearance of our UltraPorator system as a manufacturing device for clinical trials of our investigational UltraCAR-T therapies in compliance with cGMP.

In November 2020, we announced that we have successfully dosed the first patient in the PRGN-3006 Phase 1 trial using UltraCAR-T cells manufactured using the UltraPorator system.

In December 2020, the Principal Investigator of the PRGN-3006 clinical trial presented clinical progress and preliminary data from the ongoing Phase 1 trial, including a case study of a patient treated at Dose Level 2 of the No Lymphodepletion arm at the 62 nd ASH Annual Meeting and Exposition.

Later in December, we presented additional data to expand upon the preliminary data presented at the ASH Annual Meeting and Exposition.

As of November 10, 2020, the cutoff date for the results, a total of nine patients had been treated in either the No Lymphodepletion arm or the Lymphodepletion arm of the trial.

Of the nine patients treated, six were treated at either the Dose Level 1 (>3x10 4 - ≤ 1 x 10 5 UltraCAR-T cells/kg;

N=3) or the Dose Level 2 (>1x10 5 - ≤ 3 x 10 5 UltraCAR-T cells/kg;

N=3) of the No Lymphodepletion arm, and three were treated at the Dose Level 1 (>3x10 4 - ≤ 1 x 10 5 UltraCAR-T cells/kg;

N=3) of the Lymphodepletion arm.

Preliminary data from these patients showed that PRGN-3006 was well-tolerated, with no DLTs and no neurotoxicity.

Transient grade 1 to 3 cytokine release syndrome was reported in two patients, which was resolved without intervention.

There was low incidence of treatment-related adverse events and serious adverse events, and Grade 3 or greater treatment-emergent adverse events included hematologic events, decreased electrolytes, and infections.

PRGN-3006 UltraCAR-T showed encouraging expansion and persistence in peripheral blood of patients in both No Lymphodepletion and Lymphodepletion arms and across all dose levels.

Furthermore, PRGN-3006 UltraCAR-T cells showed the ability to traffic, expand, and persist in bone marrow.

In addition, we believe that our consistent ability to successfully manufacture UltraCAR-T cells at a medical center confirms the validity of our rapid, decentralized approach to manufacturing.

A case study of the patient with the longest follow-up as of the data cutoff was also presented at the ASH Annual Meeting and Exposition.

The case study patient was a 69 year old female with secondary AML and four prior lines of therapy, including induction chemotherapy, or IC, allogenic hematopoietic stem cell transplantation, or allo-HSCT, hypomethylating agent plus venetoclax, or HMA+VEN.

The patient was refractory to all therapy post allo-HSCT.

The patient had approximately 40 percent peripheral blasts and 47 percent bone marrow blasts at baseline.

The patient was treated at Dose Level 2 in No Lymphodepletion arm with a total of only 24 million UltraCAR-T cells via IV infusion.

Case study findings presented showed that, after a low dose infusion without prior lymphodepletion, PRGN-3006 UltraCAR-T cells demonstrated robust expansion and persistence in blood at seven months post-infusion.

PRGN-3006 UltraCAR-T cells demonstrated trafficking to bone marrow and the ability to expand and persist in bone marrow.

The patient showed a decline in AML blast levels in blood and bone marrow concomitant with UltraCAR-T expansion and persistence and had durable stable disease.

Enrollment is ongoing simultaneously in both the No Lymphodepletion and the Lymphodepletion arms of this Phase 1 trial.

The dose escalation phase of each arm will be followed by a dose expansion phase at the MTD.

PRGN-3006 was granted Orphan Drug designation for the treatment of AML by the FDA.

"Off-the-shelf" AdenoVerse Immunotherapy

Our AdenoVerse immunotherapy platform utilizes a library of proprietary adenovectors for the efficient gene delivery of therapeutic effectors, immunomodulators, and vaccine antigens.

We have established proprietary manufacturing cell lines and production methodologies for AdenoVerse Immunotherapies, which we believe is easily scalable for commercial supply.

We believe that our proprietary gorilla adenovectors, part of the AdenoVerse technology, have superior performance characteristics as compared to current competition, including standard human adenovirus serotype 5,or Ad5, rare human adenovirus types and other non-human primate adenovirus types.

We have established proprietary manufacturing cell lines and production methodologies from our AdenoVerse immunotherapy platform, which we believe are easily scalable for commercial supply.

We believe that our proprietary gorilla adenovectors, which are part of the AdenoVerse technology, have superior performance characteristics as compared to current competition, including standard human adenovirus serotype 5, or Ad5, rare

human adenovirus types and other non-human primate adenovirus types.

The key advantages of AdenoVerse immunotherapy platform include:

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This suitability for repeat administration stems from the very low to non-existent seroprevalence of and limited immunity to gorilla adenoviruses in the human population.

For example, our gorilla adenovector variant GC46 has been shown to have a seroprevalence of less than 6% in the United States, with low seropositive titers.

In comparison, the seroprevalence of Ad5 in the United States is estimated to be 58%, with most of seropositive individuals having high titers.

For example, our gorilla adenovector variant GC46 has been shown to have a seroprevalence of less than 6 percent in the United States, with low seropositive titers.

In comparison, the seroprevalence of Ad5 in the United States is estimated to be 58 percent, with most of seropositive individuals having high titers.

This high Ad5 seroprevalence limits the effectiveness of Ad5-based adenovectors in clinical studies.

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The use of a proprietary complementing cell line provides the necessary genetic elements for manufacture of AdenoVerse immunotherapy candidates.

We believe our AdenoVerse Immunotherapy candidates have reduced regulatory and commercialization risk due to their design which renders

them incapable of replicating and therefore less susceptible to manufacturing failures.

We believe our AdenoVerse immunotherapy candidates have reduced regulatory and commercialization risk due to their design, which renders them incapable of replicating and therefore less susceptible to manufacturing failures.

Furthermore, our gorilla adenovector manufacturing process has yielded therapeutic candidates at a very high titer and has reduced the complexity of manufacturing.

Durable antigen-specific immune response

Gorilla adenovectors have been shown to generate high-level and durable antigen-specific neutralizing antibodies and effector T cell immune responses as well as an ability to boost these antibody and T cell responses via repeat administration.

ActoBiotics ®

Our ActoBiotics platform is a unique therapeutic platform precisely tailored for specific disease modification with the potential for superior efficacy and safety via oral or topical delivery of disease-modifying therapeutics directly to the relevant local mucosal sites.

Gorilla adenovectors have been shown in preclinical studies to generate high-level and durable antigen-specific neutralizing antibodies and effector T cell immune responses, as well as an ability to boost these antibody and T cell responses via repeat administration.

cGMP Manufacturing Facility

One of our central differentiating factors and competitive gene therapy advantages is our investment in internal cGMP manufacturing capabilities in Germantown, Maryland, with the aim to reduce a myriad of risks that can impact manufacturing of viral vectors.

These include technology transfer risks when outsourcing to contract manufacturing organizations as well as process and timing risks.

Our modular cGMP facility with a small footprint was designed with agility and control in mind, focusing on rapid manufacturing and the ability to scale production appropriately to meet early-stage clinical trial needs of gene therapy vectors, especially our AdenoVerse-based therapeutics.

We are able to generate greater than 1,000 doses of early phase

clinical trial material at this facility at an expedited timeline and reduced cost compared to contract manufacturing organizations.

As a result, we feel we are in a position to be in control of meeting our gene therapy manufacturing needs for our early-phase clinical trials.

PGEN Therapeutics' most advanced programs based on the AdenoVerse immunotherapy platform include:

(i) PRGN-2009, a first-in-class, "off-the-shelf" investigational immunotherapy utilizing the AdenoVerse platform, is designed to activate the immune system to recognize and target human papillomavirus-positive, or HPV+, solid tumors, which is in a Phase 1/2 clinical trial for patients with HPV-associated cancers in collaboration with the National Cancer Institute, or NCI, pursuant to a cooperative research and development arrangement, or CRADA;

and (ii) PRGN-2012, a first-in-class, investigational "off-the-shelf" AdenoVerse immunotherapy designed to elicit immune responses directed against cells infected with HPV type 6, or HPV6, or HPV type 11, or HPV11, which recently received investigational new drug application, or IND, approval from the FDA to initiate a Phase 1 trial in patients with recurrent respiratory papillomatosis, or RRP.

PRGN-2009, a first-in-class, "off-the-shelf" investigational immunotherapy, is designed to activate the immune system to recognize and target HPV+ solid tumors.

PRGN-2009 leverages our UltraVector and AdenoVerse platforms to optimize HPV type 16, or HPV16, and HPV type 18, or HPV18, antigen design for delivery via a proprietary gorilla adenovector with a large genetic payload capacity and the ability for repeat administrations.

Guided by our bioinformatics analysis and in silico protein engineering, PRGN-2009 encodes for a novel, multi-epitope antigen design to target HPV16 and HPV18 infected cells and potentially differentiates from the competition.

PRGN-2009 has been engineered using our AdenoVerse platform to be replication deficient in vivo .

HPV infections account for 5 percent of all cancers globally, and 690,000 new cancer cases are attributable to HPV infections per year.

HPV infects the squamous cell carcinoma.

Some cervical cancers come from HPV infection of gland cells in the cervix and are referred to as adenocarcinomas.

HPV-related cancers include cervical, oropharyngeal, anal, penile, vaginal, and vulvar.

Nearly 44,000 HPV-associated cancers occur in the United States each year.

Of these, approximately 25,000 occur in women and 19,000 occur in men.

HPV is considered responsible for more than 90 percent of anal and cervical cancers, about 70 percent of vaginal and vulvar cancers, and more than 60 percent of penile cancers.

Recent studies indicate that about 70 percent of cancers of the oropharynx also may be related to HPV.

In preclinical studies, PRGN-2009 treatment induced strong HPV-specific immune response and effectively controlled solid tumors in a murine model of HPV+ head and neck cancer.

In a humanized mouse model of HPV+ cancer, PRGN-2009 treatment led to an increase in CD8 and CD4 T cells in the tumor microenvironment and a reduction in the tumor.

In a syngeneic mouse model of HPV+ cancer, repeated injections of PRGN-2009 monotherapy resulted in generation of high levels of HPV-specific T cells, and reduction in tumor burden.

The combination of PRGN-2009 with bintrafusp alfa, or M7824, an investigational bifunctional fusion protein, further reduced tumor growth, increased HPV-specific T cells, and increased T-cell infiltration into the tumor microenvironment in vivo .

PRGN-2009 is in a Phase 1/2 clinical trial for patients with HPV-associated cancers in collaboration with NCI pursuant to a CRADA.

The Phase 1 portion of the study will follow 3+3 dose escalation to evaluate the safety of PRGN-2009 administered as a monotherapy, Arm A, to determine the recommended Phase 2 dose, or R2PD, followed by an evaluation of the safety of the combination of PRGN-2009 at the R2PD and M7824, Arm B.

The Phase 1 study population includes patients with recurrent or metastatic HPV-associated cancers.

PRGN-2009 will be administered via sub cutaneous injection once every 2 weeks for three administrations and may be continued every 4 weeks for up to one year, as clinically appropriate.

M7824 will be administered on Day 1 and then every 2 weeks.

The Phase 2 portion of the study will evaluate PRGN-2009 as a monotherapy or in combination with M7824 as a neoadjuvant or induction therapy in patients with newly-diagnosed stage II/III HPV16-positive oropharyngeal cancer and patients with newly diagnosed operable stage II/III/IVA/IVB HPV+ sinonasal squamous cell cancer.

In January 2021, we announced preliminary data from the ongoing Phase 1/2 clinical trial of PRGN-2009 in patients with HPV-associated cancers.

Enrollment in the Phase 1 monotherapy dose escalation arm, Arm A, of this trial is complete, and enrollment in the Phase 1 combination arm, Arm B, has been initiated.

A total of six patients were treated in the monotherapy arm.

All patients in the monotherapy arm have received multiple PRGN-2009 administrations to date.

Preliminary data showed that repeated administrations of PRGN-2009 was well-tolerated by these patients with no DLTs.

In addition, preliminary correlative analysis by the NCI of peripheral blood mononuclear cells from three patients treated at the initial dose level showed an increase in HPV16 and/or HPV18-specific T-cell response in 100 percent (3 out of 3) patients.

Furthermore, an increase in the magnitude and breadth of immune response was seen after repeat administration of PRGN-2009.

PRGN-2012, a first-in-class, investigational "off-the-shelf" AdenoVerse immunotherapy for the treatment of RRP.

PRGN-2012 is an innovative therapeutic vaccine with optimized antigen design that uses our gorilla adenovector technology, part of our proprietary AdenoVerse platform, to elicit immune responses directed against cells infected with HPV6 and HPV11.

Gorilla adenovectors have numerous advantages, including the ability for repeat administration, the inability to replicate in vivo , which may improve safety, and the ability to deliver large payload capacity.

RRP is a rare, difficult-to-treat, and sometime fatal neoplastic disease of the respiratory tract caused by infection with HPV6 or HPV11.

RRP is classified based on age of onset as juvenile or adult.

Juvenile-onset disease has an incidence of 4 per 100,000 and adult-onset RRP has an incidence of 2 to 3 per 100,000.

There is no cure for RRP, and the current standard-of-care is repeated endoscopic debulking with ablation or excision of papillomatous lesions.

Recurrence of papilloma after surgical removal is very common, and repeated procedures are required to debulk and monitor the disease, which exposes patients to anesthetic and surgical risks and emotional distress.

Some patients require a tracheotomy and need a trach tube indefinitely to keep the breathing passage open.

RRP morbidity and mortality results from the effects of papilloma mass on the vocal cords, trachea, and lungs, which may cause voice changes, stridor, airway occlusion, loss of lung volume, and/or post-obstructive pneumonia.

Although rare, one to three percent of RRP cases can transform into invasive squamous cell carcinoma.

In addition, more than 90 percent of genital warts are related to HPV6 and HPV11 infection.

In preclinical models, PRGN-2012 has demonstrated strong HPV6 and HPV11-specific T-cell response in RRP patient samples in vitro .

In January 2021, we announced that the FDA had cleared the IND to initiate the Phase 1 clinical trial of PRGN-2012 AdenoVerse immunotherapy in adult patients with RRP.

The Phase 1 study will follow 3+3 dose escalation of PRGN-2012 as an adjuvant immunotherapy following standard-of-care surgical removal of visible papillomatosis disease.

Patients will receive up to four injections of PRGN-2012.

The primary objective of the study is to determine safety and tolerability and the recommended Phase 2 dose of PRGN-2012.

The study will enroll 3 to 6 subjects at each dose level, and 12 patients will be treated at the MTD.

PRGN-2012 is being developed in collaboration with the Center for Cancer Research at the NCI through a CRADA.

Preclinical Programs

We have a robust pipeline of preclinical programs that we are pursuing in order to drive long-term value creation.

Our pipeline includes a number of product candidates, including UltraCAR-T therapeutics for various cancers, an "off-the-shelf" AdenoVerse immunotherapy for infectious disease, and a multifunctional therapeutic for solid tumors.

We expect to continue development of various preclinical programs to identify product candidates for evaluation in clinical trials.

We are evaluating multiple UltraCAR-T candidates for treatment of hematological and solid tumors in preclinical testing.

We recently introduced our vision for a new UltraCAR-T library approach aimed at transforming the personalized cell therapy landscape for cancer patients.

Our goal is to develop and validate a library of non-viral plasmids to target tumor-associated antigens.

We are developing PRGN-2013, a preclinical stage asset based on our "off-the-shelf" AdenoVerse immunotherapy platform, to treat chronic hepatitis B virus, or HBV, infection.

HBV can cause serious health problems, including liver damage, cirrhosis, liver cancer, and death.

Preclinical studies of PRGN-2013 showed that mice treated with PRGN-2013 saw (i) a more significant cytotoxic T-cell response against more HBV epitopes and (ii) decreased plasma levels of HBsAg, the key marker of chronic HBV infection in mice.

We are also developing immuno-oncology product candidates based on our Multifunctional Therapeutic platform to target solid tumors.

Additional preclinical programs under development include an AdenoVerse cytokine therapy candidate for solid tumors and candidates to target autoimmune disorders.

We also have a number of other potential product candidates in our preclinical pipeline and, consistent with our commitment to actively manage our portfolio programs, we exercise discipline in our portfolio management by systematically evaluating data from our preclinical programs in order to make rapid "go" and "no go" decisions.

Through this process, we believe we can more effectively allocate resources to programs that we believe show the most promise and advance such programs to clinical trials.

Precigen ActoBio

ActoBio is pioneering a proprietary class of microbe-based biopharmaceuticals that enable expression and local delivery of disease-modifying therapeutics.

We refer to these microbe-based biopharmaceuticals as ActoBiotics.

Precigen ActoBio's Therapeutic Platforms

Our ActoBiotics platform is a unique therapeutic platform precisely tailored for specific disease modification with the potential for superior efficacy and safety.

ActoBiotics combine the advantages of highly selective protein-based therapeutic agents with local delivery by the well-characterized and food-grade bacterium Lactococcus lactis , or L.

ActoBiotics can be delivered orally in a capsule, through an oral rinse or in a topical solution.

ActoBiotics work via genetically modified bacteria that deliver proteins and peptides at mucosal sites, rather than the insertion of one or more genes into a human cell by means of a virus or other delivery mechanism.

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Food-grade bacterium with easy genetic manipulation

ActoBiotics combine the advantages of highly selective protein-based therapeutic agents with local delivery by the well-characterized and food-grade bacterium with L.

ActoBiotics combine the advantages of highly selective protein-based therapeutic agents with local delivery by the well-

characterized and food-grade bacterium with L.

lactis , which has a long history of safe use.

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The manufacturing process involves fermentation of genetically modified L.

lactis to generate active ingredient, followed by concentration and freeze-drying.

lactis to generate significant quantities of the therapeutic agent, followed by concentration and freeze-drying.

The process does not require the costly purification required to produce conventional biologics.

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ActoBiotics can be delivered to the oral cavity through a mouthwash, intestinally via a capsule, or through a topical formula.

Physiological dosing is low, and our ActoBiotics product candidates have been well-tolerated in pre-clinical and clinical studies.

Physiological dosing is low, and our ActoBiotics product candidates have been well-tolerated in preclinical and clinical studies.

As compared to conventional biologics, we believe ActoBiotics have the potential to provide superior safety and efficacy via the sustained release of appropriate quantities of select therapeutic agents while reducing the side-effects commonly attributed to systemic delivery and corresponding peaks in concentration of conventional biologics.

Our Product Pipeline

We are leveraging our suite of technologies along with our internal research and development expertise to develop several preclinical and clinical stage programs.

PRGN-3005 is a first-in-class, autologous CAR-T therapy that utilizes our UltraCAR-T platform to simultaneously co-express a CAR targeting MUC16, mbIL15, and kill switch genes.

We have designed our CAR to improve signaling, and selected a specific anti-MUC16 binding domain and optimized its affinity to preferentially target PRGN-3005 to tumor cells.

MUC16 is overexpressed on more than 80% of ovarian tumors, but has limited expression in healthy tissues, making it an attractive CAR-T target for ovarian cancer.

Other cancers with known overexpression of MUC16 include pancreatic, breast, lung, and bladder cancer.

PRGN-3005 is in a Phase 1 clinical trial for the treatment of advanced ovarian cancer.

Advanced ovarian cancer is often fatal, with Stage IV survival rates as low as 20%, and has limited treatment options.

Patients with ovarian cancer represent a large population, with approximately 300,000 patients diagnosed worldwide annually, including 22,000 in the US alone.

Administration of PRGN-3005 UltraCAR-T cells one day after non-viral gene transfer eliminated ovarian tumors in all treated mice.

Furthermore, PRGN-3005 UltraCAR-T cells showed significantly superior expansion and persistence in ovarian tumor-bearing mice compared to conventional CAR-T cells.

We initiated a dual-arm, non-randomized, open-label Phase 1 clinical trial of PRGN-3005 in the second half of 2019 in patients with advanced, recurrent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer.

We are conducting this trial in collaboration with The University of Washington and The Fred Hutchinson Cancer Research Center, leaders in immunotherapy and CAR-T treatments.

Patients in this investigator-initiated dose escalation trial receive either intraperitoneal, or IP (Arm A), or intravenous, or IV (Arm B), administration of PRGN-3005.

The primary objectives of this trial are to assess the safety and MTD of PRGN-3005.

For both routes of administration, PRGN-3005 will follow a 3x3 dose escalation pattern.

We expect to enroll up to 41 patients total in this study.

In November 2019, we announced that we have successfully completed dosing of patients in the first dose level of the IP arm.

Our consistent ability to successfully manufacture UltraCAR-T cells at a medical center confirms the validity of our rapid, decentralized approach to manufacturing.

Moreover, we have observed encouraging preliminary findings of PRGN-3005 UltraCAR-T kinetics in patients.

We expect to announce initial data from the IP arm in the second half of 2020.

PRGN-3006 is a first-in-class autologous CAR-T therapy that utilizes our UltraCAR-T platform to co-express a CAR to target CD33, mbIL15 and a kill switch for better precision and control.

CD33, also known as Siglec-3, is a single pass transmembrane glycoprotein and a member of the sialic acid-binding immunoglobulin-like lectin super-family.

Approximately 85-90% of AML patients express CD33 on their tumor cells.

In addition to broad expression on AML blasts, CD33 is expressed on LSCs underlying AML.

LSCs are thought to be more resistant to chemotherapy treatment and to be capable of reinitiating the disease resulting in high relapse rates for AML.

In healthy subjects, CD33 is primarily expressed on normal myeloid precursors, colony-forming cells, monocytes, and maturing granulocytes.

Since CD33 is not expressed outside the hematopoietic system or on normal hematopoietic stem cells, it is an attractive target for treatment of AML.

AML is among the most common types of leukemia in adults with approximately 20,000 AML patients diagnosed in the US annually.

AML is a heterogeneous disease with 50-70% relapse rates and rapid progression.

The prognosis for patients with AML is poor, with an average five-year survival rate of approximately 25%.

More than 10,000 cases of higher-risk MDS are diagnosed annually in the United States.

Due to the aggressive nature of AML progression, rapid availability of treatment is of even greater importance in this patient population, and our non-viral UltraCAR-T manufacturing process represents a significant advantage over current approaches that require long lead times for manufacturing.

PRGN-3006 exhibited target-specific killing of CD33 + tumor cells as well as a significant release of inflammatory cytokines such as IFNγ, upon co-culture with AML tumor cells.

PRGN-3006 cells were specifically eliminated by kill switch activator treatment, displaying functionality of the kill switch, which is intended to improve the safety profile of PRGN-3006.

In vivo, a single administration of PRGN-3006 UltraCAR-T™ cells only one day after gene transfer effectively eliminated the tumor burden and significantly improved overall survival of tumor bearing mice compared to CAR-T cells lacking mbIL15 expression (conventional CAR-T) in an aggressive xenograft model of AML.

PRGN-3006 demonstrated engraftment and significantly higher expansion and persistence in mice compared to conventional CAR-T cells, which lack mbIL15 expression.

In 2019, we initiated a dual-arm, non-randomized, investigator-initiated Phase 1/1b clinical trial of PRGN-3006 delivered via intravenous infusion in patients with relapsed or refractory AML and higher-risk MDS.

We are conducting this trial in collaboration with Moffitt Cancer Center, a pioneer in CAR-T clinical development.

In the 3x3 dose escalation phase, patients will be treated in one of the two arms:

Arm 1 will receive CAR-T cell infusion without prior lymphodepletion, and Arm 2 will receive lymphodepleting chemotherapy.

The dose escalation phase of each arm will be followed by a dose expansion phase at the MTD.

Because our UltraCAR-T cells have the potential for enhanced in vivo expansion and persistence due to expression of mbIL15, we are evaluating administration of PRGN-3006 in patients without prior lymphodepletion.

The primary objective of this trial is to assess the safety of PRGN-3006 and determine the MTD.

In November 2019, we announced that we have successfully completed dosing of patients in the first dose level of the "no lymphodepletion" arm (Arm 1).

Our ability to successfully manufacture UltraCAR-T cells for patients at a second medical center in this trial has further validated our rapid, decentralized approach to manufacturing.

PRGN-3006 was granted orphan drug designation for the treatment of AML in December 2019 by the U.S.

Food and Drug Administration, or FDA.

We have observed encouraging preliminary findings of PRGN-3006 UltraCAR-T kinetics in patients.

We are currently enrolling patients in the second cohort of the "no lymphodepletion" arm (Arm 1) and the first cohort of the "lymphodepletion" arm (Arm 2) of the trial, and expect to announce initial data from the trial in the second half of 2020.

AG019 is a first-in-class disease modifying antigen-specific immunotherapy for the prevention, delay, or reversal of T1D.

ActoBio's most advanced internal pipeline candidate, AG019, is a first-in-class disease modifying antigen-specific, investigational immunotherapy for the prevention, delay, or reversal of type 1 diabetes mellitus, or T1D.

AG019 is an easy-to-take capsule formulation of ActoBiotics engineered to deliver the autoantigen human proinsulin, or PINS, and the tolerance-enhancing cytokine human interleukin-10 to the mucosal lining of gastro-intestinal tissues in patients with T1D.

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Furthermore, AG019 treatment induced accumulation and proliferation of PINS-specific FoxP3 + Treg cells in the pancreas and peripheral lymph nodes.

AG019 is currently being studied in a Phase 1b/2a multi-center trial in participants with clinical recent-onset T1D with a residual functional mass of insulin-producing beta cells.

The primary objective of this study, which we initiated in October 2018, is to assess the safety and tolerability of different doses of AG019 alone as well as AG019 in association with teplizumab, an anti-CD3 monoclonal antibody in development by Provention Bio, Inc.

for the interception and prevention of clinical T1D, in both adolescent and adult patient groups.

We have completed treatment in the open-label Phase 1b monotherapy portion of the trial, in which four cohorts consisting of adolescent or adult patients were treated with two or six AG019 capsules daily for eight weeks.

Enrollment is ongoing in the randomized, double-blind Phase 2a combination portion.

In this portion of the trial, patients will receive daily IV infusions of teplizumab during the first 12 days of AG019 treatment and two or six AG019 capsules daily for eight weeks.

We expect to announce interim data from this trial in the third quarter of 2020.

INXN-4001, a non-viral triple effector plasmid based on our UltraVector platform designed for the constitutive expression of human S100A1, SDF-1a, and VEGF-165, is engineered to address multiple pathways of heart failure.

Utilizing a single plasmid comprising all three genes, instead of each individual gene on separately delivered plasmids, INXN-4001 can control for delivery

and ensure expression of three genes in all transfected cells.

AG019 is currently in a Phase 1b/2a clinical trial for the treatment of early-onset T1D.

The Phase 1b portion of the study evaluates the safety and tolerability of AG019 monotherapy administered as a single dose and repeated daily doses in adult and adolescent patients.

Enrollment and dosing in the Phase 1b and Phase 2a portions of the study are complete.

portion of the study investigates the safety and tolerability of AG019 in combination with teplizumab, or PRV-031.

In August 2020, we announced that the primary endpoint of assessing safety and tolerability in the Phase 1b monotherapy portion of the study was met and that preliminary results at six months after AG019 monotherapy treatment initiation showed an encouraging trend in the insulin C-peptide levels, a biomarker for T1D disease progression.

In December 2020, we announced additional data from our ongoing Phase 1b portion and initial preliminary data from the Phase 2a portion of our ongoing Phase 1b/2a clinical trial.

The additional data from the Phase 1b monotherapy portion of the trial showed that AG019 continued to be well-tolerated, with no discontinuations due to treatment-emergent adverse events.

From the perspective of clinical activity, this data showed that 58 percent (7 of 12) of patients aged 17 or older receiving the AG019 monotherapy showed stabilization of C-peptide levels during the first six months of treatment and slower decline in C-peptide levels after being treated for 12 months as compared to treatment with placebo.

In addition, a mechanistic analysis performed by an independent research group found the induction of antigen-specific tolerance in conjunction with the reduction of disease-specific T cell responses for adult patients after three months of treatment with AG019.

We believe these results indicate the potential of AG019 to preserve insulin production in early-onset T1D through AG019's capacity to induce antigen-specific immune modulation.

Data from the Phase 2a combination portion with teplizumab showed that the combination was well-tolerated.

This data showed that 70 percent of adult patients (7 of 10) experienced stabilization of C-peptide levels after six months of treatment with a trend toward higher C-peptide levels as compared to baseline levels.

Mechanistic data were consistent with the data shown in the monotherapy trial, which we believe indicates the effect may be attributed to AG019.

We believe preliminary results in the combination trial point to the potential to boost or prolong teplizumab-induced metabolic effects.

No dose-related adverse events or serious adverse events were reported in either portion of this trial.

Precigen Triple-Gene

Triple-Gene is a clinical stage gene therapy company focused on developing advanced treatments for complex cardiovascular diseases.

Triple-Gene's most advanced candidate, INXN-4001, a non-viral triple effector plasmid based on our UltraVector platform designed for the constitutive expression of human S100A1, SDF-1a, and VEGF-165, is engineered to address multiple pathways of heart failure.

Utilizing a single plasmid comprising all three genes, instead of each individual gene on separately delivered plasmids, INXN-4001 can control for delivery and ensure expression of three genes in all transfected cells.

Heart failure represents a significant unmet medical need and a major economic burden worldwide.

There are approximately 25 million heart failure patients worldwide, of whom 6 million are in the United States.

Heart failure is the number one cause of hospitalization in patients aged 65 years and older, and 50% of heart failure patients die within five years after diagnosis.

Heart failure is the number one cause of hospitalization in patients aged 65 years and older, and 50 percent of heart failure patients die within five years after diagnosis.

Heart failure is a complex and multifaceted disease most often resulting from the intersection of multiple genetic predispositions with negative environmental factors.

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Coronary sinus delivery of INXN-4001 in a large animal ischemic heart failure model showed decreased left ventricular end systolic volume and increased absolute mean ejection fraction, which are indicators of myocardial function, as well as no increase in arrhythmias compared to controls.

INXN-4001 is in a Phase 1 clinical trial, which is a first-in-human, open label study designed to evaluate the safety of retrograde coronary sinus infusion of INXN-4001 in outpatient LVAD recipients.

Twelve stable patients with implanted LVAD for mechanical support of end stage heart failure were allocated into two cohorts of six subjects each to evaluate the safety of infusing the same amount of INXN-4001 (80mg) in two volumes (40mL and 80mL) at a rate of 20mL per minute.

We have completed dosing of patients in this trial.

The initial data shows evidence of improvement in cardiac function.

We have observed beneficial trends in the distance walked during the Six Minute Walk Test and in the Left Ventricular Ejection Fraction heart function measure after six months post INXN-4001 treatment.

There have been no treatment-related adverse events reported to date.

We expect to have complete data for this Phase 1 study in 2020.

Preclinical Programs

We have a robust pipeline of preclinical programs that we are pursuing in order to drive long-term value creation.

Our pipeline includes a number of product candidates utilizing our "off-the-shelf" AdenoVerse immunotherapy, UltraCAR-T and ActoBiotics platforms that we expect to be in studies enabling Investigational New Drug applications, or INDs, or to have moved into Phase 1 clinical trials in 2020.

We are developing three product candidates utilizing our AdenoVerse Immunotherapy platform.

Of these, PRGN-2009, an "off-the-shelf" immunotherapy for which we expect to initiate a Phase 1 clinical trial in 2020, is being developed for the treatment of

HPV + cancers.

HPV + cancers represent a significant health burden in indications such as head and neck, cervical, vaginal and anal cancer.

Our AdenoVerse platform allows us to optimize the HPV antigen design for improved immune response, which differentiates our therapy from the competition.

Our preclinical research has shown that PRGN-2009 immunotherapy effectively controlled solid tumors in a murine model of HPV + head and neck cancer.

PRGN-2009 is designed to activate the immune system to recognize and target HPV + solid tumors using a gorilla adenovector with a large payload capacity and the ability for repeat injections.

PRGN-2009 is currently under development through a cooperative research and development arrangement, or CRADA, with Dr.

Jeffrey Schlom, a world-renowned investigator in immuno-oncology, at the National Cancer Institute.

This CRADA has allowed us to rapidly and cost-effectively complete preclinical work, and we expect it to have similar benefits for our forthcoming Phase 1 clinical trial.

It also provides for potential expansion to other targets and combinations.

We are also developing immuno-oncology product candidates based on our Multifunctional Therapeutic platform.

This platform allows us to simultaneously target multiple pathways to address senescence and trafficking of T lymphocytes in the tumor microenvironment.

PRGN-5001 Multifunctional Therapeutic has exhibited the ability to enhance T cell activation and superior anti-tumor effects compared to anti-PD1 treatment in different humanized mouse models, including colorectal, lung, and cervical cancers, that do not respond well to anti-PD1 treatments.

The preclinical data supports the potential for expansion to multiple targets.

We plan to initiate IND-enabling studies for PRGN-5001 in 2020 and we are evaluating the optimal path forward for our Multifunctional Therapeutic platform, including ongoing partnership discussions.

We also have a number of other potential product candidates in our preclinical pipeline and, consistent with our commitment to actively manage our portfolio programs, we plan to systematically evaluate data from our preclinical programs in order to make rapid "go" and "no go" decisions with respect to those candidates.

Through this process, we will allocate resources to programs that we believe show the most promise and advance such programs to the clinic.

Partnered Programs

We also are engaged in a number of collaborations, pursuant to which our platforms are being used to advance additional product candidates.

AG013 (Oragenics, Inc.)

ActoBio is in collaboration with Oragenics for the continued development and commercialization of AG013 for use in the treatment of OM in humans through the administration of an effector via genetically modified bacteria.

AG013 has been granted fast track designation by the FDA.

AG013, built on the ActoBiotics platform, is a convenient and well-tolerated oral rinsing solution to deliver human Trefoil Factor 1, or hTFF1, via genetically modified L.

lactis is freeze dried and then mixed with a raspberry-flavored solution that the patient swishes after every meal.

The swishing causes the delivery of hTFF1 to buccal mucosa, which is intended to prevent mucosal tissue damage and induce subsequent repair.

OM is a side effect of chemo- or radio-therapy in cancer patients caused by the breakdown of the mucosal lining and results in the formation of painful oral ulcers.

This condition leads to nutritional deficits due to an inability to eat and drink.

There are highly unmet medical needs for the prevention and treatment of OM, with no drug approved to prevent the condition in the broad cancer population and few treatments with confirmed efficacy available to manage OM.

There are approximately 770,000 cancer patients annually in the United States that are at increased risk of developing OM.

AG013 was shown to be well-tolerated by head and neck cancer patients that were receiving induction chemotherapy in a completed Phase 1b single blind, placebo-controlled study in head and neck cancer patients receiving induction chemotherapy.

The Phase 1b data showed that patients receiving AG013 experienced fewer days with ulcerative OM, or UOM, and fewer unscheduled office and emergency room visits as a result of UOM, as compared to patients that received the placebo.

A total of 29% of patients treated with AG013 reported fewer than two days of UOM while all placebo-treated patients experienced more than two days of UOM.

In addition, a 40% reduction in unscheduled office and emergency room visits compared to placebo was observed, as well as a 35% reduction in percentage of days with UOM compared to placebo.

AG013 is now in a Phase 2 clinical trial for the treatment of oral mucositis in patients with head and neck cancer.

We expect interim data from this Phase 2 study in the first half of 2020.

AG013 has been granted fast track designation by the FDA and orphan drug designation by the European Union.

Pursuant to the collaboration with Oragenics, ActoBio is entitled to certain milestone payments and royalties related to the development and commercialization of AG013.

FCX-007 and FCX-013 (Castle Creek Pharma)

We have a collaboration with Fibrocell Sciences, Inc., which is now a wholly owned subsidiary of Castle Creek Pharmaceutical Holdings, Inc., to advance product candidates FCX-007, which initiated a pivotal Phase 3 clinical trial for the treatment of recessive dystrophic epidermolysis bullosa (RDEB) in July 2019, and FCX-013, which is currently enrolling the Phase 1 portion of its Phase 1/2 clinical trial for the treatment of localized scleroderma.

FCX-007 and FCX-013 each have been granted Orphan Drug designation, Rare Pediatric Disease designation and Fast Track designation by the FDA.

The FDA has also granted FCX-007 Regenerative Medicine Advanced Therapy designation.

Pursuant to the collaboration, we license our technology platforms to Fibrocell for use in certain specified fields and in exchange we have received and are entitled to certain access fees, milestone payments, royalties, and sublicensing fees related to the development and commercialization FCX-007 and FCX-013.

CGF166 (Novartis AG)

We are party to a research collaboration and license agreement through a wholly owned subsidiary with Novartis Institutes for BioMedical Research, Inc., or Novartis, for the discovery and development of novel treatments for hearing loss and balance disorders.

Under the terms of the agreement, our wholly owned subsidiary licensed world-wide rights to our preclinical hearing loss and balance disorders program to Novartis in exchange for an upfront payment and certain milestone payments related to the development and commercialization of certain licensed products.

We are also entitled to tiered royalties on the annual net sales of the licensed products should any achieve commercialization.

Currently, one of our product candidates, CGF166, is in a Phase 1/2 clinical trial for the treatment of hearing loss and balance disorders in collaboration with Novartis under this agreement.

Our Manufacturing Strategy

A core focus of our research and development program to date has been reducing risk, minimizing cost, and addressing drawbacks associated with conventional manufacturing approaches with the goal of improving safety and efficacy.

As such, we have both developed therapeutic candidates that reduce manufacturing risk by eliminating the need for centralized manufacturing, and

strategically invested in internal manufacturing capabilities to de-risk our clinical production.

UltraCAR-T Manufacturing

Our development of rapid and successful overnight manufacturing of UltraCAR-T therapies at medical centers signifies a paradigm shift in CAR-T therapy by eliminating a multitude of manufacturing and timing risks associated with conventional CAR-T therapies.

Our proprietary technologies and unique manufacturing approach rely on non-viral plasmid DNA and the elimination of ex vivo expansion, leading to reduced manufacturing time and cost.

This manufacturing process has significant competitive advantages over conventional approaches, and our intent is for it to take place directly in numerous treatment centers, which can improve the accessibility of our therapies for patients.

See "Our Therapeutic Platforms - UltraCAR-T" for more information.

cGMP Manufacturing Facility

These include technology transfer risks when outsourcing to contract manufacturing organizations as well as process and timing risks.

This modular cGMP facility with a small footprint was designed with agility and control in mind, focusing on rapid manufacturing and the ability to scale production appropriately to meet early-stage clinical trial needs of gene therapy vectors;

especially our AdenoVerse based therapeutics.

We are able to generate greater than 1,000 doses of early phase clinical trial material at this facility at an expedited timeline and reduced cost compared to contract manufacturing organizations.

As a result, we feel we are in a position to be in control of meeting our gene therapy manufacturing needs for our early-phase clinical trials.

ActoBiotics Manufacturing

Our microbe-based therapeutic platform, ActoBiotics, can deliver protein-based therapeutic agents locally using well-characterized and safe food-grade bacterium L.

We have established an efficient and reliable cGMP manufacturing process for the production of ActoBiotics that we believe is easily scalable for commercial supply.

The manufacturing process involves fermentation of genetically modified L.

lactis to generate the active ingredient, followed by concentration and freeze-drying.

This process provides a competitive advantage, we believe, because there is no need for the costly purification process required to produce conventional biologics.

See "Our Therapeutic Platforms - ActoBiotics" for more information.

We recently completed our Phase 1 clinical trial of INXN-4001, which was a first-in-human, open label study designed to evaluate the safety of retrograde coronary sinus infusion, or RCSI, of INXN-4001 in outpatient left ventricular assist device, or LVAD, recipients.

Twelve stable patients with implanted LVAD for mechanical support of end stage heart failure were allocated into two cohorts of six subjects for infusion of the same amount of INXN-4001 (80mg) in either 40mL or 80mL via RCSI at a rate of 20mL per minute.

The primary objectives of the Phase 1 study are to evaluate the safety of INXN-4001 infusion into the myocardium of LVAD patients and to demonstrate safety and feasibility of RCSI.

Secondary endpoints include improvements in the six minute walk test, or 6MWT, duration and distance and quality of life, as assessed by Kansas City Cardiomyopathy Questionnaire, or KCCQ, responses.

We have completed dosing and follow-up of patients in this trial.

In August 2020, we provided six-month follow-up data from the Phase 1 study of INXN-4001.

Twelve chronic heart failure patients were treated with INXN-4001 in either Cohort 1 (80 mg/40 mL;

n=6) or Cohort 2 (80 mg/80 mL;

n=6), and ten were

evaluated for six-month follow-up.

The study has met the primary endpoints to evaluate safety and feasibility for INXN-4001.

The infusions of INXN-4001 were overall well tolerated, with no adverse events attributed to INXN-4001, whereas one serious adverse event was considered related to the infusion procedure.

Furthermore, preliminary assessment of the secondary endpoints show improvement by at least five points in total KCCQ score, a validated tool qualified by the FDA for Clinical Outcome Assessment, was observed in 50 percent of patients evaluable (5 out of 10) at the six-month follow-up visit, These included four patients treated in Cohort 1 and one patient treated in Cohort 2.

Of the evaluable patients, 50 percent (4 out of 8) had an improvement in the 6MWT (> 50 meters in distance walked) at six months post-infusion compared to pre-treatment baseline.

The Phase 1 trial has now been completed, and analysis of final results is ongoing.

Precigen Exemplar

Historically, researchers have lacked animal models that faithfully represent human diseases.

As a result, a sizeable barrier has blocked progress in the discovery of human disease mechanisms;

novel diagnostics, procedures, devices, prevention strategies and therapeutics;

and the ability to predict in humans the efficacy of those next-generation procedures, devices, and therapeutics.

Exemplar's MiniSwine models are genetically engineered to exhibit a wide variety of human disease states, which provides a more accurate platform to test the efficacy of new medications and devices.

Partnered Program

We have partnered with Castle Creek Biosciences, Inc.

(formerly Fibrocell Science, Inc.), or Castle Creek, to advance product candidates D-Fi (debcoemagene autoficel), formerly designated FCX-007, for the treatment of recessive dystrophic epidermolysis bullosa, or RDEB, and FCX-013 for the treatment of localized scleroderma.

In October 2020, Castle Creek announced the dosing of the first patient in the ongoing Phase 3 trial of D-Fi and the dosing of the first patient in the ongoing Phase 1/2 trial of FCX-013.

The FDA has granted Orphan Drug designation to D-Fi for the treatment of Dystrophic Epidermolysis Bullosa, which includes RDEB.

In addition, D-Fi has been granted Rare Pediatric Disease designation, Fast Track designation, and Regenerative Medicine Advanced Therapy designation by the FDA for treatment of RDEB.

The FDA has granted Orphan Drug designation to FCX-013 for the treatment of localized scleroderma.

In addition, FCX-013 has been granted Rare Pediatric Disease designation and Fast Track designation for the treatment of moderate to severe localized scleroderma.

Pursuant to the collaboration, we licensed our technology platforms to Castle Creek for use in certain specified fields, and in exchange, we received and were entitled to certain access fees, milestone payments, royalties, and sublicensing fees related to the development and commercialization of product candidates.

In March 2020, we and Castle Creek terminated the original collaboration agreement by mutual agreement, with the parties agreeing that FCX-007 and FCX-013 would be treated as "Retained Products" under the terms of the original agreement.

Castle Creek retains a license to continue to develop and commercialize the Retained Products within the field of use for so long as Castle Creek continues to pursue such development and commercialization, and we are also entitled to certain royalties with respect to the Retained Products.

We are also required to perform certain drug product manufacturing activities related to the Retained Products.

Healthcare Business

While we believe that our novel approach to developing the next generation of gene and cell therapies to target the most urgent and intractable challenges in immuno-oncology, autoimmune disorders, and infectious diseases provides us with competitive advantages, our industry is highly competitive and subject to rapid and significant technological change.

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Our ability to compete successfully will depend on our ability to develop proprietary technologies that can be used to produce products that reach the market in a timely manner and are technologically superior to and/or are less expensive than other products on the market.

The availability of reimbursement from government and other third-party payors will also significantly affect the pricing and competitiveness of our products.

Our competitors may also obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.

The availability of reimbursement from government and other third-party payers will also significantly affect the pricing and competitiveness of our products.

Key product features that would affect our ability to effectively compete with other therapeutics include the efficacy, safety and convenience of our products, as well as the availability of intellectual property protection.

Immuno-oncology

Our lead product candidates include PRGN-3005 for the treatment of ovarian cancer and PRGN-3006 for the treatment of AML, which are built on our UltraCAR-T platform.

While we are employing a novel approach, there are a number of competitors pursuing

CAR-T cell therapies for the treatment of cancer.

We believe that Bristol-Myers Squibb and MaxCyte are developing CAR-T based treatments for ovarian cancer and Celyad, Mustang Bio, MolMed, Amgen (Gilead / Kite partnership), Cellectis S.A., and Allogene Therapeutics are also using CAR-T technology to develop product candidates for the treatment of AML.

Our lead product candidates include PRGN-3005 for the treatment of ovarian cancer and PRGN-3006 for the treatment of AML, which are built on our UltraCAR-T platform, and PRGN-2009, which is based on our AdenoVerse immunotherapy platform.

While we are employing a novel approach, there are a number of competitors pursuing CAR-T cell therapies for the treatment of cancer.

We believe that, among others, Bristol-Myers Squibb, Tmunity Therapeutics, and MaxCyte are developing CAR-T based treatments for ovarian cancer and TCR2 Therapeutics is developing TCR-T based treatment for ovarian cancer.

We believe that Celyad, Mustang Bio, Amgen, Cellectis S.A., and Allogene Therapeutics are also using CAR-T technology to develop product candidates for the treatment of AML.

We believe that INOVIO Pharmaceuticals, AstraZeneca, Transgene SA, and Advaxis Immunotherapies are developing immunotherapies against HPV-associated cancers.

Bristol-Myers Squibb's product candidate, JCAR020, is a MUC16-IL-12 armored T-cell therapy being developed to treat ovarian cancer.

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JCAR020 is engineered with "armored CAR" technology to co-express CAR and IL-12, a cytokine that can help overcome the inhibitory effects that the tumor micro-environment can have on T cell activity.

Tmunity Therapeutics is developing Tm Tn-MUC 01 CAR-T for various solid tumors including ovarian cancer.

This candidate targets TnMUC-1 antigen on tumor cells.

Tmunity Therapeutics is also developing TmFRα01 CAR-T targeting folate receptor alpha for ovarian cancer.

MaxCyte's MCY-M11 is a mesothelin-specific human mRNA CAR-T cell therapy being developed to treat ovarian cancer.

MCY-M11 is a non-viral approach that uses repeated infusions of mesothelin-specific messenger RNA (mRNA) transfected T cells transiently expressing CAR to permit prospective control of 'on-target/off-tumor' toxicity.

For the treatment of AML using CAR-T therapies, we believe that Celyad, Mustang Bio, and MolMed have product candidates in the most advanced clinical trials.

Celyad's product candidate is an NKG2D-based CAR-T approach that uses the OptimAb manufacturing process, which generates a higher frequency of less differentiated CAR-T cells.

Celyad's product candidate exhibited enhanced anti-tumor activity in preclinical studies and is now being studied with and without lymphodepletion.

Mustang Bio's product candidate is an anti-CD123 CAR-T cell therapy.

CD123 is widely expressed on bone marrow cells of patients with myelodysplastic syndromes, as well as in hematologic malignancies, including AML, and Mustang Bio's MB-102 (CD123 CAR T) is a CAR-T cell therapy that is produced by engineering patient T cells to recognize and eliminate CD123-expressing tumors.

MolMed is developing an anti-CD44v6 CAR-T cell therapy that involves isolating the patient's T cells and modifying them ex vivo with a viral vector.

The T cells are engineered to express the CAR and the HSV-TK suicide gene already used in Zalmoxis ® .

The CAR facilitates the lymphocytes ability to recognize and kill the tumor cells, while the suicide gene allows for the elimination of the T lymphocytes in the case of a toxic reaction against the patient's healthy tissue.

We believe that Amgen and Cellectis S.A.'s products are in Phase 1 clinical trials.

Amgen is developing an FMS-like tyrosine kinase 3, or FLT3, CAR-T cell therapy utilizing autologous T cells genetically modified ex vivo to express a transmembrane CAR to target FLT3 protein on the surface of AML cells irrespective of FLT3 mutational status.

TCR2 Therapeutics' TC-210 targets mesothelin and is based on TCR Fusion Construct T cells, or TRuC-T cells, technology and is manufactured using lentiviral transduction of autologous T cells.

For the treatment of AML using CAR-T therapies, we believe that Celyad and Mustang Bio have product candidates in the most advanced clinical trials.

Celyad's product candidate, CYAD-02, is an NKG2D-based CAR-T with co-expression of a single shRNA targeting NKG2DL, MICA and MICB, that uses the OptimAb manufacturing process, which generates a higher frequency of less differentiated CAR-T cells.

CYAD-02 is in clinical trials for r/r AML or MDS patients.

Mustang Bio's product candidate, MB-102, is an autologous CAR-T cell therapy that is produced by engineering patient T cells to recognize and eliminate CD123-expressing tumors.

Amgen is developing AMG 553, an FMS-like tyrosine kinase 3, or FLT3, CAR-T cell therapy utilizing autologous T cells genetically modified ex vivo to express a transmembrane CAR to target FLT3 protein on the surface of AML cells irrespective of FLT3 mutational status.

Cellectis S.A.

is also developing an anti-CD123 CAR-T cell therapy, which utilizes gene editing, lentivector transduction and "Pulse Agile" electroporation technology.

Finally, Allogene Therapeutics' anti-FLT3 CAR-T cell therapy, which we believe is in preclinical development for AML, is manufactured using healthy donor T-cells that are engineered to express a gene-edited CAR directed against FLT3, a receptor tyrosine kinase with high expression in AML stem cells and utilizes an off-switch activated by rituximab to enable CAR-T cell depletion via CDC and ADCC.

In addition to our direct competitors that are using CAR-T therapies specifically for the treatment of ovarian cancer and AML, the CAR-T technology space has significant other competition including from multiple companies and their collaborators, such as Novartis and University of Pennsylvania, Gilead, Adaptimmune and GSK, Autolus Therapeutics, and Bellicum Pharmaceuticals.

We also face competition from non-cell based cancer treatments offered by other companies such as Amgen, AstraZeneca, Incyte, Merck, and Roche.

See "Our Therapeutic Platforms - UltraCAR-T," "Our Product Pipeline - PRGN-3005" and "Our Product Pipeline - PRGN-3006" for a discussion of the features that we believe differentiate UlltraCAR-T treatments in general and PRGN-3005 and PRGN-3006 specifically from our competitors.

is also developing UCART123, an allogeneic anti-CD123 CAR-T cell therapy, which utilizes lentivector transduction followed by TALEN-mediated gene editing to eliminate expression of TCRαβ from donor T cells.

Finally, Allogene Therapeutics' allogeneic CAR-T therapies ALLO-316 and ALLO-819, targeting FLT3 and CD70, respectively, which we believe are in preclinical development for AML, are manufactured using healthy donor T-cells that are engineered using lentiviral transduction to express CAR followed by gene editing to eliminate expression of TCR to reduce the potential of rejection of therapy by a patient's immune system.

In addition to our direct competitors that are using CAR-T therapies specifically for the treatment of ovarian cancer and AML, the CAR-T technology space has significant other competition including from multiple companies and their collaborators, such as Novartis and University of Pennsylvania, Kite and Gilead, Adaptimmune and GSK, Autolus Therapeutics, Poseida Therapeutics, and Bellicum Pharmaceuticals.

We also face competition from non-cell based cancer treatments offered by other companies such as Amgen, AstraZeneca, Incyte, Merck, Abbvie, and Roche.

See "Our Therapeutic Platforms - UltraCAR-T," "Our Product Pipeline - PRGN-3005" and "Our Product Pipeline - PRGN-3006" for a discussion of the features that we believe differentiate UltraCAR-T treatments in general and PRGN-3005 and PRGN-3006 specifically from our competitors.

For the treatment of HPV-associated cancers, we believe that INOVIO Pharmaceuticals, AstraZeneca, and Transgene S.A.

are developing immunotherapies that are in clinical testing.

TG4001 is an investigational therapeutic cancer vaccine candidate using an attenuated and modified poxvirus, or MVA, as a vector expressing the HPV16 E6 and E7 proteins and interleukin-2.

We believe TG4001 is in a clinical trial in combination with anti-PD-L1 antibody avelumab for recurrent HPV+ cancers.

INOVIO's lead investigational candidate VGX-3100 is a plasmid DNA based vaccine designed to increase T cell immune responses against the E6 and E7 antigens of HPV16 and HPV18.

VGX-3100 is in clinical trials for precancerous cervical dysplasia.

We believe AstraZeneca's MEDI0457, an investigational DNA vacine designed by INOVIO, is in clinical trials for various HPV-associated cancers.

MEDI0457 is a multi-component DNA vaccine that uses different DNA plasmids to express modified sequences for E6 and E7 antigens of HPV16 and HPV18 and immune activator interleukin-12, or IL-12.

developing BVAC-C, which is based on CeliVax technology that uses patient-derived B cells and monocytes transfected with E6/E7 recombination gene of HPV16 and HPV18 and loaded with an adjuvant for HPV-associated cancers.

In addition to our direct competitors developing vaccines for treatment of HPV-associated cancers, various development-stage companies are involved in different vaccine and immunotherapy technologies, including Advaxis Immunotherapies, Bavarian Nordic, and Altimmune.

We also face competition from non-vaccine based approaches being developed by companies such as Kite, Iovance, Bristol-Myers Squibb, and Merck.

Infectious Diseases

Our lead product candidate is PRGN-2012, which is based on our AdenoVerse immunotherapy platform, for the treatment of RRP.

While we believe our approach for PRGN-2012 is novel based on the design of antigen targeting HPV6 and HPV11 and use of our gorilla adenovector, we face competition in the treatment of RRP.

We believe our main competitor in the field is INOVIO Pharmaceuticals with their investigational DNA vaccine INO-3107 targeting HPV6 and HPV11 antigens.

Autoimmune Disorders

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While we believe AG019 is the first disease-modifying treatment for T1D, there are a number of competitors pursuing immunotherapy product candidates to treat T1D.

We believe that our primary competitors with respect to the development of immunotherapies for T1D are Caladrius BioSciences, Midatech Pharma, and MerciaPharma.

We believe that our primary competitors with respect to the development of immunotherapies for T1D are Provention Bio, Midatech Pharma, and MerciaPharma.

Intellectual Property

As we advance technologies, correspondingly, we apply a multilayered approach for protecting intellectual property relating to the inventions we have developed internally as well as those we have acquired from third parties, such as by assignment or by in-license.

We seek patent protection in the United States and in other countries for our inventions and discoveries, and we develop and protect our key know-how and trade secrets relating to our platform technologies as well as to the product candidates we are developing with our subsidiaries and through our collaborations.

We seek patent protection for our platform technologies with a focus on our product pipeline, including but not limited to our (i) various switch technologies;

(ii) gene delivery technologies;

and (iii) our portfolio around various genetic componentry such

as specialized vectors containing these genetic componentry.

We apply a multilayered approach for protecting intellectual property relating to the inventions we have developed internally, as well as those we have acquired from third parties, such as by assignment or by in-license.

As we advance technologies, we evaluate and determine under the circumstances what type or types of intellectual property is appropriate for the technology, including patents, trademarks, know-how and trade secret protections.

We seek patent protection in the United States and in other countries for our inventions, and we develop and protect our know-how and trade secrets relating to our platform technologies, as well as to our pipeline products including those of our subsidiaries and collaborators.

For instance, we pursue protection to switch technologies, gene delivery technologies, and genetic componentry related to our pipeline products.

In addition, we seek patents covering specific collaborator's products.

Our success depends, in part, upon our ability to obtain patents and maintain adequate protection for our intellectual property relating to our technologies and product pipeline candidates.

We have adopted a strategy of seeking patent protection in the United States and in other jurisdictions globally as we deem appropriate under the circumstances, with respect to certain of the technologies used in or relating to our technologies and product pipeline candidates.

For instance, where we believe appropriate, we have also filed counterpart patents and patent applications in other jurisdictions, including Australia, Argentina, Brazil, Canada, China, Europe, Hong Kong, India, Indonesia, Israel, Japan, Korea, Mexico, New Zealand, Philippines, Russia, Singapore, South Africa and Taiwan.

We focus our intellectual property on aspects of our platforms and technologies that provide for the design and creation of cells, vectors and components for our pipeline and the pipelines of our collaborators, as well as technologies directed to improve delivery and expression of our pipeline products.

Our success depends, in part, upon our ability to obtain patents and maintain adequate protection for our intellectual property relating to our technologies and product pipeline.

For instance, where we believe appropriate, we have counterpart patents and patent applications in other jurisdictions, such as Australia, Brazil, Canada, China, Europe, Hong Kong, India, Indonesia, Israel, Japan, Korea, Mexico, New Zealand, Philippines, Russia, Singapore, South Africa and Taiwan.

In the future, we may file in these or additional jurisdictions as deemed appropriate for the protection of our technologies.

As of December 31, 2019 , we owned at least 55 issued United States patents and 55 pending United States patent applications relating to certain aspects of our platforms and technologies, and we have pursued counterpart patents and patent applications in other jurisdictions around the world, as we have deemed appropriate.

We continue to actively develop our portfolio through the filing of new patent applications, provisional and continuations or divisionals relating to our technologies, methods and products as we and our collaborators deem appropriate.

We divested of 20 issued United States patents and 23 pending United States patent applications as part of the Transactions.

We have strategic positioning with respect to our key technologies directed to:

As of December 31, 2020, we owned or in-licensed at least 55 issued United States patents and 40 pending United States patent applications relating to various aspects of our platforms and technologies, and we have pursued counterpart patents and patent applications in other jurisdictions around the world, as we have deemed appropriate.

We continue to actively develop our portfolio through the filing of new patent applications, provisional and continuations or divisionals relating to our advancing technologies, methods and products as we and our collaborators deem appropriate.

We work to maintain protection for our key technologies including:

our various switch technologies, with a last to expire patent currently in 2038;

our portfolio around various gene delivery technologies and their use, with a last to expire patent in 2040;

our portfolio around various genetic componentry such as specialized vectors containing these genetic componentry and their use, with a last to expire patent in 2039.

and our portfolio around various genetic componentry such as specialized vectors containing these genetic componentry and their use, with a last to expire patent in 2042.

Although we have no certainty that these patents will not be subject to challenge in the future, as of this filing, there are currently no material contested proceedings and/or third-party claims with respect to any of these patent portfolios.

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We further solidify our intellectual property protection through a combination of trade secrets, know-how, confidentiality, nondisclosure and other contractual provisions, and security measures to protect our confidential and proprietary information related to each platform and collaborator program.

We regularly assess and review the risks and benefits of protecting our developments through each aspect of intellectual property available to us.

We regularly assess and review the risks and benefits of protecting our developments through various aspects of intellectual property available to us.

Because we rely on trade secrets, know-how, and continuing technological advances to protect various aspects of our technology, we require our employees, consultants and scientific collaborators to execute confidentiality and invention assignment agreements with us to maintain the confidentiality of our trade secrets and proprietary information.

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Regulatory Environment

With our diverse portfolio of proprietary technologies and novel therapeutic candidates, we are subject to significant and diverse regulations governing research, operations and product approval.

With our diverse portfolio of proprietary technologies and novel therapeutic candidates, we are subject to significant and diverse regulations governing, among other things, research, operations and product approval.

Regulatory compliance is critical to our ability to operate, our management of potential liabilities, and ultimately, our freedom to sell our products.

Moreover, and as discussed below and in "Risk factors - Risks associated with our business strategy," the products we are pursuing or are produced by us are subject to extensive regulation.

Moreover, the products we are pursuing or are produced by us are subject to extensive regulation.

We also rely on our collaborators' compliance with laws and regulations applicable to the products they produce.

We do not independently monitor whether our collaborators comply with applicable laws and regulations.

Please see the risk factor entitled "Markets in which we and our collaborators are developing products using our technologies are subject to extensive regulation, and we rely on our collaborators to comply with all applicable laws and

regulations."

Please see the risk factor entitled "We rely on third parties, including through collaborations, to develop and commercialize some of our product candidates.

Markets in which our collaborators are developing product candidates using our technologies are subject to extensive regulation, and we rely on our collaborators to comply with all applicable laws and regulations."

Environmental regulations affecting us and our collaborators

We and our collaborators are subject to various federal, state and local environmental laws, rules and regulations, including those relating to the discharge of materials into the air, water and ground, the generation, storage, handling, use, transportation and disposal of hazardous materials and the health and safety of employees with respect to laboratory activities required for the development of products and technologies.

the generation, storage, handling, use, transportation and disposal of hazardous materials;

and the health and safety of employees with respect to laboratory activities required for the development of products and technologies.

These laws and regulations require us and our collaborators to obtain environmental permits and comply with numerous environmental restrictions.

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All of our employees must comply with safety instructions and procedures, which are codified in our employment policies.

Federal and state laws and regulations impose requirements on the production, importation, use and disposal of chemicals and genetically-modified microorganisms, or GMMs, which impact us and our collaborators.

Our and our collaborators' processes may contain GE organisms which, when used in industrial processes, are considered new chemicals under the Toxic Substances Control Act, or TSCA, program of the United States Environmental Protection Agency, or EPA.

Federal and state laws and regulations impose requirements on the production, importation, use, and disposal of chemicals and genetically-modified microorganisms which impact us and our collaborators.

Our and our collaborators' processes may contain genetically engineered organisms which, when used in industrial processes, are considered new chemicals under the Toxic Substances Control Act program of the United States Environmental Protection Agency, or EPA.

These laws and regulations would require us and our collaborators to obtain and comply with the EPA's Microbial Commercial Activity Notice process to operate.

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Human therapeutics regulation

Government authorities in the United States, at the federal, state and local level, and in other countries extensively regulate, among other things, the research, development, testing, manufacture, including any manufacturing changes, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, import and export of pharmaceutical products such as those being developed by our collaborators.

Governmental authorities in the United States, at the federal, state and local level, and in other countries extensively regulate, among other things, the research, development, testing, manufacture, including any manufacturing changes, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, sale, marketing, import and export of therapeutic products such as those being developed by us and our collaborators.

The processes for obtaining regulatory approvals in the United States and in foreign countries, along with subsequent compliance with applicable statutes, regulations, and requirements imposed by regulatory agencies, require the expenditure of substantial time and financial resources.

In the United States, pharmaceuticals must receive approval from the FDA before being marketed.

In the United States, pharmaceuticals and biological products must receive approval from the FDA before being marketed.

The FDA approves drug products other than biological products through its authority under the Federal Food, Drug, and Cosmetic Act, or FDCA, and implementing regulations.

The FDA licenses biological drug products, or biologics, through its authority under the Public Health Service Act, or PHSA, and implementing regulations.

The FDA licenses biological products, or biologics, through its authority under the Public Health Service Act, or PHSA, and implementing regulations.

The development processes for obtaining FDA approval for a non-biological drug product under the FDCA and for biologic licensure under the PHSA are generally similar but have product-related differences reflected in regulations and in FDA guidance documents.

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The process required by the FDA before a pharmaceutical product candidate may be marketed generally involves the following:

completion of preclinical laboratory tests and in vivo studies in accordance with the FDA's current Good Laboratory Practice regulations and standards, and other applicable requirements;

• completion of preclinical laboratory tests and in vivo studies in accordance with applicable regulatory requirements, which may include the FDA's current Good Laboratory Practice regulations and the Animal Welfare Act;

• submission to the FDA of an IND for human clinical testing, which must become effective before human clinical trials commence;

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• preparation and submission to the FDA of an application for marketing approval that includes substantial evidence of safety, purity and potency for a biologic, or of safety and efficacy for a non-biologic drug, including from results of nonclinical testing and clinical trials;

satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the product candidate is produced to assess compliance with cGMP and to assure that the facilities, methods and controls are adequate to preserve the product candidate's identity, safety, strength, quality, potency and purity;

• satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the product candidate is produced to assess compliance with cGMP and that the methods and controls are adequate to assure the product candidate's identity, safety, strength, quality, potency and purity;

• potential FDA inspection of the nonclinical and clinical trial sites that generated the data in support of the application;

• FDA review and approval of the application.

Preclinical testing

Before testing any product candidate in humans in the United States, a company must develop preclinical data, generally including laboratory evaluation of the product candidate's chemistry and formulation, as well as toxicological and pharmacological studies in animal species to assess safety and quality.

Certain types of animal studies must be conducted in compliance with the FDA's Good Laboratory Practice regulations and the Animal Welfare Act, which is enforced by the Department of Agriculture.

IND application

A person or entity sponsoring clinical trials in the United States to evaluate a product candidate's safety and effectiveness must submit to the FDA, prior to commencing such trials, an IND application, which contains preclinical testing results and other data and information that allow the FDA to evaluate whether there is an adequate basis for testing the drug in humans.

If the FDA does not object to the IND application within 30 days of submission, the clinical testing proposed in the IND may begin.

Even after the IND has gone into effect and clinical testing has begun, the FDA may put clinical trials on "clinical hold," suspending or, in some cases, ending them because of safety concerns or for other reasons.

Human clinical trials under an IND

Clinical trials involve administering the product candidate to healthy volunteers or patients under the supervision of qualified investigators.

Clinical trials must be conducted and monitored in accordance with the FDA's regulations.

Clinical trials must be conducted and monitored in accordance with the FDA's regulations, such as GCP requirements.

Each clinical trial must also be conducted under a protocol that details, among other things, the study objectives, parameters for monitoring safety, and the efficacy criteria, if any, to be evaluated.

The protocol is submitted to the FDA as part of the IND and reviewed by the agency.

Further, each clinical trial must be reviewed and approved by an Institutional Review Board, or IRB, at or servicing each institution at which the clinical trial will be conducted.

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 clinical trials are minimized and are reasonable in relation to anticipated benefits.

Clinical trials involving recombinant DNA at institutions that receive any funding from the National Institutes of Health also must be reviewed by an institutional biosafety committee, an institutional committee that reviews and oversees basic and clinical research that utilizes recombinant DNA at that institution.

The sponsor of a clinical trial, the investigators, and IRBs each must comply with requirements and restrictions that govern, among other things, obtaining informed consent from each study subject, complying with the protocol and investigational plan, adequately monitoring the clinical trial, and timely reporting adverse events.

Clinical trials involving recombinant or synthetic nucleic acid molecules, such as DNA, conducted at institutions that receive any funding from the National Institutes of Health also must be reviewed by an institutional biosafety committee, an institutional committee that reviews and oversees basic and clinical research that utilizes recombinant DNA at that institution.

The sponsor of a clinical trial or the sponsor's designated responsible party may be required to register certain information about the trial and disclose certain results on government or independent registry websites, such as clinicaltrials.gov .

Human clinical trials typically are conducted in three sequential phases that may overlap or be combined:

The product candidate is introduced into healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain early understanding of its effectiveness.

The product candidate is introduced into a small number of healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain early understanding of its effectiveness.

For some product candidates for severe or life-threatening diseases, especially when the product candidate may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients with the targeted disease.

The product candidate is administered and evaluated in a limited patient population to identify possible adverse effects and safety risks, to evaluate preliminary efficacy evidence for specific targeted diseases and to determine dosage tolerance, optimal dosage and dosing schedule.

The product candidate is administered to an expanded patient population, often at geographically dispersed clinical trial sites, in adequate and well-controlled clinical trials to generate sufficient data to evaluate the safety and efficacy of the non-biologic drug, or the safety, purity, and potency of the biologic.

These clinical trials are intended to establish the overall risk/benefit ratio of the product candidate and provide an adequate basis for product labeling.

The product candidate is administered to an expanded patient population with the target disease or disorder, often at geographically dispersed clinical trial sites, in adequate and well-controlled clinical trials to generate sufficient data to evaluate the safety and efficacy of the non-biologic drug, or the safety, purity, and potency of the biologic.

These clinical trials are intended to establish the overall risk/benefit profile of the product candidate and provide an adequate basis for product labeling.

Post-approval clinical trials, sometimes referred to as Phase 4 clinical trials, may be conducted, or may be required to be conducted, after initial approval to further assess the risk/benefit profile of the product and to gain additional experience from treatment of patients in the intended indication, including for long-term safety follow-up.

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and long-term follow-up measures to observe delayed adverse effects in subjects exposed to investigational gene therapies when the risk of such effects is not low or when the gene therapy utilizes genome-editing technology, shows signs of persistence, has the potential for latency and reactivation, or genetically alters the human genome.

Compliance with cGMP requirements

Drug and biologics manufacturers must comply with applicable cGMP regulations.

Manufacturers and others involved in the manufacture and distribution of such products also must register their establishments with the FDA and certain state agencies.

Both domestic and foreign manufacturing establishments must register and provide additional information to the FDA upon

their initial participation in the manufacturing of drugs.

Establishments may be subject to periodic, unannounced inspections by the FDA and other government authorities to ensure compliance with cGMP requirements and other laws.

Discovery of problems may result in a government entity placing restrictions on a product, manufacturer or holder of an approved product, and may extend to requiring withdrawal of the product from the market.

United States review and approval processes

The results of the preclinical tests and clinical trials, together with detailed information relating to the product's CMC and proposed labeling, among other things, are submitted to the FDA as part of an application requesting approval to market the product for one or more uses, or indications.

When an application is submitted, the FDA makes an initial determination as to

whether the application is sufficiently complete to be accepted for review.

If the application is not, the FDA may refuse to accept the application for filing and request additional information.

A refusal to file, which requires resubmission of the application with the requested additional information, delays review of the application.

For gene therapies, selecting patients with applicable genetic defects is often a necessary condition to effective treatment and may require diagnostic devices that the FDA has cleared or approved prior to or contemporaneously with approval of the gene therapy.

Under the Pediatric Research Equity Act, or PREA, marketing applications generally must contain data to assess the safety and effectiveness of the biologic product candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product candidate is safe and effective.

Under the Pediatric Research Equity Act, or PREA, certain marketing applications generally must contain data to assess the safety and effectiveness of the product candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product candidate is safe and effective.

The FDA may grant deferrals for submission of data or full or partial waivers.

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The FDA may impose restrictions and conditions on product distribution, prescribing or dispensing in the form of a Risk Evaluation and Mitigation Strategy, or REMS, or otherwise limit the scope of any approval.

In addition, the FDA may require post-marketing clinical trials designed to further assess a non-biologic drug's safety and effectiveness, or a biologic's safety, purity, and potency, and testing and surveillance programs to monitor the safety of approved products that have been commercialized.

In addition, the FDA may require postmarketing clinical trials designed to further assess the risk/benefit profile of the product and to gain additional experience from treatment of patients in the intended indication, including for long-term safety follow-up.

Compliance with cGMP requirements

Drug and biologics manufacturers must comply with applicable cGMP regulations.

Manufacturers and others involved in the manufacture and distribution of such products also must register their establishments with the FDA and certain state agencies.

Both domestic and foreign manufacturing establishments must register and provide additional information to the FDA upon their initial participation in the manufacturing of drugs.

Establishments may be subject to periodic, unannounced inspections by the FDA and other government authorities to ensure compliance with cGMP requirements and other laws.

Discovery of problems may result in a government entity placing restrictions on a product, manufacturer or holder of an approved product application and may extend to requiring withdrawal of the product from the market.

Orphan Drug Designation in the United States

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A sponsor of a product application that has received an orphan drug designation is also granted tax incentives for clinical research undertaken to support the application.

In addition, the FDA will typically coordinate with the sponsor on research study design for an orphan drug and may exercise its discretion to grant marketing approval on the basis of more limited

product safety and efficacy data than would ordinarily be required, based on the limited size of the applicable patient population.

In addition, the FDA may coordinate with the sponsor on research study design for an orphan drug and may exercise its discretion to grant marketing approval on the basis of more limited product safety and efficacy data than would ordinarily be required, based on the limited size of the applicable patient population.

Orphan drug designation does not, however, change the legal standard required for a product candidate to obtain FDA approval.

Fast Track Designation

The FDA has a number of expedited review programs for drugs that are intended for the treatment of a serious or life-threatening condition.

As one example, under the agency's Fast Track program, the sponsor of a new drug candidate may request the FDA to designate the product for a specific indication as a Fast Track product concurrent with or after the filing of the IND for the product candidate, if nonclinical and clinical data demonstrate the product's potential to address unmet medical needs and the product is intended to treat a serious condition.

The FDA must determine if the product candidate qualifies for Fast Track designation within 60 days after receipt of the sponsor's request.

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The FDA may grant regenerative medicine advanced therapy, or RMAT, designation to regenerative medicine therapies, which may include cell therapies, human gene therapies, therapeutic tissue engineering products, and human cell and tissue products, if certain criteria are met.

In particular, a drug may be eligible for RMAT designation if the drug is a regenerative medicine therapy as defined in Section 506(g)(8) of the Federal Food, Drug, and Cosmetic Act;

In particular, a drug may be eligible for RMAT designation if the drug is a regenerative medicine therapy as defined in Section 506(g)(8) of the FDCA;

the drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition;

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Changes to the product, manufacturing process, or facility often require prior FDA approval before being implemented and other types of changes to the approved product, such as adding new indications and additional labeling claims, are also subject to further FDA review and approval.

Additionally, the FDA may require postmarketing studies or clinical trials, changes to a product's approved labeling, including the addition of new warnings and contraindications, or the implementation of other risk management measures, including distribution restrictions, if new safety information emerges.

Failure to comply with the applicable requirements may result in administrative, judicial, civil or criminal actions and adverse publicity.

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In 2010, the federal Biologics Price Competition and Innovation Act, or BPCIA, was enacted, creating a statutory pathway for licensure, or approval, of biological products that are biosimilar to, and possibly interchangeable with, reference biological products licensed under the Public Health Service Act.

Under the BPCIA, innovator manufacturers of original biological products are granted 12 years of exclusive use after first licensure before biosimilar versions of such products can be licensed for marketing in the United States.

Under the BPCIA, innovator manufacturers of original biological products are granted 12 years of marketing exclusivity after first licensure before biosimilar versions of such products can be licensed for marketing in the United States.

This means that the FDA may not approve an application for a biosimilar product that references data in an innovator's Biologics License Application, or BLA, until 12 years after the date of approval of the reference biological product, with a potential six-month extension of exclusivity if certain pediatric studies are conducted and the results are reported to the FDA.

A biosimilar application may be submitted four years after the date of licensure of the reference biological product, but the FDA cannot

approve the application until the full exclusivity period has expired.

A biosimilar application may be submitted four years after the date of licensure of the reference biological product, but the FDA cannot approve the application until the full exclusivity period has expired.

This 12-year exclusivity period operates independently from other protections that may apply to biosimilar competitors, including patents that are held for those products.

Additionally, the BPCIA establishes procedures by which the biosimilar applicant must provide information about its application and product to the reference product sponsor, and by which information about potentially relevant patents is shared and litigation over patents may proceed in advance of approval.

Additionally, the BPCIA establishes procedures by which the biosimilar applicant must provide information about its application and product to the reference product sponsor and by which information about potentially relevant patents may be shared and litigation over patents may proceed in advance of approval.

The BPCIA also provides a period of exclusivity for the first biosimilar to be determined by the FDA to be interchangeable with the reference product.

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Other regulatory exclusivity may be granted to drugs, including, but not limited to, three-year and five-year exclusivity granted to non-biologic drugs under the Drug Price Competition and Patent Term Restoration Act of 1984, also referred to as the Hatch-Waxman Amendments.

Depending upon the timing, duration, and specifics of FDA approval of product candidates, some of a sponsor's United States patents may be eligible for limited patent term extension under the Hatch-Waxman Amendments.

Depending upon the timing, duration, and specifics of FDA approval of a product candidate, some of a sponsor's United States patents may be eligible for limited patent term extension under the Hatch-Waxman Amendments.

The Hatch-Waxman Amendments permit a patent restoration term of up to five years as compensation for patent term lost during product development and the FDA regulatory review process.

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Foreign regulation of human therapeutics

In addition to regulations in the United States, our subsidiaries, such as PGEN and ActoBio, and our collaborators that are focused on the development of human therapeutic products will be subject to a variety of foreign regulations governing clinical trials and commercial sales and distribution of the products enabled by our technologies.

In addition to regulations in the United States, our subsidiaries, such as PGEN Therapeutics and ActoBio, and our collaborators that are focused on the development of human therapeutic products will be subject to a variety of foreign regulations governing clinical trials and commercial sales and distribution of the products enabled by our technologies.

Whether or not the developer obtains FDA approval for a product, they must obtain approval by the comparable regulatory authorities of foreign countries or economic areas, such as the European Union, before they may commence clinical trials or market products in those countries or areas.

The approval process and requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary greatly from place to place, and the time may be longer or shorter than that required for FDA approval.

Regulation of microbes and microbial products

The use of GMMs, such as our yeast and methanotroph strains, is subject to laws and regulations in many countries.

In the United States, the EPA regulates the commercial use of many GMMs as well as potential products produced from GMMs.

Various states within the United States could choose to regulate products made with GMMs as well.

While the strain of genetically-modified yeast that we use, S.

cerevisiae, is eligible for exemption from EPA review because it is generally recognized as safe, we must satisfy certain criteria to achieve this exemption, including, but not limited to, use of compliant containment structures and safety procedures.

We expect to encounter GMM regulations in most if not all of the countries in that we may seek to make our products;

however, the scope and nature of these regulations will likely vary from country to country.

If we cannot meet the applicable requirements in countries in which we intend to produce our products using GMMs, then our business will be adversely affected.

Non-Healthcare Assets and Transition to Our Core Healthcare Business Model

Historically, we focused on programming biological systems for application across a variety of diverse end markets, including health, food, energy, and environment, but we have also consistently evolved the way in which we apply our synthetic biology technologies and the opportunities on which we have focused.

In January 2020, we announced that we are increasing our focus on certain of our healthcare opportunities, which reflect our most-advanced platforms, and in connection therewith we divested a number of our non-healthcare assets and changed our name to Precigen, Inc.

However, we continue to own our methane bioconversion business and our established bovine genetics company.

Prior to refocusing our business on healthcare, we sought to apply our synthetic biology technologies to a broad universe of markets.

In order to operate in such a variety of markets, we built our business around collaborations, such as ECCs and JVs.

Over time, we evolved away from entering into new collaborations and considered ways to reorganize our business to best leverage our

technology assets and focus on the opportunities that we believe are of the most immediate promise.

Effective January 1, 2018, we transferred substantially all of our gene and cell therapy assets for human health to a newly-formed wholly owned subsidiary, PGEN, and we consolidated therapeutic applications of our proprietary ActoBiotics platform under ActoBio, another wholly owned subsidiary.

In May 2019, we announced the alignment of our operations into two units focused on healthcare and bioengineering in order to better deploy resources, realize inherent synergies and position the company for growth with a core focus on healthcare.

In January 2020, we furthered our plans to enhance our focus on the healthcare industry when we sold a number of our bioengineering assets, or the TS Biotechnology Sale, to TS Biotechnology.

Kirk, who is the former CEO of Precigen and is currently the Executive Chairman and a member of our board of directors, serves as the Senior Managing Director and Chief Executive Officer of Third Security and owns 100 percent of the equity interests of Third Security.

The assets divested in the TS Biotechnology Sale included our domain name dna.com and all of our equity interests in (1) Blue Marble AgBio LLC, or Blue Marble AgBio, a Delaware limited liability company, that we formed to hold our agricultural biotechnology assets, (2) ILH Holdings, Inc., or ILH Holdings, a Delaware corporation, which housed our yeast fermentation technology platform for the biologic production of active pharmaceutical ingredients and other fine chemicals, (3) Intrexon Produce Holdings, Inc., or IPHI, a Delaware corporation, which owns Okanagan Specialty Fruits, Inc., or Okanagan Specialty Fruits, the agricultural company developing non-browning apple without the use of any artificial additives, (4) Intrexon UK Holdings Inc., or Intrexon UK Holdings, a Delaware corporation, which owns Oxitec, Ltd., or Oxitec, the developer of an insect-based biological control system, (5) Oragenics, which is developing antibiotics against infectious disease and, in collaboration with ActoBio, treatments for oral mucositis, and (6) SH Parent, Inc., or SH Parent, a Delaware corporation, which held our ownership interests in Surterra Holdings, Inc., or Surterra, a cannabinoid-based wellness company.

In addition, in January 2020, in a separate transaction, we sold our interest in EnviroFlight, LLC, or EnviroFlight, to Darling.

See "Notes to the Consolidated Financial Statements - Note 3 " appearing elsewhere in this Annual Report for a discussion of the Transactions and the discontinued operations.

Remaining Non-Healthcare Businesses

While our primary focus is in healthcare, after the Transactions we continue to have two non-healthcare businesses:

our methane bioconversion business, MBP Titan, LLC, or MBP Titan, and our established bovine genetics company, Trans Ova Genetics, L.C., or Trans Ova.

MBP Titan is our standalone subsidiary comprising our Methane Bioconversion Platform, or MBP, and our associated technologies, personnel, and facilities.

Our MBP is designed to turn natural gas into more valuable and usable energy and chemical products through novel, highly engineered bacteria that utilize specific energy feedstocks.

This technology can use pipeline grade natural gas, to synthesize commercial end products, such as isobutanol for gasoline blending, 2,3 Butanediol for conversion to synthetic rubber and 1,4 Butanediol for polyester.

Traditional methods of feedstock conversion for fuel production and other materials are costly, wasteful and often come with significant environmental impact.

The MBP production method has the potential to transform the generation of drop-in fuels, synthetic rubber, plastic material, and animal feed through less resource intensive and more sustainable approaches than conventional methods.

In aggregate, the value of such fuel and chemical products and animal feed are significant, representing the potential of billions of dollars in estimated market opportunity.

We are currently assessing the appropriate next steps with respect to the future of our MBP platform, which could include a financing directly into MBP Titan, or other strategic alternatives.

As part of this assessment, we are also considering the future of our joint ventures with Intrexon Energy Partners and Intrexon Energy Partners II.

See "Notes to the Consolidated Financial Statements - Note 5" appearing elsewhere in this Annual Report for a discussion of Intrexon Energy Partners and Intrexon Energy Partners II and other significant collaborations between us and our JVs.

Anti-Kickback, False Claims, and Other Marketing and Fraud and Abuse Laws

Healthcare providers, physicians and others will play a primary role in the recommendation and prescription of any products for which we obtain marketing approval.

Our future arrangements with healthcare providers, patients and third-party payers will expose us to broadly applicable United States fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and collaborative partners through which we market, sell and distribute any products for which we obtain marketing approval.

Restrictions under applicable federal and state healthcare laws and regulations are discussed in the "Risk Factors" section below.

In the United States, we may be subject to data privacy and security laws and regulations by both the federal government and the states in which we conduct our business.

The legislative and regulatory landscape for privacy and data protection continues to evolve, and there has been an increasing focus on privacy and data protection issues which may affect our business.

Numerous federal and state laws and regulations, including state data breach notification laws, state health information and/or genetic privacy laws and federal and state consumer protection laws (e.g., Section 5 of the Federal Trade Commission, or FTC, Act and the California Consumer Privacy Act, or CCPA), govern the collection, use, disclosure, and protection of health-related and other personal information.

Many of these laws differ from each other in significant ways and may not have the same

effect, thus complicating compliance efforts.

Compliance with these laws is difficult, constantly evolving, and time consuming.

Federal regulators, state attorneys general, and plaintiffs' attorneys, including class action attorneys, have been and will likely continue to be active in this space.

The Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes requirements relating to the privacy, security and transmission of individually identifiable health information.

We may obtain health information from third parties, such as research institutions, that are subject to privacy and security requirements under HIPAA.

Although we are not directly subject to HIPAA other than with respect to providing certain employee benefits, we could potentially be subject to criminal penalties if we, our affiliates, or our agents knowingly obtain, use, or disclose individually identifiable health information maintained by a HIPAA-covered entity in a manner that is not authorized or permitted by HIPAA.

In addition, the CCPA became effective on January 1, 2020 and establishes certain requirements for data use and sharing transparency, and provides California residents certain rights concerning the use, disclosure, and retention of their personal data.

The CCPA and its implementing regulations have already been amended multiple times since their enactment.

Similarly, there are a number of legislative proposals in the United States, at both the federal and state level that could impose new obligations or limitations in areas affecting our business.

These laws and regulations are evolving and subject to interpretation, and may impose limitations on our activities or otherwise adversely affect our business.

The CCPA and evolving legislation may require us, among other things, to update our notices and develop new processes internally and with our partners.

Healthcare Reform

In the United States and some foreign jurisdictions, there have been, and continue to be, a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could, among other things, prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities, and affect our ability, or the ability of any collaborators, to profitably sell any products for which we, or they, obtain marketing approval.

We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we, or any collaborators, may receive for any approved products.

The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively, the Affordable Care Act, has substantially changed the way healthcare is financed by both governmental and commercial payers and significantly impacts the pharmaceutical industry.

Certain provisions of the Affordable Care Act have been subject to judicial challenges, as well as efforts to repeal, replace, or otherwise modify them or to alter their interpretation or implementation.

For example, the Tax Cuts and Jobs Act, or Tax Act, enacted on December 22, 2017 eliminated the tax-based payment for individuals who fail to maintain minimum essential coverage under section 5000A of the Internal Revenue Code of 1986, as amended, commonly referred to as the "individual mandate," effective January 1, 2019.

Additional legislative changes, regulatory changes, and judicial challenges related to the Affordable Care Act remain possible.

It is unclear how the Affordable Care Act and its implementation, as well as efforts to repeal, replace, or otherwise modify, or invalidate, the Affordable Care Act, or portions thereof, will affect our business.

In addition, other legislative changes have been proposed and adopted since the Affordable Care Act was enacted.

For example, the Budget Control Act of 2011, as amended, among other things led to aggregate reductions in Medicare payments for all items and services, including prescription drugs and biologics, to service providers of, on average, 2 percent per fiscal year beginning April 1, 2013, and, due to subsequent legislation, continuing until 2030 (with the exception of a temporary suspension from May 1, 2020, through March 31, 2021) unless Congress takes additional action.

It is possible that the Affordable Care Act, as currently enacted or may be amended in the future, as well as other healthcare reform measures that may be adopted in the future, and their implementation may result in additional reductions in Medicare and other healthcare funding, more rigorous coverage criteria, and new payment methodologies and in additional downward pressure on coverage and payment and the price that we receive for any approved product.

Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from commercial payers.

The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our products.

Transition to Our Core Healthcare Business Model

Historically, we developed technology platforms for application across a variety of diverse end markets, including health, food, energy, and environment.

In January 2020, we announced that we were increasing our focus on our healthcare opportunities, which reflected our most advanced platforms, and in connection therewith, we divested a number of our non-healthcare assets and changed our name to Precigen, Inc.

These transactions included the sale of a number of our non-healthcare assets, or the TS

Biotechnology Sale, to TS Biotechnology Holdings, LLC, or TS Biotechnology, an entity formed by Third Security, LLC, or Third Security.

Kirk, who is the former CEO of Precigen and is currently the Executive Chairman and a member of our board of directors, serves as the Senior Managing Director and Chairman of Third Security and owns 100 percent of the equity interests of Third Security.

In addition, in January 2020, in a separate transaction, we sold our interest in EnviroFlight, LLC, or EnviroFlight, to Darling Ingredients, Inc., or Darling.

As a result of market uncertainty driven by the COVID-19 pandemic and the state of the energy sector raising significant challenges for the strategic alternatives pursued by MBP Titan, LLC, or MBP Titan, our methane bioconversion business, beginning in the second quarter of 2020 and throughout the remainder of 2020, we suspended MBP Titan's operations, preserved certain of MBP Titan's intellectual property, terminated all of its personnel, and undertook steps to dispose of its other assets and obligations.

The wind down of MBP Titan's activities was substantially complete by December 31, 2020, with the final disposition of certain property and equipment and the facility operating lease occurring in January 2021.

This discontinuation of operations represented the continuation of a strategic shift that we commenced in early 2020 to becoming a primarily healthcare company advancing technologies and products that address complex healthcare challenges.

After the wind down of MBP Titan, certain assets and contractual obligations which were originally related to MBP Titan continue to be managed at the Precigen corporate level.

These remaining assets and contractual obligations include our equity interests in and collaboration agreements with Intrexon Energy Partners, LLC, or Intrexon Energy Partners, and Intrexon Energy Partners II, LLC, or Intrexon Energy Partners II, including the associated deferred revenue remaining under each collaboration agreement, as well as the associated intellectual property.

See also "Notes to the Consolidated Financial Statements - Note 3" appearing elsewhere in this Annual Report for additional discussion of our discontinued operations.

See "Notes to the Consolidated Financial Statements - Note 5" appearing elsewhere in this Annual Report for a discussion of Intrexon Energy Partners and Intrexon Energy Partners II.

Non-Healthcare Business

At December 31, 2020, our only non-healthcare business is our established bovine genetics company, Trans Ova Genetics, L.C., or Trans Ova.

Trans Ova is internationally recognized as a provider of industry-leading bovine reproductive technologies.

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Through extensive research programs and applied science, Trans Ova has developed and implemented new technologies that, we believe, have helped to move the science of bovine genetic improvement forward.

We and Trans Ova are evaluating the optimal means to utilize these technology assets and Trans Ova's broad customer base and deep industry knowledge to maximize the value of the business.

We continue to evaluate the optimal means to utilize these technology assets and Trans Ova's broad customer base and deep industry knowledge to maximize the value of the business.

As of December 31, 2020, Trans Ova had 183 production employees.

Trans Ova's primary domestic production facilities, including approximately 360 acres of land, are located in Sioux Center, Iowa.

The land and facilities are primarily used for our embryo

transfer and in vitro fertilization processes, as well as housing livestock used in such processes.

As of December 31, 2019, Trans Ova also leased or owned regional production facilities and land in California, Maryland, Missouri, New York, Oklahoma, South Dakota, Texas, and Washington for these purposes.

The land and facilities are primarily used for our embryo transfer and IVF processes, as well as housing livestock used in such processes.

As of December 31, 2020, Trans Ova also leased or owned regional production facilities and land in California, Maryland, Missouri, South Dakota, Texas, Washington, and Wisconsin for these purposes.

Non-Healthcare Assets

Energy Markets

MBP Titan differentiates itself through its use of cellular engineering experience and suite of technologies to develop environmentally-friendly products in the chemical and animal feed industries.

While we believe this proprietary platform holds the potential to modernize the existing gas-to-liquids industry by generating important fuels and chemicals at a fraction of the cost of traditional conversion methods, any products MBP Titan develops will still compete with legacy technologies and approaches to fuel production.

Many of MBP Titan's competitors in the energy market are significantly larger than MBP Titan and have significantly greater financial, technical and human resource capabilities.

Further, MBP Titan is still developing our products and scaling them, while its competitors, who are utilizing more traditional methods, have the benefit of developed processes that are accepted by the market.

In addition, there are others, including competitors with better financial, technical, and resources, and more experience, pursuing alternatives fuels as well as companies pursuing technologies based on the conversion of methanotrophs in the energy sector.

MBP Titan's ability to compete successfully will depend on its ability to develop and produce products that can be scaled to reach the market in a timely manner and are environmentally superior to and/or are less expensive to produce than other products on the market.

Animal Genetics Market

We believe Trans Ova's focus on continuous research and use of applied science allow Trans Ova to develop and implement new technologies that will help move the science of bovine genetic improvement forward rapidly and differentiate it from its competitors.

We believe Trans Ova's focus on continuous research and use of applied science allows Trans Ova to develop and implement new technologies that will help move the science of bovine genetic improvement forward rapidly and differentiate it from its competitors.

However, there are a number of companies that compete with Trans Ova, including traditional breeding companies and other companies that use advanced reproductive technologies.

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Finally, Trans Ova's competitors that operate using more traditional breeding techniques may enjoy greater market acceptance over Trans Ova, and other companies, that utilize genetic manipulation, semen sorting and cloning techniques.

Energy and Chemical Regulation

The environmental regulations discussed above also govern the development, manufacture and marketing of energy and chemical products.

Chemical products produced by us and our collaborators may be subject to government regulations in our target markets.

In the United States, the EPA administers the requirements of the TSCA, which regulates the commercial registration, distribution and use of many chemicals.

Before an entity can manufacture or distribute significant volumes of a chemical, it needs to determine whether that chemical is listed in the TSCA inventory.

If the substance is listed, then manufacture or distribution can commence immediately.

If not, then in most cases a "Chemical Abstracts Service" number registration and pre-manufacture notice must be filed with the EPA, which has 90 days to review the filing.

A similar requirement exists in Europe under the REACH regulation.

Additional regulations may apply to specific subsets of chemicals such as, for example, fuel products that are subject to regulation by various government agencies including, in the United States, the EPA and the California Air Resources Board.

Our Historic Operations

Until the closing of the Transactions, we operated under a strategy that allowed us to focus on our core expertise in synthetic biology while developing many different commercial product candidates via collaborations in a broad range of industries or end markets.

We built our business primarily around the formation of ECCs, as well as certain research collaborations.

Over time, our strategy has evolved away from ECC-type collaborations to relationships and structures that provided us with more control and ownership over the development process and commercialization path.

In these new relationships and structures, we had more of the responsibility to fund the projects and execute on product candidate development.

Eventually, we aligned our businesses into two units comprising our healthcare and bioengineering assets, a number of which we sold in early 2020.

Some of the key businesses that we divested in connection with our focus on healthcare, include the following operating subsidiaries and JVs:

Okanagan Specialty Fruits, Inc.

Okanagan is the pioneering agricultural company behind the world's first non-browning apple without the use of any artificial

Under our control, we worked with Okanagan to scale up its commercial supplies of non-browning apples and to develop new commercial tree fruit varieties intended to provide benefits to the entire supply chain, from growers to consumers.

In 2020, we sold Okanagan in the TS Biotechnology Sale.

AquaBounty Technologies, Inc.

AquaBounty Technologies, Inc., or AquaBounty, is a company focused on improving productivity in commercial aquaculture, including the development of the AquAdvantage Salmon, an Atlantic salmon that has been genetically enhanced to reach market size in less time than conventionally farmed Atlantic salmon and approved by the FDA.

Until October 2019, AquaBounty was a partially owned subsidiary of ours.

In October 2019, we sold our ownership interests held in AquaBounty to an affiliate of Third Security.

In February 2016, we entered into a series of transactions involving a predecessor to EnviroFlight, or Old EnviroFlight, Darling, and a newly formed venture between us and Darling, EnviroFlight.

This series of integrated transactions resulted in us acquiring substantially all of the assets of Old EnviroFlight and contemporaneously contributing all of these assets, with the exception of certain developed technology, and $3 million of cash to EnviroFlight in exchange for a non-controlling, 50 percent membership interest in EnviroFlight.

Our contributions to EnviroFlight included an exclusive license to the developed technology that was retained by us.

Darling received the remaining 50 percent membership interest in EnviroFlight as consideration for terminating rights previously held in the developed technology with Old EnviroFlight.

EnviroFlight was formed to generate high nutrition, low environmental impact animal and fish feed, as well as fertilizer products, from black soldier fly larvae.

On January 2, 2020, we sold all of our interests in EnviroFlight to Darling.

Oxitec Limited

Oxitec is a pioneering company in biological insect control solutions.

Oxitec is developing products that use genetic engineering to control insect pests that spread disease and damage crops.

Among the applications of its platform, which uses advanced genetics and molecular biology, Oxitec has developed innovative solutions for controlling Aedes aegypti , a mosquito that is a known vector for the transmission of infectious disease including dengue fever, chikungunya, and Zika virus and, in conjunction with its collaborators, is pursuing solutions that target certain agricultural crop pests.

Oxitec is pursuing regulatory and commercial approvals for its insect solutions in a number of countries, including the United States.

In 2020, we sold Oxitec in the TS Biotechnology Sale.

COVID-19 Impact

COVID-19 has had and continues to have an extensive impact on the global health and economic environments.

The health and safety of our employees is of the utmost importance.

Our essential employees are practicing appropriate safety measures, including social distancing and use of personal protective equipment.

These efforts have permitted us to continue to advance our programs, with the ultimate goal of benefiting patients.

Commencing in the second half of March 2020, our healthcare business began to experience delays to certain of our clinical trials as a result of COVID-19.

For example, starting in March 2020, ActoBio temporarily suspended the last cohort of the Phase 1b/2a clinical trial for AG019 as a proactive measure to protect the welfare and safety of patients, caregivers, clinical site staff, our employees, and contractors.

The temporary suspension of the AG019 trial was voluntary and was not related to any patient safety issues in the study.

The voluntary suspension of the AG019 trial was lifted in June 2020, and the study is recruiting patients again.

Additionally, from April to May 2020, enrollment of new patients in our PRGN-3005 Phase 1 trial was temporarily suspended due to a mandated hold on certain early and late-stage clinical trials at the Fred Hutchinson Cancer Research Center in Seattle that was instituted in light of the COVID-19 pandemic.

Recruitment resumed in the PRGN-3005 trial in May 2020.

At this time, we do not expect that these suspensions will result in significant overall delay.

Furthermore, uncertainty regarding the duration and severity of the ongoing pandemic may adversely impact our clinical as well as preclinical pipeline candidates in the future.

Notwithstanding the foregoing, as the COVID-19 pandemic continues to evolve, we may experience additional delays to our clinical trials, including related to enrollment, site closures, reduced availability of key personnel, or our ability to receive the necessary approvals from the FDA or other regulatory agencies to advance our programs.

We are also closely monitoring the impact of COVID-19 on other aspects of our business.

While Trans Ova and Exemplar have not experienced any significant impacts as a result of COVID-19 at this time, we are unable to reliably quantify or estimate what future impacts may be.

In addition, we have taken certain steps with respect to our operations of MBP Titan as a result of the impacts of the COVID-19 pandemic and other factors.

See "Transition to Our Core Healthcare Business Model" above.

Given the dynamic nature of these circumstances, the full impact of the COVID-19 pandemic on our ongoing business, results of operations, and overall financial performance cannot be reasonably estimated at this time.

For more information regarding the risks associated with COVID-19 and its impact on our business, see "Risk Factors - Risks Related to Our Business."

Reportable Segments

Through March 31, 2019, we operated as a single operating segment.

In April 2019, in our efforts to better deploy resources and realign our business, our chief operating decision maker, or CODM, began assessing the operating performance of and allocating our resources for several operating segments using Segment Adjusted EBITDA.

As of December 31, 2019, taking into account the effect of the Transactions, our reportable segments are (i) PGEN Therapeutics, (ii) ActoBio, (iii) MBP Titan, and (iv) Trans Ova.

As of December 31, 2020, our reportable segments are (i) PGEN Therapeutics, (ii) ActoBio, (iii) Trans Ova, and (iv) the Human Biotherapeutics division.

These identified reportable segments met the quantitative thresholds to be reported separately for the year ended December 31, 2020.

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Research and Development

As of December 31, 2019 , we had 366 research and development employees.

As of December 31, 2020, we had 140 employees supporting our research and development functions of our healthcare operations, including operational and facility activities.

We incurred expenses of $41.6 million, $66.7 million and $333.0 million in 2020, 2019, and 2018, respectively, on research and development activities for continuing operations.

We anticipate that our research and development expenditures could increase as we focus on the healthcare industry and further advance our internally developed programs, including those we reacquired from former collaborators in 2018.

As of December 31, 2019 , our primary domestic research and development operations were located in laboratory facilities in Germantown, Maryland;

South San Francisco, California;

and Davis, California;

and our primary international research and development operations were located in laboratory facilities in Budapest, Hungary;

Ghent, Belgium;

Campinas, Brazil;

and Oxford, England.

In connection with the Transactions, we no longer have research and development facilities in Davis, California;

Budapest, Hungary;

Campinas, Brazil;

and Oxford, England and have reduced our research and development employees to 227 as of February 1, 2020.

We anticipate that our research and development expenditures could increase as we advance our healthcare programs and platforms.

As of December 31, 2020, our primary domestic research and development operations were located in laboratory facilities in Germantown, Maryland, and our primary international research and development operations were located in a laboratory facility in Ghent, Belgium.

Financial Information

Collaboration revenues, product revenues, service revenues and other revenues and operating income for each of the last three fiscal years, along with assets as of December 31, 2019 and 2018 , are set forth in the consolidated financial statements, which are included in Item 8 of this Annual Report.

Collaboration revenues, product revenues, service revenues and other revenues and operating loss for each of the last three fiscal years, along with assets as of December 31, 2020 and 2019, are set forth in the consolidated financial statements, which are included in Item 8 of this Annual Report.

Financial information about geographic areas is set forth in "Notes to the Consolidated Financial Statements - Note 20" appearing elsewhere in this Annual Report.

As of December 31, 2019 , we had 770 full-time and 87 part-time employees.

As of February 1, 2020, after the closing of the Transactions, we had 601 full-time employees and 79 part-time employees, of which 210 full-time and 18 part-time employees supported healthcare and 391 full-time and 61 part-time employees supported our remaining non-healthcare assets.

We consider our employee relations to be good.

As we continue to streamline our operations and focus on healthcare, we believe the ratio of healthcare and non-healthcare employees will continue to change, with an expected decrease in the number of employees dedicated to supporting our remaining non-healthcare assets.

Corporate information

We are a Virginia corporation formed in 1998 and our principal executive offices are located at 20374 Seneca Meadows Parkway, Germantown, MD 20876, and our telephone number is (301) 556-9900.

Human Capital Management

As of December 31, 2020, we had 194 employees in support of our healthcare operations, of which 140 support our research and development functions including operational and facility activities.

Of these research and development employees, 59 have

advanced degrees, of which 35 are PhDs.

Our corporate employees provide support to all of our operating subsidiaries and are responsible for the execution of all corporate functions, including executive, operational, finance, information technology, legal, and corporate communications.

In addition to our healthcare operations, Trans Ova employs 229 full-time employees and 54 part-time employees.

None of our employees are represented by a collective bargaining agreement.

We structure our compensation packages to compete for the best scientific talent.

Our compensation packages include a competitive base salary and bonus, the issuance of equity incentives, and health and wellness benefits, including a health insurance plan with a Platinum actuarial value.

We are proud of the fact that our domestic healthcare operations and corporate functions include 40 percent of employees in ethnic and racial minority groups and also the fact that 46 percent of the same population of employees are women.

Our recent employee development initiatives included employee training targeting specific areas of interest, executive and manager coaching, and performance management which encompass performance goals and competency evaluations.

We implemented safety protocols in response to the COVID-19 pandemic including increased cleaning protocols, employee preventative measures, contract tracing, and bi-weekly virus testing.

These measures enabled us to have the majority of our research and development employees return to their workplaces by early June 2020.

Additional Information

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What changed 10-K

Item 1. Business