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Item 1. Business

2022-02-24 compared with 2021-02-26 · 417 added, 324 removed, 811 unchanged (48% of the section changed)

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Our mission is to translate the promise of gene editing into a broad class of differentiated, transformational medicines for diseases with high unmet need.

We have developed a proprietary genome editing platform based on CRISPR technology and we continue to expand its capabilities.

We have developed a proprietary gene editing platform based on CRISPR technology and we continue to expand its capabilities.

CRISPR uses a protein-RNA complex composed of an enzyme, including either Cas9 (CRISPR associated protein 9) or Cas12a (CRISPR from Prevotella and Francisella 1, also known as Cpf1), bound to a guide RNA molecule designed to recognize a particular DNA sequence.

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Our product development strategy is to target diseases of high unmet need where we aim to make differentiated, transformational medicines using our gene editing platform.

We are advancing both in vivo gene-editing medicines, in which the medicine is injected or infused into the patient to edit the cells inside their body, and ex vivo gene-edited cell medicines, in which cells are edited with our technology and then administered to the patient.

While our discovery efforts have ranged across several diseases and therapeutic areas, the two areas where our programs are more mature are our in vivo medicines to treat ocular diseases and ex vivo gene-edited cell medicines to treat hemoglobinopathies and cancer.

For our in vivo gene-editing medicines, we are leveraging an adeno-associated virus (“AAV”)-mediated editing platform with our proprietary Staphylococcus aureus Cas9 (“SaCas9”) to develop these medicines.

In ocular diseases, our most advanced program is designed to address a specific genetic form of retinal degeneration called Leber congenital amaurosis 10 (“LCA10”), a disease that leads to blindness and for which we are not aware of any available therapies and only one other potential treatment is in clinical trials in the United States and Europe.

In mid-2019, we initiated our Phase 1/2 BRILLIANCE clinical trial for EDIT-101, an experimental gene-editing medicine to treat LCA10 .

We plan to enroll up to 18 patients in the United States and Europe in up to five cohorts.

We completed dosing of the first cohort, the adult low-dose cohort, in 2020.

Due to an absence of severe adverse events or dose limited toxicity in adults treated in the first cohort, the inclusion criteria of the protocol was modified to allow inclusion of subjects with better than light perception vision only.

Although we experienced slowed enrollment in 2020 for subsequent cohorts due to the ongoing impact of the COVID-19 pandemic, in the first quarter of 2021 we initiated dosing of the second cohort, the adult mid-dose cohort.

We expect to announce initial clinical data in 2021 .

We believe our preclinical results to date with EDIT-101 validate our platform technology, including its potential application to other ocular diseases, such as Usher syndrome 2A (“USH2A”) , a form of retinitis pigmentosa that also includes hearing loss, and autosomal dominant retinitis pigmentosa 4 (“adRP4”) , a progressive form of retinal degeneration characterized by initial night blindness early in life followed by loss of peripheral vision and eventual complete blindness , as well as diseases of other organs and tissues.

In 2019, we achieved in vivo preclinical proof of concept and declared a development candidate, referred to as EDIT-102, for USH2A.

We have also advanced preclinical studies for our adRP4 program , and expect to declare a development candidate for the treatment of adRP4 by the end of 2021 .

We are advancing in vivo gene editing medicines, in which the medicine is injected or infused into the patient to edit the cells inside their body, ex vivo gene-edited cell medicines, in which cells collected from a patient are edited with our technology and then administered back to that same patient, and cellular therapy medicines, in which we use our technology to edit induced human pluripotent stem cells that are subsequently differentiated into effector cells, such as natural killer (“NK”) cells, to develop medicines that can be administered to a patient .

While our discovery efforts have ranged across several diseases and therapeutic areas, the areas where our programs are more mature are our in vivo medicines to treat ocular diseases, our ex vivo gene-edited cell medicines to treat hemoglobinopathies and our cellular therapy medicines to treat cancer.

For our in vivo gene editing medicines, we are leveraging an adeno-associated virus (“AAV”)-mediated editing platform with our proprietary Staphylococcus aureus Cas9 (“SaCas9”) and Acidaminococcus sp.

Cas12a (“AsCas12a”) to develop medicines.

In ocular diseases, our most advanced program is designed to address a specific genetic form of retinal degeneration called Leber congenital amaurosis 10 (“LCA10”), a CEP290-related retinal degenerative disorder that leads to blindness and for which we are not aware of any available therapies.

In mid-2019, we initiated our Phase 1/2 BRILLIANCE clinical trial of EDIT-101, an experimental gene editing medicine to treat LCA10 .

EDIT-101 has been granted Rare Pediatric Disease and Orphan Drug designations from the U.S.

Food and Drug Administration (“FDA”) and Orphan Designation from the European Medicines Agency (“EMA”).

The BRILLIANCE trial is designed to assess the safety, tolerability, and efficacy of EDIT-101.

We initially planned to enroll up to 18 patients in the United States and Europe in up to five cohorts, and in 2021 completed dosing of the first three cohorts, the adult low-, mid- and high-dose cohorts.

We are expanding enrollment in one or more of the previously completed adult cohorts to explore dose response and support establishment of registrational trial endpoints.

We anticipate establishing these registrational trial endpoints by the end of 2022.

We remain on track to complete dosing of the pediatric mid-dose cohort in the first half of 2022, and expect to initiate dosing of the pediatric high-dose cohort in 2022.

In the third quarter of 2021, we released preliminary clinical data from the first six patients with LCA10 treated with EDIT-101 demonstrating a favorable safety profile and encouraging signals of clinical benefit.

For additional information regarding these clinical data, please see “Business—Our Gene Editing Medicine Programs—In Vivo Gene Editing Medicines - Ocular —Leber Congenital Amaurosis 10.” We expect to provide a clinical update on the

BRILLIANCE trial in the second half of 2022, including safety and efficacy assessments on all patients who have had at least six months of follow-up evaluations.

We believe that our achievement of proof-of-concept with EDIT-101 validates our foundational in vivo technology, including its potential application to other ocular diseases, such as autosomal dominant retinitis pigmentosa (“adRP”), a progressive form of retinal degeneration characterized by initial night blindness early in life followed by loss of peripheral vision and eventual complete blindness, and Usher syndrome 2A (“USH2A”), a form of retinitis pigmentosa that also includes hearing loss, as well as diseases of other organs and tissues.

In December 2021, we declared a development candidate, referred to as EDIT-103, which we are progressing towards investigational new drug (“IND”)-enabling studies, for treatment of rhodopsin-associated adRP (“RHO-adRP”).

We also continue to optimize our previously declared development candidate for USH2A, referred to as EDIT-102.

We expect to declare an additional development candidate for an in vivo ocular indication in 2022.

We are leveraging our AAV-mediated editing platform and expertise in ocular therapies to pursue additional therapeutic areas to treat other organ and tissues that are accessible by AAV.

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We believe that advances in genome editing will both improve the characteristics of current cellular medicines and also expand the universe of cellular medicines that can be developed.

To this end, we have established capabilities to efficiently and specifically edit hematopoietic stem cells (“HSCs”), natural killer (“NK”) cells and T cells, which we believe can lead to best-in-class medicines for hemoglobinopathies and cancer.

For our ex vivo gene-edited cell medicines, our lead program is EDIT-301, an experimental medicine to treat sickle cell disease , a severe inherited blood disease that causes premature death, and beta-thalassemia, another inherited blood disorder characterized by severe anemia.

In December 2020, we submitted an investigational new drug application (“IND”) to the U.S.

Food and Drug Administration (“FDA”) for the initiation of a Phase 1/2 clinical trial of EDIT-301, which we refer to as our RUBY trial, for the treatment of sickle cell disease.

In January 2021, the FDA cleared the start of enrollment and dosing of patients in the first phase of the study (which will validate the safety and beneficial effects of the cell editing process).

Dosing of the first subject is expected to occur in 2021.

In parallel, the FDA has imposed a partial clinical hold and requested we develop a potency assay to ensure that the characteristics of the product released are as expected and confirmed by clinical data collected in the first patients treated.

We also aim to file an IND for EDIT-301 for the treatment of beta-thalassemia by the end of 2021 .

The CRISPR nuclease used in our EDIT-301 program is a proprietary engineered form of Cas12a for which we have exclusively licensed the foundational intellectual property to develop and commercialize human therapeutics.

We believe our editing approach, including targeting the HBG1 and HBG2 promoters in the beta-globin locus where naturally occurring fetal hemoglobin inducing mutations reside (“ HBG1/2”) as well as the use of Cas12a, differentiates us from other genome editing companies with sickle cell disease programs and positions us to develop a potentially best-in-class medicine to treat sickle cell disease and beta-thalassemia.

We have also continued to develop our capabilities to generate cells from induced pluripotent stem cells (“iPSCs”) to develop engineered cell medicines to treat cancer.

For example, in 2019, we advanced development of engineered iPSC-derived NK (“iNK”) cell medicines for solid tumors using technology from BlueRock Therapeutics LP (“BlueRock”) and generated edited NK cells from iPSCs with significantly increased anti-cancer activity.

We aim to accelerate the development of iNK cell medicines for the treatment of solid tumor cancers in 2021.

We are also advancing alpha-beta T cell experimental medicines in collaboration with Juno Therapeutics, Inc., a wholly owned subsidiary of Bristol-Myers Squibb Company (“Juno Therapeutics”).

For our allogeneic, off-the-shelf medicines, we edit cells from iPSCs that are subsequently differentiated into effector cells, such as NK cells or T cells.

The engineered cells are then administered to the patient.

To this end, we have established capabilities to efficiently and specifically edit hematopoietic stem cells, which we believe can lead to best-in-class medicines for hemoglobinopathies.

For our ex vivo gene-edited cell medicines, our lead program is EDIT-301, an experimental medicine to treat sickle cell disease, a severe inherited blood disease that causes premature death, and transfusion-dependent beta-thalassemia (“TDT”), the most severe form of beta-thalassemia, another inherited blood disorder characterized by severe anemia.

In January 2021, the FDA cleared the start of enrollment and dosing of patients in the first phase of our Phase 1/2 clinical trial of EDIT-301, which we refer to as our RUBY trial, for the treatment of sickle cell disease.

This study is designed to validate the safety and beneficial effects of the cell editing process.

The RUBY trial is currently enrolling study participants and is on track to begin dosing in the first half of 2022 with initial clinical results expected by the end of 2022 .

Prior to initiating a registrational trial, we will be required to develop a potency assay to ensure that the characteristics of the product released are as expected and confirmed by clinical data collected in the first patients treated, in response to an FDA partial clinical hold .

In November 2021, we filed an IND application for a Phase 1/2 clinical trial of EDIT-301 for the treatment of TDT, which was cleared by the FDA in December 2021.

We expect to initiate dosing in this trial during 2022.

The CRISPR nuclease used in our EDIT-301 program is a proprietary engineered AsCas12a enzyme for which we have exclusively licensed the foundational intellectual property to develop and commercialize human therapeutics.

We believe our editing approach, including targeting the HBG1 and HBG2 promoters to mimic naturally occurring human mutations, analogous to patients with naturally occurring hereditary persistence of fetal hemoglobin, and the use of AsCas12a, which has demonstrated high efficiency editing of multipotent long-term hematopoietic stem cells for sustained efficacy and durability, is potentially a more effective approach with better long-term safety than other editing targets and mechanisms and positions us to develop a potentially best-in-class medicine to treat sickle cell disease and TDT.

In cellular therapy medicines, we continue to develop our capabilities to generate cells from induced human pluripotent stem cells (“iPSCs”) to develop engineered cell medicines to treat cancer.

We are able to edit cells from iPSCs that are subsequently differentiated into effector cells, such as NK cells or T cells.

These engineered cells are then administered to the patient.

We believe these approaches and expertise will allow us to develop allogeneic, off-the-shelf engineered cell medicines, as opposed to relying on obtaining cells directly from a patient.

These allogeneic cell medicines have the potential to greatly reduce the costs and complexity of engineered cells and increase the number and type of cancers that we can potentially address.

These allogeneic cell medicines have the potential to greatly reduce the costs and complexity of engineered cells and increase the number and type of cancers that we have the potential to address.

We have advanced development of engineered iPSC-derived NK (“iNK”) cell medicines for solid tumors and generated edited NK cells from iPSCs with significantly increased anti-cancer activity.

In December 2021, we declared a development candidate, referred to as EDIT-202, a highly differentiated iNK investigational medicine with double knock-in and double knock-out gene edits that are intended to enhance adaptive immune response and improve cell proliferation, cytolytic activity and persistence, as well as overcome suppressive tumor microenvironments.

We expect to advance EDIT-202 in preclinical development during 2022.

We are also advancing alpha-beta T cell experimental medicines for the treatment of solid and liquid tumors in collaboration with Bristol Myers Squibb Company (“BMS”) through its wholly owned subsidiary, Juno Therapeutics, Inc.

(“Juno Therapeutics”).

This collaboration, which leverages our Cas9 and AsCas12a platform technologies, has resulted in six ongoing programs, including one development candidate.

We also continue to evaluate the application of our iPSC platform to additional cell types beyond iNK and alpha-beta T cells.

Our Core Capability — Gene Editing

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We are able to make a blunt cut, cut either strand of the DNA, or create overhangs of differing length.

This may be a critical component of improved HDR-driven approaches because the type of DNA cut can influence the type of repair mechanism used by a cell in response to that cut.

This may be a critical component of improved HDR-driven approaches because the type of DNA

cut can influence the type of repair mechanism used by a cell in response to that cut.

We believe the ability to modify CRISPR technology to allow for different types of cuts will expand the potential of our gene editing platform.

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Firstly, a lower molecular weight enzyme will have advantages for delivering the endonuclease using a viral vector due to the inherent size limitations of most such delivery systems.

For example, the Cas9 enzyme from Staphylococcus aureus (“ S.

aureus ” or “SaCas9”) is significantly smaller than that from Streptococcus pyogenes (“ S.

For example, the Cas9 enzyme from SaCas9 is significantly smaller than that from Streptococcus pyogenes (“ S.

pyogenes ” or “SpCas9”) (3,159 vs.

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The ability to understand the quality and composition of the guide RNA is an essential component to developing product candidates that have the potential to be safe and efficacious medicines.

In addition to state-of-the-art mass spectrometry and sequencing methodologies to understand the absolute composition of our guide RNAs, we have developed two-step synthesis methods which results in guide RNAs which we believe are significantly superior to those generated by other approaches.

This method allows us to independently synthesize and purify guide RNAs in multiple parts and covalently couple them using a proprietary catalyst-free chemistry.

These covalently coupled, dual-guide RNAs retain the advantages afforded by a single guide RNA and we believe are of higher quality than a guide RNA made by a single synthesis reaction.

We believe this method will lead to higher quality gene editing medicines.

In order to understand the absolute composition of our guide RNAs, we utilize state-of-the-art mass spectrometry and sequencing methodologies.

Our gene editing platform includes multiple modular delivery modes that can be efficiently adapted to deliver different CRISPR gene editing components to address the specific needs of each disease targeted.

Our strategy is to leverage existing delivery technologies to target cell types of interest while developing next generation capabilities as warranted.

We are currently using, and will continue to use, a variety of delivery approaches, including AAVs and electroporation.

We are currently using, and will continue to use, a variety of delivery approaches, including AAVs, electroporation and lipid nanoparticles.

For example, we have taken advantage of the smaller S.

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These results are consistent across multiple cell donors and multiple target genes.

We also have developed a new gene editing technology referred to as SLEEK (SeLection by Essential-gene Exon Knock-in) to enable high knock-in efficiencies with different transgenes, while also ensuring robust, transgene expression.

Preclinical data demonstrated that SLEEK results in the knock-in of multiple clinically relevant transgenes through a proprietary process that selects for cells containing the knock-in cargo.

In addition, high percentage knock-in efficiencies were enabled by our proprietary engineered AsCas12a nuclease.

More than 95% knock-in efficiencies were observed in various clinically relevant target cells using the AsCas12a nuclease, including iPSCs, T cells, and NK cells.

Additionally, we believe SLEEK may be used to fine-tune the expression levels of transgene cargos, an important

attribute of next-generation cell therapy medicines.

We believe SLEEK is an optimal approach to achieve highly efficient multi-transgene knock-in for the next generation of cell therapy medicines, and we are leveraging this technology across our oncology programs, including for treatment of a variety of solid tumors.

To optimize the specificity of our product candidates, there are a number of different aspects of the product configuration that we customize in addition to the sequence and quality of the guide RNA, including the length of the guide RNA, the type of Cas9 or Cas12a enzyme, including engineered forms, the delivery vector, the use of tissue-selective promoters, and the duration of exposure all contribute to overall specificity.

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In ocular diseases, our most advanced in vivo gene-edited medicine, EDIT-101, is designed to treat LCA10.

We are leveraging our experience with the LCA10 program to support the development of therapies for other eye diseases, including USH2A and adRP4.

We are leveraging our experience with the LCA10 program to support the development of therapies for other eye diseases, including RHO-adRP and USH2A.

Leber Congenital Amaurosis 10

Leber congenital amaurosis (“LCA”) is a heterogeneous group of inherited retinal dystrophies caused by mutations in at least 18 different genes and is the most common cause of inherited childhood blindness, with an incidence of two to three per 100,000 live births worldwide.

Leber congenital amaurosis (“LCA”) is a heterogeneous group of inherited retinal dystrophies caused by mutations in at least 18 different genes and is a leading common cause of inherited childhood blindness, with an incidence of two to three per 100,000 live births worldwide.

Symptoms of LCA appear within the first year of life with significant vision loss, rapid involuntary movements of the eyes, painful eye response to bright light, and absence of measurable electroretinogram recordings due to a lack of functional photoreceptor cells.

The most common form of the disease is LCA10, a monogenic disorder that represents approximately 20-30% of all LCA subtypes.

The most common form of the disease is LCA10, a monogenic disorder that represents approximately 20% to 30% of all LCA subtypes.

LCA10 is caused by autosomal recessive mutations in the CEP290 gene, which encodes a protein required for the survival and proper function of photoreceptor cells.

The most frequently found mutation within the CEP290 gene, occurring in approximately 85% of north and west European patients with LCA10, is an A to G nucleotide change that disrupts normal splicing, or processing, of the gene message, ultimately resulting in a deficiency of functional CEP290 protein.

The most frequently found mutation within the CEP290 gene, occurring in approximately 85% of north and west European patients with LCA10, is an A to G nucleotide change, referred to as an IVS26 mutation, that disrupts normal splicing, or processing, of the gene message, ultimately resulting in a deficiency of functional CEP290 protein.

Decreased CEP290 protein leads to loss of the outer segments of photoreceptor cells and function over time, which leads to blindness.

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Based on these studies, we have prespecified a therapeutic target of 10% productive editing of photoreceptors with the assumption that each productively edited photoreceptor will be fully functional.

Preclinical studies

We tested EDIT-101 in preclinical studies by delivering several dose quantities of EDIT-101 subretinally in mice that had a humanized CEP290 gene.

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Similar studies in mice showed that editing was rapid, achieving maximum levels by six weeks, and stable with changes maintained for the 26 weeks of the study at an AAV dose that has been safely administered to humans.

In mid-2019, we and our then-partner Allergan Pharmaceuticals International Limited (together with its affiliates, “Allergan”) initiated an initial Phase 1/2 clinical trial which is an open-label, single ascending dose trial of EDIT-101 in adult and pediatric (i.e., ages 3 to 17 years) patients with retinal degeneration caused by a homozygous or compound heterozygous mutation of the CEP290 gene, which is referred to as an IVS26 mutation.

Patients will receive a single dose of EDIT-101 administered via subretinal injection in one eye.

Approximately 18 patients will be enrolled at approximately eight trial centers in the United States and Europe.

Up to five cohorts across three doses will be enrolled in this clinical trial.

Clinical trial

In mid-2019, we and our then-partner Allergan Pharmaceuticals International Limited (together with its affiliates, “Allergan”) initiated an initial Phase 1/2 clinical trial referred to as the BRILLIANCE trial, which is an open-label, single ascending dose trial of EDIT-101 in adult and pediatric (i.e., ages 3 to 17 years) patients with retinal degeneration caused by a homozygous or compound heterozygous IVS26 mutation of the CEP290 gene.

Patients receive a single dose of EDIT-101 administered via subretinal injection in one eye.

The primary endpoint of the trial is an assessment of safety and tolerability, and the secondary endpoint is to evaluate and identify endpoints of efficacy of a single dose of EDIT-101 on change from baseline in various parameters.

Efficacy will be evaluated at multiple timepoints, including core measures every three months for the first year and then less frequently thereafter.

In March 2020, we announced the first patient in this clinical trial was dosed, and we completed dosing of the adult low-dose cohort by the end of 2020.

To date, there have been no reported severe adverse events or dose limited toxicity with respect to the patients in the first cohort.

We experienced slowed enrollment for subsequent cohorts due to the ongoing impact of the COVID-19 pandemic.

However, we initiated dosing of the adult mid-dose cohort in the first quarter of 2021.

We expect to announce initial clinical data in 2021.

As a result of the termination of our collaboration with Allergan in August 2020, we have regained full responsibility for this clinical trial.

Other Eye Diseases

We are also pursuing the development of therapies for eye diseases other than LCA10, including USH2A and adRP4.

We believe that our experience with the LCA10 program supports the development of therapies for these other eye diseases.

For example, the successful construction and testing of the components of the AAV vector we are pursuing for EDIT-101 continue to inform our approach to treating the most common cause of USH2A.

was initially planned to enroll up to 18 patients in up to five cohorts at approximately eight trial centers in the United States and Europe.

I n 2021, we completed dosing of the first three cohorts, the adult low-, mid- and high-dose cohorts.

There have been no reported severe adverse events or dose limited toxicities observed in these first three cohorts.

We are expanding enrollment in one or more of the previously completed adult cohorts to explore dose response and support establishment of registrational trial endpoints.

We anticipate establishing these registrational trial endpoints by the end of 2022.

We remain on track to complete dosing of the pediatric mid-dose cohort in the first half of 2022, and expect to initiate dosing of the pediatric high-dose cohort in 2022.

In September 2021, we announced preliminary clinical data, consisting of patient safety and efficacy assessments, from the ongoing BRILLIANCE trial.

The data related to the first six patients dosed in the trial:

two in the adult low-dose cohort and four in the adult mid-dose cohort.

Patients received a single administration of EDIT-101 via subretinal injection in one eye and are monitored every three months for the first year after dosing, and less frequently in the following two years.

No dose-limiting toxicities, which are defined as vision-threatening toxicities or severe non-ocular adverse events that occur before or at the week four visit and assessed by the investigator as being related to EDIT-101 and not the administration procedure, or serious adverse events were reported in the first six adult patients treated.

Efficacy was assessed based on available data from five subjects treated in the low-dose and mid-dose cohorts who had at least three months of post-treatment follow-up, focusing on those measures demonstrated to be consistent and reproducible in subjects with CEP290-related retinal degeneration, including best corrected visual acuity (“BCVA”), full-field light sensitivity threshold (“FST”) testing and ability to navigate standardized navigation courses, or Visual Function Navigation (“VNC”).

Two of three subjects in the mid-dose cohort followed for up to six months showed early efficacy signals providing clinical evidence of gene editing and suggesting potential clinical benefits, including improvements in BCVA, FST, and/or mobility navigation.

We expect to provide a clinical update on the BRILLIANCE trial in the second half of 2022, including safety and efficacy assessments on all patients who have had at least six months of follow-up evaluations.

Retinitis Pigmentosa

adRP is an inherited autosomal dominant disease in which a single copy of the human rhodopsin mutation is sufficient to cause the retinal disorder.

The disease results in initial night blindness early in life followed by loss of peripheral vision and eventual complete blindness.

More than 150 addressable mutations in the RHO gene have been identified, and there are currently no approved treatments.

We believe there are approximately 7,500 RHO-adRP patients in the United States and over 12,000 in Europe.

Leveraging our EDIT-101 learnings, in 2021, we declared a new development candidate, EDIT-103, for treatment of RHO-adRP.

EDIT-103 uses two AAV vectors to simultaneously remove the disease-causing mutant gene and replace it with a functioning rhodopsin gene in order to preserve photoreceptor function.

Preclinical studies of EDIT-103 in non-human primates demonstrated productive editing levels of more than 95% and that these edits resulted in production of approximately 37% of normal RHO protein levels, which we believe to be a therapeutically effective level.

This program continues to advance towards IND-enabling studies.

We believe that our dual-AAV approach in EDIT-103, simultaneously knocking out and replacing a gene in the same cell in vivo , is a significant technical breakthrough, potentially leading to findings that could address other autosomal dominant diseases, where gain of negative function requires correction.

Usher Syndrome 2A

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Our initial goal in this research program is to address mutations within exon 13, which contains the highest percentage of USH2A gene mutations.

We believe there are over 4,500 USH2A patients with the mutation we aim to correct in the United States and Europe and over 40,000 in the rest of the world .

We have declared a development candidate, EDIT-102, to treat USH2A patients.

EDIT-102 is comprised of the same proprietary enzyme, vector and promoter as EDIT-101.

We tested EDIT-102 in preclinical studies of human cell lines and demonstrated approximately 47% productive editing in the cells that resulted in such cells expressing 60% more USH2A messenger RNA as compared to the unedited cells.

In other preclinical studies, we tested EDIT-102 in humanized retinal organoids, which are three-dimensional structures derived from human pluripotent stem cells and can serve as an in vitro model of retinas.

These studies demonstrated noticeable increases in the proper localization of the usherin complex in the photoreceptor cells at 120-140 days, as compared to retinal organoids formed from cells that contained a patient-derived mutation in exon 13.

Retinitis Pigmentosa

Mutations in the human rhodopsin (“RHO”) gene account for 25% of all forms of adRP4, a progressive form of retinal degeneration characterized by initial night blindness early in life followed by loss of peripheral vision and eventual complete blindness.

More than 150 mutations in the RHO gene have been identified, with the most prevalent allele in the United States representing approximately 10% of all patients with adRP4.

We believe there are over 18,000 adRP4 patients with mutations in the RHO gene in the United States and Europe and over 15,000 in the rest of the world.

Leveraging our EDIT-101 and EDIT-102 learnings, we are developing a novel approach to treat all forms of adRP4 resulting from mutations in the RHO gene and aim to declare a development candidate, potentially using the same enzyme and vector as EDIT-101, by the end of 2021.

We believe there are approximately 5,300 USH2A patients with the mutation we aim to correct in the United States and over 8,000 in Europe.

An optimized version of our development candidate, EDIT-102, for treatment of USH2A-associated retinitis pigmentosa is in lead optimization.

Using a dual-vector approach with an AsCas12a nuclease, we have enhanced productive editing by approximately 350% compared to the initial construct of this therapy.

Other Ocular Indications

We are also working on other undisclosed indications in the eye taking advantage of our experience in ocular diseases, including our proof-of-concept with EDIT-101 for LCA10, and our range of delivery solutions.

We expect to declare an additional development candidate for an in vivo ocular indication in 2022.

In Vivo Gene Editing Medicines – Early Discovery Programs

We believe the curative potential for gene editing is significant in light of the over 6,000 human genetic disorders.

In addition to our ocular programs, we hope to leverage our expertise in developing gene-editing medicines utilizing AAV delivery to expand our in vivo programs to treat additional diseases and therapeutic areas, including neuromuscular, liver, hematological, central nervous system and cardiological disorders.

Under our research collaboration with AskBio, we are aiming to develop a therapy to treat a neurological disease.

In addition to our ocular programs, we hope to leverage our expertise in developing gene editing medicines utilizing AAV delivery to expand our in vivo programs to treat additional diseases and therapeutic areas, including a neurological disease under our research collaboration with AskBio.

Ex Vivo Gene Editing Cell Medicines

Our most advanced ex vivo gene-edited cell medicine, EDIT-301, is designed to treat sickle cell disease and beta-thalassemia.

We are also developing multiple ex vivo gene-edited cell medicines for the potential treatment of different cancers, including solid tumors.

In our collaboration with Juno Therapeutics, we are researching and developing engineered alpha-beta T cell therapies to treat cancer and autoimmune diseases.

In our wholly owned oncology programs, we are further developing our capabilities to generate certain engineered NK cells from iPSCs that we edit to treat solid tumors.

We are also collaborating with BlueRock to increase our technical capabilities in such programs.

Ex Vivo Gene Editing Cell Medicines – Hemoglobinopathies

We are developing an approach for gene editing in HSCs to support the advancement of research programs to treat non-malignant hematological diseases, including sickle cell disease and beta thalassemia.

There are over 165,000 sickle cell disease patients, and over 15,000 beta-thalassemia patients, in the United States and Europe.

Patients suffering from sickle cell disease have a median life expectancy of 42-47 years, while those with beta-thalassemia typically suffer from chronic anemia, often requiring lifelong blood transfusions that can result in iron overload that requires separate treatment.

In ex vivo -gene edited cell medicines, we are developing an approach for gene editing in hematopoietic stem cells to support the advancement of research programs to treat non-malignant hematological diseases.

Our most advanced ex vivo gene-edited cell medicine, EDIT-301, is designed to treat sickle cell disease and transfusion-dependent beta-thalassemia.

We estimate that there are over 165,000 sickle cell disease patients, and over 45,000 TDT patients, in the United States and Europe.

Patients suffering from sickle cell disease have a median life expectancy of 42-47 years, while those with TDT typically suffer from chronic anemia, often requiring lifelong blood transfusions that can result in iron overload that requires separate treatment.

We are actively pursuing a distinct gene editing approach to treating these hemoglobinopathies.

Our primary criteria for a successful product candidate include high and pancellular fetal hemoglobin ("HbF") with a best-in-class safety profile.

To this end, we have developed EDIT-301, an experimental, autologous cell therapy that targets the HBG1/2 promoter in the beta-globin gene to stimulate HbF production, to treat sickle cell disease.

Our primary criteria for a successful product candidate include high and pancellular fetal hemoglobin (“HbF”) with a best-in-class safety profile.

To this end, we have developed EDIT-301, an experimental, autologous cell therapy that targets the HBG1/2 promoter and disrupts the binding site of the BCL11A , consistent with observed naturally occurring human mutations.

These mutations mimic the asymptomatic condition of hereditary persistence of fetal hemoglobin (“HPFH”).

By editing the HBG1/2 promoter in the beta-globin gene, we seek to generate protective changes that increase HbF production similar to HPFH, thereby ameliorating sickle cell disease and TDT symptoms.

We believe that mimicking a combination of HPFH mutations that elevate HbF could be more effective than recreating a single point mutation.

EDIT-301 is the first experimental medicine in development generated using CRISPR/Cas12a (also known as Cpf1) gene editing.

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To get the high levels of beta-globin required for an efficacious therapy, there will be cells in the CD34+ population, which are cells that contain the long-term stem cells that repopulate the hematopoietic lineages, that carry more than twenty copies of the viral genome.

These random integration

events have the potential to inadvertently activate or inactivate genes involved in cell function and tumorigenesis.

These random integration events have the potential to inadvertently activate or inactivate genes involved in cell function and tumorigenesis.

As such, we believe our approach to editing the beta-globin locus provides the highest likelihood of providing clinical benefit in patients while minimizing potential safety risks.

Preclinical studies

Using our approach in preclinical studies, we tested the ability of CD34+ cells obtained from healthy donors and edited at the beta-globin locus to induce fetal hemoglobin.

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We also observed that approximately 90% of these cells were HbF positive, demonstrating that HbF expression was pan-cellular, which we believe is likely a critical property for potential clinical benefit.

For these reasons, we believe our approach of editing the hemoglobin locus to increase fetal hemoglobin has the potential to generate differentiated medicines to benefit patients with sickle cell disease and beta thalassemia.

In January 2021, the FDA cleared the initiation of the safety phase of our Phase 1/2 RUBY clinical trial for EDIT-301 for sickle cell disease, and permitted us to begin dosing patients, which we expect to occur in 2021.

This trial is a single-arm, open-label, multi-center Phase 1/2 study designed to assess the safety and efficacy of EDIT-301 in patients with sickle cell disease.

Clinical trial

In January 2021, the FDA cleared the initiation of the safety phase of our Phase 1/2 RUBY clinical trial for EDIT-301 for sickle cell disease and permitted us to begin dosing patients.

This trial is a single-arm, open-label, multi-center Phase 1/2 study designed to assess the safety and efficacy of EDIT-301 in patients with severe sickle cell disease.

Enrolled patients will receive a single administration of EDIT-301.

We are manufacturing components of the clinical trial materials.

We also aim to file an IND for EDIT-301 for the treatment of beta-thalassemia by the end of 2021.

Our IND for EDIT-301 permits us to proceed with the safety portion of our Phase 1/2 RUBY clinical trial.

Prior to commencing the efficacy portion of the RUBY clinical trial, we will be required to resolve the partial clinical hold on EDIT-301 related to developing a potency assay to ensure that the characteristics of the product released are as expected and confirmed by clinical data collected in the first patients treated .

We have begun clinical manufacturing operations for the trial, including successfully editing patient cells ex vivo .

We are on track to dose the first patient in the trial in the first half of 2022 and expect initial clinical results by the end of 2022.

We do not expect that the overall timing for clinical development of EDIT-301 will be affected by the partial clinical hold.

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If the partial clinical hold is not lifted on the Phase 1/2 RUBY clinical trial, we will not be able to collect the efficacy data of EDIT-301 necessary to support an application for approval.

Ex Vivo Gene Edited Cell Medicines – Oncology

In November 2021, we filed an IND application for a Phase 1/2 clinical trial of EDIT-301 for the treatment of TDT, which was cleared by the FDA in December 2021.

Preparations to initiate a Phase 1/2 clinical trial designed to assess the safety, tolerability, and preliminary efficacy of EDIT-301 for the treatment of TDT are underway.

We expect to dose the first TDT patient during 2022.

Cellular Therapy Medicines

We are also developing multiple cellular therapy medicines for the treatment of different cancers.

In our wholly owned oncology programs, we are developing our capabilities to generate certain engineered NK cells from iPSCs that we edit to treat solid tumors.

In our collaboration with BMS, we are researching and developing engineered alpha-beta T cell therapies to treat solid and liquid tumors leveraging our platform technologies, including Cas9 and AsCas12a.

We also continue to evaluate the application of our iPSC platform to additional cell types beyond iNK and alpha-beta T cells.

Natural Killer Cells

We are developing gene-edited NK cell medicines to treat solid tumors.

The American Cancer Society estimates that there are over 1.6 million new cases of solid tumor cancers, linked to over 500,000 deaths, annually in the United States.

NK cells are innate immune cells that can recognize tumor cells by a variety of mechanisms, including multiple innate receptors that recognize cells that do not express T cell antigens and cells that express stress ligands.

NK cells are innate immune cells that can recognize tumor cells by a variety of mechanisms, including multiple innate receptors that recognize cells that do not express T cell antigens and

cells that express stress ligands.

NK cells are also part of a process known as antibody-directed cellular cytotoxicity (“ADCC”) by which therapeutic antibodies are directed to and kill tumor cells.

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Once we have obtained the cells, we then edit them to increase certain of the natural properties of the cell to better enable them to treat solid tumors, such as the cells persistence in vivo , its ability to withstand the tumor micro-environment, improved ability to cause ADCC and improved recognition of tumor cells.

In preclinical studies, we achieved 70-100% editing in five genes in iPSCs.

For one such edited iPSC, the resulting edited iNKs killed 74% of cultured cells while unedited cells only killed 2% of cultured cells.

We aim to accelerate the development of iNK cell medicines for the treatment of solid tumor cancers in 2021.

In preclinical studies, we achieved 70% to 100% editing in five genes in iPSCs.

In December 2021, we declared a development candidate for the treatment of solid tumors, referred to as EDIT-202, an iPSC-derived iNK investigational medicine with double knock-in and double knock-out gene edits.

For EDIT-202, we edit iPSCs using an engineered AsCas12a nuclease to knock-in both CD16 and membrane-bound Interleukin-15 (“IL-15”).

These edits are designed to increase ADCC, when combined with tumor-targeting antibodies, and prolong iNK cell persistence.

We also edit the iPSCs to knock-out both the CISH and TGFβ-receptor 2 genes, edits that are designed to improve iNK cell effector function and provide resistance to TGFβ-mediated NK suppression in the tumor micro-environment.

From these edited iPSCs, we obtain an engineered iPSC clone for evaluation to ensure optimal characteristics and from which to create a master cell bank.

Using this master cell bank, we have the ability to expand and differentiate the edited iPSC into iNK cells for EDIT-202.

We believe this approach has the potential to create an allogeneic “off-the-shelf” NK cell therapy medicine with enhanced activity against solid tumors.

In preclinical studies, evaluation of EDIT-202 in an in vivo mouse ovarian cancer model showed that a single dose of EDIT-202, combined with three doses of the cancer drug trastuzumab, resulted in enhanced anti-tumor activity compared with wild type iNKs with the same trastuzumab dosage, and also significant tumor reduction after six days and complete tumor clearance in 40% of the mice tested by day 31.

In vitro studies demonstrated that EDIT-202 was also able to persist for a significantly longer period of time without exogenous cytokines relative to unedited iNK cells.

We expect to advance this therapy in preclinical development during 2022.

Alpha-Beta T Cells

Engineered T cells, including alpha-beta T cells, have shown encouraging clinical activity against multiple cancers, culminating in the recent approval of two such therapies in the United States.

Engineered T cells, including alpha-beta T cells, have shown encouraging clinical activity against multiple cancers, culminating in recent approvals of such therapies in the United States.

Because of these promising results, there is significant interest in the medical community in expanding the application of this technology across a broader range of cancers and patients.

We believe that our genome editing technology has the potential to improve multiple properties of these alpha-beta T cell therapies.

Alpha-beta cells are part of the adaptive immune system and recognize tumors with endogenous alpha-beta T cell receptors or CARs or engineered T cell receptors (“Engineered TCRs”).

If we are successful, genome-edited engineered alpha-beta T cells have the potential to significantly expand the types of cancers treatable by CAR/ Engineered TCR alpha-beta T cells and to improve the outcomes of these therapies.

Through our collaboration with Juno Therapeutics, we have applied our genome editing technology to multiple gene targets in order to improve the efficacy and safety of CAR/ Engineered TCR alpha-beta T cells directed against a range of tumor types.

In addition, we have optimized genome editing components and delivery methods compatible with engineered alpha-beta T cell manufacturing methods developed by Juno Therapeutics.

Gamma Delta T Cells

Like NK cells, gamma delta T cells are part of the innate immune system.

We have retained rights to develop gamma delta T cell therapies to treat cancer, and we hope to leverage our capabilities and expertise in alpha-beta T cells and our NK cell programs to develop such therapies.

Alpha-beta cells are part of the adaptive immune system and recognize tumors with endogenous alpha-beta T cell receptors or CARs or engineered T cell receptors (“eTCRs”).

If we are successful, genome-edited engineered alpha-beta T cells have the potential to significantly expand the types of cancers treatable by CAR/ eTCR alpha-beta T cells and to improve the outcomes of these therapies.

Through our collaboration with BMS, we have applied our Cas9 and AsCas12a platform technologies to multiple gene targets in order to improve the efficacy and safety of CAR/eTCR alpha-beta T cells directed against a range of tumor types.

In addition, we have optimized genome editing components and delivery methods compatible with engineered alpha-beta T cell manufacturing methods developed by BMS.

To date, this collaboration has resulted in six ongoing programs, including one development candidate.

For example, BMS recently announced its strategy for its gene editing cell therapy to treat certain human papilloma virus-associated solid tumors.

This investigational medicine uses our Cas9a editing technology to make three edits in donor-derived T cells, which resulted in improved tumor killing and anti-tumor efficacy compared to wild type cells in in vitro and in vivo studies conducted by BMS.

Our Collaborations and Licensing Strategy

Juno Therapeutics Collaboration and License Agreement

In May 2015, we entered into a collaboration and license agreement with Juno Therapeutics for the research and development of engineered T cells with CARs and Engineered TCRs that have been genetically modified to recognize and kill other cells.

In May 2015, we entered into a collaboration and license agreement with Juno Therapeutics, now a subsidiary of BMS, for the research and development of engineered T cells with CARs and eTCRs that have been genetically modified to recognize and kill other cells.

We and Juno Therapeutics amended and restated this agreement in May 2018 and November 2019 (the “Juno Collaboration Agreement”) and, in connection with the amendment and restatement in November 2019, we entered into a license agreement with Juno Therapeutics (such agreement, the “Juno License Agreement,” and together with the Juno Collaboration Agreement, the “Juno Agreements”).

Under the terms of the Juno Collaboration Agreement, we received an upfront payment of $25.0 million, amendment fees totaling $75.0 million and have received five milestone payments totaling $15.0 million, in addition to certain opt-in fees.

Under the terms of the Juno Collaboration Agreement, we received an upfront payment of $25.0 million, amendment fees totaling $75.0 million and have received milestone payments totaling $15.0 million, in addition to certain opt-in fees.

The Juno Agreements relate to technology used to edit or modify the genome of a cell in connection with the research, development, manufacture, commercialization or other exploitation of T cells that express or have ever expressed T cell receptor dimers consisting of an alpha (α) chain and a beta (β) chain (such cells, “Alpha-beta T Cells”), and T cells derived from pluripotent stem cells or any other precursor cell (such cells, “Other Derived T Cells”), subject to certain exclusions for certain of our existing obligations.

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As such, we may develop such gamma delta T Cells.

recognize or modulate the expression of up to twenty gene targets selected by Juno Therapeutics (each, a “Research Program”) for the purpose of identifying the RNP Complexes that may be used in the creation of potential drug development candidates.

The initial research term is five years from the effective date of the Juno Collaboration Agreement.

During the research term under the Juno Collaboration Agreement, we may research ribonucleoprotein complexes comprising an RNA-guided engineered nuclease paired with an oligonucleotide (“RNP Complexes”) that recognize or modulate the expression of up to twenty gene targets selected by Juno Therapeutics (each, a “Research Program”) for the purpose of identifying the RNP Complexes that may be used in the creation of potential drug development candidates.

The initial research term is five years from the November 2019 effective date of the Juno Collaboration Agreement.

Juno Therapeutics may extend the research term for up to two one-year periods upon written notice to us and payment to us of a mid to high single digit million-dollar payment upon each extension.

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We have the right to terminate the Juno License Agreement on a program-by-program basis in the event that Juno Therapeutics fails to make any undisputed payment to us and has not cured such payment breach within the cure period.

Other than Juno Therapeutics’ right to wind-down its operations with respect to

Juno Licensed Products during the twelve months following the date of effectiveness of termination, all licenses and other exclusive rights granted under the Juno License Agreement shall terminate.

Other than Juno Therapeutics’ right to wind-down its operations with respect to Juno Licensed Products during the twelve months following the date of effectiveness of termination, all licenses and other exclusive rights granted under the Juno License Agreement shall terminate.

Allergan Agreement

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In July 2018, Allergan exercised its option to develop and commercialize EDIT-101 and we subsequently entered into a co-development and commercialization agreement with Allergan under which we agreed to co-develop and equally split profits and losses for EDIT-101 in the United States.

In connection with entering into this agreement, Allergan paid us a one-time up-front payment of $90.0 million.

Allergan also paid us $15.0 million in connection with Allergan exercising its option for the LCA10 program and $25.0 million in connection with the acceptance of the IND for the LCA10 program.

Allergan was acquired by AbbVie Inc.

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In addition, we are obligated to use commercially reasonable efforts to develop and commercialize a product directed to each of four collaboration targets, one of which is LCA10.

In connection with our entry into the termination agreement, we made a one-time aggregate payment of $20.0 million to Allergan.

In addition, we will make certain payments on achievements of clinical and regulatory milestones up to $20.0 million for each target program and aggregated sales milestones for all products covered by the termination agreement up to $90.0 million.

Under this agreement, we will make certain payments on achievements of clinical and regulatory milestones up to $20.0 million for each target program and aggregated sales milestones for all products covered by the termination agreement up to $90.0 million.

We are also obligated to pay royalties in a low-single digit percentage, subject to reduction under specified circumstances, on net sales of specified products.

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We are a party to a number of license agreements under which we license patents, patent applications, and other intellectual property from third parties.

The licensed intellectual property covers, in part, CRISPR-related compositions of matter and their use for genome editing.

The licensed intellectual property covers, in part, CRISPR-related compositions

of matter and their use for genome editing.

These licenses impose various diligence and financial payment obligations on us.

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and providing Harvard and Broad with certain rights to designate, and reserve all rights to, gene targets for which the designating institution has an interest in researching and developing products that would otherwise be covered by rights licensed to us.

of Technology (“MIT”) and Broad, certain patents co-owned by MIT, The Rockefeller University (“Rockefeller”), and Broad, and certain patents co-owned by MIT, Broad and Harvard.

The licenses granted to us under the Cas9-I License Agreement include rights to certain patents solely owned by Harvard (the “Harvard Cas9-I Patent Rights”), certain patents co-owned by the Massachusetts Institute of Technology (“MIT”) and Broad, certain patents co-owned by MIT, The Rockefeller University (“Rockefeller”), and Broad, and certain patents co-owned by MIT, Broad and Harvard.

We refer to all the patents and patent applications licensed to us under the Cas9-I License Agreement as the Harvard/Broad Cas9-I Patent Rights.

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We also must pay an annual license maintenance fee ranging from the low- to mid-five figures to the low-six figures, depending on the calendar year.

This annual license maintenance fee is creditable against royalties owed on licensed products and services in the same year as the maintenance fee is paid.

annual license maintenance fee is creditable against royalties owed on licensed products and services in the same year as the maintenance fee is paid.

We are obligated to reimburse Broad and Harvard for expenses associated with the prosecution and maintenance of the Harvard/Broad Cas9-I Patent Rights, including expenses associated with any interference proceedings in the USPTO, any opposition proceedings in the EPO, or any other inter partes or other post grant proceedings in these or other jurisdictions where we are seeking patent protection.

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We are also obligated to make additional payments to Broad and Harvard, collectively, of up to an aggregate of $54.0 million upon the occurrence of certain sales milestones per licensed product for the prevention or treatment of a human disease that afflicts at least a specified number of patients in the aggregate in the United States.

Broad and Harvard are collectively

entitled to receive clinical and regulatory milestone payments totaling up to $4.1 million in the aggregate per licensed product approved in the United States and at least one jurisdiction outside the United States for the prevention or treatment of a human disease that afflicts fewer than a specified number of patients in the aggregate in the United States or a specified number of patients per year in the United States, which we refer to as an ultra-orphan disease.

Broad and Harvard are collectively entitled to receive clinical and regulatory milestone payments totaling up to $4.1 million in the aggregate per licensed product approved in the United States and at least one jurisdiction outside the United States for the prevention or treatment of a human disease that afflicts fewer than a specified number of patients in the aggregate in the United States or a specified number of patients per year in the United States, which we refer to as an ultra-orphan disease.

We are also obligated to make additional payments to Broad and Harvard, collectively, of up to an aggregate of $36.0 million upon the occurrence of certain sales milestones per licensed product for the prevention or treatment of an ultra-orphan disease.

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patent applications and we may not have any rights under any foreign patents that issue from any foreign equivalents thereof.

Pursuant to the Cpf1 License Agreement, and as of December 31, 2020, we have certain rights under three U.S.

patent, 12 pending U.S.

Pursuant to the Cpf1 License Agreement, and as of December 31, 2021, we have certain rights under five U.S.

patents, 13 pending U.S.

patent applications, five European patents and related validations, six pending European patent applications, and other related patent applications in jurisdictions outside of the United States and Europe.

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Any sublicense agreement cannot include the right to grant further sublicenses without the written consent of Broad.

In addition, any sublicense agreements must contain certain terms, including a provision requiring the sublicensee to indemnify the Cpf1 Institutions according to the same terms as are provided in the Cpf1 License Agreement and a statement that the Cpf1 Institutions are intended third party beneficiaries of the sublicense agreement for certain purposes.

Agreement and a statement that the Cpf1 Institutions are intended third party beneficiaries of the sublicense agreement for certain purposes.

The licenses granted to us under the Cpf1 License Agreement are subject to retained rights of the U.S.

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A Cpf1 Third Party Proposed Product Request must be accompanied by a research, development and commercialization plan reasonably satisfactory to Broad, including evidence that the third party has, or reasonably expects to have, access to any necessary intellectual property and funding.

Broad may not grant a Cpf1 Third Party Proposed Product Request

(i) if we, directly or through any of our affiliates, sublicensees, or collaborators are researching, developing, or commercializing a product directed to the same gene target that is the subject of the Cpf1Third Party Proposed Product Request (“Cpf1 Licensee Product”) and we can demonstrate such ongoing efforts to Broad’s reasonable satisfaction, or (ii) if we, directly or through any of our affiliates or sublicensees, wish to do so either alone or with a collaboration partner, and we can demonstrate to Broad’s reasonable satisfaction that we are interested in researching, developing, and commercializing a Cpf1 Licensee Product, that we have a commercially reasonable research, development, and commercialization plan to do so, and we commence and continue reasonable commercial efforts under such plan.

Broad may not grant a Cpf1 Third Party Proposed Product Request (i) if we, directly or through any of our affiliates, sublicensees, or collaborators are researching, developing, or commercializing a product directed to the same gene target that is the subject of the Cpf1Third Party Proposed Product Request (“Cpf1 Licensee Product”) and we can demonstrate such ongoing efforts to Broad’s reasonable satisfaction, or (ii) if we, directly or through any of our affiliates or sublicensees, wish to do so either alone or with a collaboration partner, and we can demonstrate to Broad’s reasonable satisfaction that we are interested in researching, developing, and commercializing a Cpf1 Licensee Product, that we have a commercially reasonable research, development, and commercialization plan to do so, and we commence and continue reasonable commercial efforts under such plan.

If we, directly or through any of our affiliates, sublicensees, or collaborators, are not researching, developing, or commercializing a Cpf1 Licensee Product nor able to develop and implement a plan reasonably satisfactory to Broad, Broad may grant an exclusive or non-exclusive license to the third party on a gene target-by-gene target basis.

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If we undergo a change of control during the term of the Cpf1 License Agreement, certain of these clinical and regulatory milestone payments will be increased by a certain percentage in the mid double-digits.

We are also obligated to make additional payments to Broad and Wageningen, collectively, of up to an aggregate of $54.0 million upon the occurrence of certain sales milestones per licensed product for the prevention or treatment of a human disease that afflicts at least a specified number of patients in the aggregate in the United States.

the aggregate in the United States.

Broad and Wageningen are collectively entitled to receive clinical and regulatory milestone payments totaling up to $6.0 million in the aggregate per licensed product approved in the United States, the European Union and Japan for the prevention or treatment of an ultra-orphan disease.

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Our obligation to pay royalties will expire on a product-by-product and country-by-country basis upon the later of the expiration of the last to expire valid claim of the Cpf1 Patent Rights that covers each licensed product or licensed service in each country or the tenth anniversary of the date of the first commercial sale of the product or service.

If we sublicense any of the Cpf1 Patent Rights to a third party, Broad and Wageningen, collectively, have the right to

receive high single-digit to low double-digit percentages of the sublicense income, depending on the stage of development of the products or services in question at the time of the sublicense.

If we sublicense any of the Cpf1 Patent Rights to a third party, Broad and Wageningen, collectively, have the right to receive high single-digit to low double-digit percentages of the sublicense income, depending on the stage of development of the products or services in question at the time of the sublicense.

Under the Cpf1 License Agreement, Broad and Wageningen are also entitled, collectively, to receive success payments in the event our market capitalization reaches specified thresholds ascending from a high nine digit dollar amount to $10.0 billion (“Market Cap Success Payments”) or sale of our company for consideration in excess of those thresholds, (“Company Sale Success Payments,” which with the Market Cap Success Payments, the “Success Payments”).

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However, our royalty obligations, discussed above, may survive expiration or termination.

We have the right to terminate the Cpf1 License

Agreement at will upon four months’ written notice to Broad.

We have the right to terminate the Cpf1 License Agreement at will upon four months’ written notice to Broad.

Either party may terminate the Cpf1 License Agreement upon a specified period of notice in the event of the other party’s uncured material breach of a material obligation, such notice period varying depending on the nature of the breach.

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Our in-licensed patents and patent applications cover various aspects of our genome editing platform technology, including CRISPR systems that employ Cas9 including S.

aureus Cas9, high-fidelity Cas9 nucleases and Cas9 PAM variants, self-inactivating forms of Cas9, Cas9 nickases, CRISPR systems that employ Cas12a including Cas12a nickases and other variants and self-inactivating forms of Cas12a, and also CRISPR systems that employ viral vectors for delivery, single guide RNAs, or modified guide RNAs, including guide nucleic acids containing both DNA and RNA components.

and RNA components.

We also have filed patent applications and have in-licensed rights to filed patent applications directed to each of the four components of our genome editing platform technology.

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The term of individual patents depends upon the legal term for patents in the countries in which they are granted.

In most countries, including the United States, the patent term is 20 years from the earliest claimed filing date of

a non-provisional patent application in the applicable country.

In most countries, including the United States, the patent term is 20 years from the earliest claimed filing date of a non-provisional patent application in the applicable country.

In the United States, a patent’s term may, in certain cases, be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over a commonly owned patent or a patent naming a common inventor and having an earlier expiration date.

The Drug Price Competition and Patent Term Restoration Act of 1984 extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, only one patent applicable to each regulatory review period may be extended and only those claims covering the approved drug or a method for using it may be extended.

As of December 31, 2020, we owned nine U.S.

As of December 31, 2021, we owned 16 U.S.

patents, 67 pending U.S.

non-provisional patent applications, seven European patents and related validations, 56 pending European patent applications, five pending U.S.

provisional patent applications, seven pending PCT patent applications, and other related patent applications in jurisdictions outside the United States and Europe that are related to our CRISPR technology and which include claims directed to our genome editing platform, including our directed editing component, as well as composition of matter and method of use claims for our therapeutic programs, including LCA10 and other genetic and infectious eye disorders, and engineered T cells.

non-provisional patent applications, 13 European patents and related validations, 59 pending European patent applications, 21 pending U.S.

provisional patent applications, four pending PCT patent applications, and other related patent applications in jurisdictions outside the United States and Europe that are related to our CRISPR technology and which include claims directed to our genome editing platform, including our directed editing component, as well as composition of matter and method of use claims for our therapeutic programs, including LCA10 and other genetic and infectious eye disorders, and engineered T cells.

Three of these U.S.

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For more information regarding these license agreements, please see the section of this Annual Report on Form 10-K titled “Business —Intellectual Property Licenses.”

As of December 31, 2020, we owned two U.S.

As of December 31, 2021, we owned three U.S.

patents, five pending U.S.

non-provisional patent applications, one European patent and related validations, two pending European patent applications, and seven pending foreign patent applications, which are directed to compositions of matter, including guide RNAs directed to CEP290, and methods of use for the treatment of LCA10.

non-provisional patent applications, three pending U.S.

provisional patent applications, one European patent and related validations, three pending European patent applications, and eight pending foreign patent applications, which are directed to compositions of matter, including guide RNAs directed to CEP290, and methods of use for the treatment of LCA10.

Our current issued U.S.

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patent applications would be expected to expire between 2035 and 2039, excluding any additional term for patent term adjustments or patent term extensions.

As of December 31, 2020, our registered trademark portfolio consisted of registrations in the United States for EDITAS, EDITAS in Stylized Letters and the Infinity Logo, registrations in Australia, China, the European Union, Japan and Switzerland for EDITAS, registrations in Australia, China, the European Union, Japan and Switzerland for the Infinity Logo and a registration in the European Union for UDITAS.

As of December 31, 2021, our registered trademark portfolio consisted of registrations in the United States for EDITAS, EDITAS in Stylized Letters and the Infinity Logo, registrations in Australia, China, the European Union, Japan, Switzerland and the United Kingdom for EDITAS, registrations in Australia, China, the European Union, Japan, Switzerland and the United Kingdom for the Infinity Logo and registrations in the European Union and United Kingdom for UDITAS.

The biotechnology and pharmaceutical industries, including in the gene therapy, genome editing and cell therapy fields, are characterized by rapidly advancing technologies, intense competition, and a strong emphasis on intellectual property and proprietary products.

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Our platform and product focus is the development of therapies using CRISPR technology.

Other companies developing CRISPR technology or therapies using CRISPR technology include Arbor Biotechnologies, Caribou Biosciences, CRISPR Therapeutics, ERS Genomics, Intellia Therapeutics, Locus Biosciences, ToolGen Inc.

TRACR Hematology and Vertex Pharmaceuticals.

Other companies developing CRISPR Cas9 or Cas12a technology or therapies using CRISPR Cas9 or Cas12a technology include Caribou Biosciences, CRISPR Therapeutics, ERS Genomics, Intellia Therapeutics, ToolGen, Vertex Pharmaceuticals, and Verve Therapeutics.

In addition, there have been and may continue to be discoveries of new CRISPR-based gene editing technologies.

There are additional companies developing therapies using other genome editing technologies, including base editing, prime editing, transcription activator-like effector nucleases, meganucleases, Mega-TALs and zinc finger nucleases.

The companies developing these other genome editing technologies include Beam Therapeutics, Prime Medicine, bluebird bio, Cellectis, Poseida Therapeutics, Precision Biosciences and Sangamo Therapeutics.

Additional companies developing cell and gene therapy products include Abeona Therapeutics, Adverum Biotechnologies, AGTC Therapeutics, Audentes Therapeutics, Fate Therapeutics, Inc., Graphite Bio, Homology Medicines, Nkarta, Inc., REGENXBIO, Sarepta Therapeutics, Solid Biosciences, Spark Therapeutics, uniQure and Voyager Therapeutics.

There are additional companies developing therapies using related CRISPR genome editing technologies, including other CRISPR nucleases, base editing, prime editing and gene writing.

These companies include Arbor

Biotechnologies, Beam Therapeutics, Chroma Medicine, KSQ Therapeutics, Locus Biosciences, Mammoth Biosciences, Metagenomi, Poseida Therapeutics, Prime Medicine, Scribe Therapeutics, Tessera Therapeutics, and Tune Therapeutics.

There are also companies developing therapies using transcription activator-like effector nucleases, meganucleases, Mega-TALs and zinc finger nucleases.

These companies include 2Seventy Bio, Allogene Therapeutics, bluebird bio, Cellectis, Precision Biosciences, and Sangamo Therapeutics.

Additional companies developing cell therapy products include Catamaran Bio, Celularity, Century Therapeutics, Cytovia Therapeutics, Fate Therapeutics, Graphite Bio, Nkarta, ONK Therapeutics, Shoreline Biosciences, and Wugen Therapeutics.

Additional companies developing gene therapy products include Abeona Therapeutics, Adverum Biotechnologies, AGTC Therapeutics, Astellas Gene Therapies, Generation Bio, Homology Medicines, REGENXBIO, Sarepta Therapeutics, Solid Biosciences, Spark Therapeutics, uniQure and Voyager Therapeutics.

In addition to competition from other genome editing therapies, gene therapies or cell medicine therapies, any products that we may develop may also face competition from other types of therapies, such as small molecule, antibody, protein, oligonucleotide, or ribonucleic acid therapies.

For example, ProQR Therapeutics N.V.

is conducting a Phase I/II clinical trial for its experimental treatment using antisense oligonucleotide technology for LCA10.

In addition, many of our current or potential competitors, either alone or with their collaboration partners, may have greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, and marketing approved products than we do.

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Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient

registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we may develop.

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Manufacturing

We currently perform some manufacturing activities such as the production of guide RNA for our various internal and partner programs and some pre-clinical and early-phase clinical production for our ex vivo gene edited cell medicines.

These activities are performed on site at our existing facilities or, in the case of EDIT-301 for sickle cell disease, at current good manufacturing practice-compliant space leased by us and staffed by our employees.

These activities are performed on site at our existing facilities or at current good manufacturing practice-compliant space leased by us.

We contract with third parties for the manufacturing of all other materials for preclinical studies and our clinical trials.

We have limited manufacturing operations and do not own or operate any substantial manufacturing facilities for the production of our program materials.

We currently have no plans to build our own clinical or commercial scale manufacturing capabilities.

The use of contracted manufacturing and reliance on collaboration partners is relatively cost-efficient and has eliminated the need for our direct investment in manufacturing facilities and additional staff early in development.

We have limited manufacturing operations and do not own or operate any substantial manufacturing facilities for large-scale production of our program materials.

While we have limited early-phase clinical manufacturing capabilities, we currently have no plans to build our own late-stage clinical or commercial scale manufacturing capabilities.

The use of contracted manufacturing and reliance on collaboration partners is relatively cost-efficient and has eliminated the need for substantial direct investment in manufacturing facilities and additional staff early in development.

Although we rely on contract manufacturers, we have personnel with manufacturing experience to oversee our contract manufacturers.

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In particular, some of our research programs target potentially larger indications.

Data, the size of the development programs, the size of the

target market, the size of a commercial infrastructure, and manufacturing needs may all influence our strategies in the United States, Europe, and the rest of the world.

Data, the size of the development programs, the size of the target market, the size of a commercial infrastructure, and manufacturing needs may all influence our strategies in the United States, Europe, and the rest of the world.

Government Regulation and Licensure of Products

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In the United States, our candidate products would be regulated as biological products, or biologics, under the Public Health Service Act (the “PHSA”) and the Federal Food, Drug and Cosmetic Act (the “FDCA”) and its implementing regulations and guidances.

A company, institution, or organization which takes responsibility for the initiation and management of a clinical development program for such products, and their approval by regulatory authorities, is generally referred to as a sponsor.

The failure to comply with the applicable U.S.

requirements at any time during the product development process, including non-clinical testing, clinical testing, the approval process or post-approval process, may subject an applicant to delays in the conduct of the study, regulatory review and approval, and/or administrative or judicial sanctions.

requirements at any time during the product development process, including non-clinical testing, clinical testing, the approval process or post-approval process, may subject a sponsor to delays in the conduct of the study, regulatory review and approval, and/or administrative or judicial sanctions.

An applicant seeking approval to market and distribute a new biologic in the United States generally must satisfactorily complete each of the following steps:

● preclinical laboratory tests, animal studies and formulation studies all performed in accordance with the FDA’s Good Laboratory Practice (“GLP”) regulations;

● preclinical laboratory tests, animal studies and formulation studies all performed in accordance with the FDA’s Good Laboratory Practice (“GLP”) regulations and standards;

● completion of the manufacture, under current Good Manufacturing Practices (“cGMP”) conditions, of the drug substance and drug product that the sponsor intends to use in human clinical trials along with required analytical and stability testing;

● submission to the FDA of an IND application for human clinical testing, which must become effective before human clinical trials may begin;

● design of a clinical protocol and submission to the FDA of an IND application for human clinical testing, which must become effective before human clinical trials may begin;

● approval by an independent institutional review board (“IRB”) representing each clinical site before each clinical trial may be initiated;

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Clinical holds are imposed by the FDA whenever there is concern for patient safety and may be a result of new data, findings, or developments in clinical, nonclinical, and/or chemistry, manufacturing, and controls.

This order issued by the FDA would delay either a proposed clinical study or cause suspension of an ongoing study, until all outstanding concerns have been adequately addressed and the FDA has notified the company that investigations may proceed.

This order issued by the FDA would delay either a proposed clinical study or cause suspension of an ongoing study, until all

outstanding concerns have been adequately addressed and the FDA has notified the company that investigations may proceed.

This could cause significant delays or difficulties in completing planned clinical studies in a timely manner.

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The GCP requirements encompass both ethical and data integrity standards for clinical trials.

The FDA’s regulations are intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical trials, as well as the quality and integrity of the resulting data.

The FDA’s regulations are intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical trials, as

well as the quality and integrity of the resulting data.

They further help ensure that non-IND foreign trials are conducted in a manner comparable to that required for clinical trials in the United States.

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Clinical testing also must satisfy extensive GCP rules and the requirements for informed consent.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur.

These reports must include a development safety update report, or DSUR.

In addition, IND safety reports must be submitted to the FDA for any of the following:

serious and unexpected suspected adverse reactions;

findings from other studies or animal or in vitro testing that suggest a significant risk in humans exposed to the drug;

and any clinically important increase in the case of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board (“DSMB”).

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These studies are used to gain additional experience from the treatment of patients in the intended therapeutic indication and to document a clinical benefit in the case of biologics approved under accelerated approval regulations.

If the FDA approves a product while a company has ongoing clinical trials that were not necessary for approval, a company may be able to use the data from these clinical trials to meet all or part of any Phase 4 clinical trial requirement or to request a change in the product labeling.

If the FDA approves a product while a company has ongoing clinical trials that were not necessary for approval, a company may be able to use the data from these clinical

trials to meet all or part of any Phase 4 clinical trial requirement or to request a change in the product labeling.

Failure to exhibit due diligence with regard to conducting Phase 4 clinical trials could result in withdrawal of approval for products.

Information about clinical trials must be submitted within specific timeframes to the NIH for public dissemination on its ClinicalTrials.gov website.

Sponsors of clinical trials are required to register and disclose certain clinical trial information on a public registry (clinicaltrials.gov) maintained by the U.S.

National Institutes of Health, or NIH.

The NIH’s Final Rule on registration and reporting requirements for clinical trials became effective in 2017, and both NIH and the FDA have recently signaled the government’s willingness to begin enforcing those requirements against non-compliant clinical trial sponsors.

The failure to submit clinical trial information to clinicaltrials.gov, as required, is a prohibited act under the FDCA with violations subject to potential civil monetary penalties of up to $10,000 for each day the violation continues.

Pediatric Studies

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In addition, FDA will meet early in the development process to discuss pediatric study plans with sponsors and FDA must meet with sponsors by no later than the end-of-phase 1 meeting for serious or life-threatening diseases and by no later than 90 days after FDA’s receipt of the study plan.

The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.

Additional requirements and procedures relating to deferral requests and requests for extension of

deferrals are contained in the Food and Drug Administration Safety and Innovation Act, or FDASIA.

The FDA maintains a list of diseases that are exempt from PREA requirements due to low prevalence of disease in the pediatric population.

Congress amended the FDA Reauthorization Act of 2017, or FDARA.

Previously, drugs that had been granted orphan drug designation were exempt from the requirements of the Pediatric Research Equity Act.

Under the amended section 505B, beginning on August 18, 2020, the submission of a pediatric assessment, waiver or deferral will be required for certain molecularly targeted cancer indications with the submission of an application or supplement to an application.

The FDA may, on its own initiative or at the request of the sponsor, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.

A deferral may be granted for several reasons, including a finding that the product or therapeutic candidate is ready for approval for use in adults before pediatric trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric trials begin.

The law requires the FDA to send a PREA Non-Compliance letter to sponsors who have failed to submit their pediatric assessments required under PREA, have failed to seek or obtain a deferral or deferral extension or have failed to request approval for a required pediatric formulation.

Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation, although FDA has taken steps to limit what it considers abuse of this statutory exemption in PREA by announcing that it does not intend to grant any additional orphan drug designations for rare pediatric subpopulations of what is otherwise a common disease.

Special Regulations and Guidance Governing Gene Therapy Products

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The NIH, including its Novel and Exceptional Technology Research Advisory Committee (“NExTRAC”), also advises the FDA on gene therapy issues and other issues related to emerging biotechnologies.

The FDA and the NIH have published guidance documents with respect to the development and submission of gene therapy protocols.

The FDA and the NIH have published guidance documents with respect to the development and submission of gene therapy

The FDA has issued various guidance documents regarding gene therapies, including recent final guidance documents released in January 2020 relating to chemistry, manufacturing and controls information for gene therapy INDs, long-term follow-up after the administration of gene therapy products, gene therapies for rare diseases and gene therapies for retinal disorders, as well as draft guidance in January 2021 for Human Gene Therapy for Neurodegenerative Diseases.

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Delaying, denying, limiting, or refusing inspection by the FDA may lead to a product being deemed to be adulterated.

Review and Approval of a BLA

Submission and Filing of a BLA

The results of product candidate development, preclinical testing, and clinical trials, including negative or ambiguous results as well as positive findings, are submitted to the FDA as part of a BLA requesting license to market the product.

The BLA must contain extensive manufacturing information and detailed information on the composition of the product and proposed labeling as well as payment of a user fee.

Under federal law, the submission of most BLAs is subject to an application user fee, which for federal fiscal year 2021 is $2,875,842 for an application requiring clinical data.

The sponsor of a licensed BLA is also subject to an annual program fee, which for fiscal year 2021 is $336,432.

Under federal law, the submission of most BLAs is subject to an application user fee, which for federal fiscal year 2022 is $3.1 million for an application requiring clinical data.

The sponsor of a licensed BLA is also subject to an annual program fee, which for fiscal year 2022 is more than $369.000.

Certain exceptions and waivers are available for some of these fees, such as an exception from the application fee for products with orphan designation and a waiver for certain small businesses.

The FDA has 60 days after submission of the application to conduct an initial review to determine whether it is sufficient to accept for filing based on the agency’s threshold determination that it is sufficiently complete to permit substantive review.

Once the submission has been accepted for filing, the FDA begins an in-depth review of the application.

Under the goals and policies agreed to by the FDA under the PDUFA, the FDA has ten months in which to complete its initial review of a standard application and respond to the applicant, and six months for a priority review of the application.

The FDA conducts a preliminary review of all applications within 60 days of receipt and must inform the sponsor at that time or before whether an application is sufficiently complete to permit substantive review.

In pertinent part, FDA’s regulations state that an application “shall not be considered as filed until all pertinent information and data have been received” by the FDA.

In the event that FDA determines that an application does not satisfy this standard, it will issue a Refuse to File, or RTF, determination to the applicant.

On the other hand, once the submission has been accepted for filing, the FDA begins an in-depth review of the application.

Under the goals and policies agreed to by the FDA under the PDUFA, the FDA has ten months in which to complete its initial review of a standard application and respond to the sponsor, and six months for a priority review of the application.

The FDA does not always meet its PDUFA goal dates for standard and priority BLAs.

The review process may often be significantly extended by FDA requests for additional information or clarification.

The review process and the PDUFA goal date may be extended by three months if the FDA requests or if the applicant otherwise provides additional information or clarification regarding information already provided in the submission within the last three months before the PDUFA goal date.

The review process and the PDUFA goal date may be extended by three months if the FDA requests or if the sponsor otherwise provides additional information or clarification regarding information already provided in the submission within the last three months before the PDUFA goal date.

In connection with its review of a BLA, the FDA may refer the application to an advisory committee for review, evaluation, and recommendation as to whether the application should be approved.

In particular, the FDA may refer applications for novel biologic products or biologic products that present difficult questions of safety or efficacy to an advisory committee.

Typically, an advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates, and provides a recommendation as to whether the application should be approved and under what conditions.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

The FDA’s Decision on a BLA

Under the PHSA, the FDA may approve a BLA if it determines that the product is safe, pure, and potent and the facility where the product will be manufactured meets standards designed to ensure that it continues to be safe, pure, and potent.

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An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

If the application is not approved, the FDA will issue a complete response letter, which will contain the conditions that must be met in order to secure final approval of the application, and when possible will outline recommended actions the sponsor might take to obtain approval of the application.

Sponsors that receive a complete response letter may submit to the FDA information that represents a complete response to the issues identified by the FDA.

If the application is not approved, the FDA will issue a complete response letter (“CRL”), which will contain the conditions that must be met in order to secure final approval of the application, and when possible will outline recommended actions the sponsor might take to obtain approval of the application.

Sponsors that receive a CRL may submit to the FDA information that represents a complete response to the issues identified by the FDA.

Such resubmissions are classified under PDUFA as either Class 1 or Class 2.

The classification of a resubmission is based on the information submitted by

an applicant in response to an action letter.

The classification of a resubmission is based on the information submitted by a sponsor in response to an action letter.

Under the goals and policies agreed to by the FDA under PDUFA, the FDA has two months to review a Class 1 resubmission and six months to review a Class 2 resubmission.

The FDA will not approve an application until issues identified in the complete response letter have been addressed.

The FDA may also refer the application to an advisory committee for review, evaluation, and recommendation as to whether the application should be approved.

In particular, the FDA may refer applications for novel biologic products or biologic products that present difficult questions of safety or efficacy to an advisory committee.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

If the FDA approves a new product, it may limit the approved indications for use of the product.

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After approval, many types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.

Fast Track, Breakthrough Therapy, Priority Review and Regenerative Advanced Therapy Designations

The FDA is authorized to designate certain products for expedited review if they are intended to address an unmet medical need in the treatment of a serious or life-threatening disease or condition.

These programs are referred to as fast track designation, breakthrough therapy designation, priority review designation and regenerative advanced therapy designation.

Specifically, the FDA may designate a product for fast track review if it is intended, whether alone or in combination with one or more other products, for the treatment of a serious or life-threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition.

For fast track products, sponsors may have greater interactions with the FDA and the FDA may initiate review of sections of a fast track product’s application before the application is complete.

This rolling review may be available if the FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a fast track product may be effective.

The sponsor must also provide, and the FDA must approve, a schedule for the submission of the remaining information and the sponsor must pay applicable user fees.

However, the FDA’s time period goal for reviewing a fast track application does not begin until the last section of the application is submitted.

In addition, the fast track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process.

Second, in 2012, Congress enacted the Food and Drug Administration Safety and Innovation Act (“FDASIA”).

This law established a new regulatory scheme allowing for expedited review of products designated as “breakthrough therapies.” A product may be designated as a breakthrough therapy if it is intended, either alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

The FDA may take certain actions with respect to breakthrough therapies, including holding meetings with the sponsor throughout the development process;

providing timely advice to the product sponsor regarding development and approval;

involving more senior staff in the review process;

assigning a cross-disciplinary project lead for the review team;

and taking other steps to design the clinical trials in an efficient manner.

Third, the FDA may designate a product for priority review if it is a product that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness.

The FDA determines, on a case-by-case basis, whether the proposed product represents a significant improvement when compared with other available therapies.

Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting product reaction, documented enhancement of patient compliance that may lead to improvement in serious outcomes, and evidence of safety and effectiveness in a new subpopulation.

A priority designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months.

With passage of the Cures Act in December 2016, Congress authorized the FDA to accelerate review and approval of products designated as regenerative advanced therapies.

A product is eligible for this designation if it is a regenerative medicine therapy that is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product has the potential to address unmet medical needs for such disease or condition.

The benefits of a regenerative advanced therapy designation include early interactions with FDA to expedite development and review, benefits available to breakthrough therapies, potential eligibility for priority review and accelerated approval based on surrogate or intermediate endpoints.

Accelerated Approval Pathway

The FDA may grant accelerated approval to a product for a serious or life-threatening condition that provides meaningful therapeutic advantage to patients over existing treatments based upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.

The FDA may also grant accelerated approval for such a condition when the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality (“IMM”) and that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

Products granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.

For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit.

Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints.

An intermediate clinical endpoint is a measurement of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a product, such as an effect on IMM.

The FDA has limited experience with accelerated approvals based on intermediate clinical endpoints, but has indicated that such endpoints generally may support accelerated approval where the therapeutic effect measured by the endpoint is not itself a clinical benefit and basis for traditional approval, if there is a basis for concluding that the therapeutic effect is reasonably likely to predict the ultimate clinical benefit of a product.

The accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required to measure the intended clinical benefit of a product, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly.

Thus, accelerated approval has been used extensively in the development and approval of products for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity and the duration of the typical disease course requires lengthy and sometimes large trials to demonstrate a clinical or survival benefit.

The accelerated approval pathway is usually contingent on a sponsor’s agreement to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe the product’s clinical benefit.

As a result, a product candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or post-approval clinical trials to confirm the effect on the clinical endpoint.

Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies, would allow the FDA to withdraw the product from the market on an expedited basis.

All promotional materials for product candidates approved under accelerated regulations are subject to prior review by the FDA.

Expedited Review Programs

The FDA is authorized to expedite the review of applications in several ways.

None of these expedited programs, however, changes the standards for approval but they may help expedite the development or approval process of product candidates.

● Fast Track designation :

Candidate products are eligible for Fast Track designation if they are intended to treat a serious or life-threatening condition and demonstrate the potential to address unmet medical needs for the condition.

Fast Track designation applies to the combination of the product candidate and the specific indication for which it is being studied.

In addition to other benefits, such as the ability to have greater interactions with the FDA, the FDA may initiate review of sections of a Fast Track application before the application is complete, a process known as rolling review.

● Breakthrough Therapy designation.

To qualify for the Breakthrough Therapy program, product candidates must be intended to treat a serious or life-threatening condition and preliminary clinical evidence must indicate that such product candidates may demonstrate substantial improvement on one or more clinically significant endpoints over existing therapies.

The FDA will seek to ensure the sponsor of a Breakthrough Therapy product candidate receives intensive guidance on an efficient development program, intensive involvement of senior managers and experienced staff on a proactive, collaborative and cross-disciplinary review and rolling review.

● Priority review.

A product candidate is eligible for priority review if it treats a serious condition and, if approved, it would be a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention compared to marketed products.

FDA aims to complete its review of priority review applications within six months as opposed to 10 months for standard review.

● Accelerated approval.

Drug or biologic products studied for their safety and effectiveness in treating serious or life-threatening conditions and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval.

Accelerated approval means that a product candidate may be approved on the basis of adequate and well controlled clinical trials establishing that the product candidate has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity and prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, the FDA may require that a sponsor of a drug or biologic product candidate receiving accelerated approval perform adequate and well controlled post-marketing clinical trials.

In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials.

● Regenerative advanced therapy.

With passage of the 21st Century Cures Act, or the Cures Act, in December 2016, Congress authorized the FDA to accelerate review and approval of products designated as regenerative advanced therapies.

A product is eligible for this designation if it is a regenerative

medicine therapy that is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product candidate has the potential to address unmet medical needs for such disease or condition.

The benefits of a regenerative advanced therapy designation include early interactions with the FDA to expedite development and review, benefits available to Breakthrough Therapies, potential eligibility for priority review and accelerated approval based on surrogate or intermediate endpoints.

Post-Approval Regulation

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● injunctions or the imposition of civil or criminal penalties.

The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market.

Pharmaceutical products may be promoted only for the approved indications and in accordance with the provisions of the approved label.

Although health care providers may prescribe products for off-label uses in their professional judgment, drug manufacturers are prohibited from soliciting, encouraging or promoting unapproved uses of a product.

The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.

The FDA strictly regulates the marketing, labeling, advertising and promotion of prescription drug products placed on the market.

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are not approved by the FDA, as reflected in the product’s prescribing information.

In the United States, health care professionals are generally permitted to prescribe drugs for such uses not described in the drug’s labeling, known as off-label uses, because the FDA does not regulate the practice of medicine.

However, FDA regulations impose rigorous restrictions on manufacturers’ communications, prohibiting the promotion of off-label uses.

It may be permissible, under very specific, narrow conditions, for a manufacturer to engage in nonpromotional, non-misleading communication regarding off-label information, such as distributing scientific or medical journal information.

In September 2021, the FDA published final regulations which describe the types of evidence that the agency will consider in determining the intended use of a drug or biologic.

If a company is found to have promoted off-label uses, it may become subject to adverse public relations and administrative and judicial enforcement by the FDA, the Department of Justice, or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities.

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Orphan drug exclusivity means that the FDA may not approve another sponsor’s marketing application for the same product for the same indication for seven years, except in certain limited circumstances.

In particular, the concept of what constitutes the "same drug"

for purposes of orphan drug exclusivity remains in flux in the context of gene therapies, and the FDA has issued recent draft guidance suggesting that it would not consider two gene therapy products to be different drugs solely based on minor differences in the transgenes or vectors.

In particular, the concept of what constitutes the “same drug” for purposes of orphan drug exclusivity remains in flux in the context of gene therapies, and the FDA has recently issued guidance indicating it would consider two gene therapy products for the same indication to be different, thus each eligible for orphan drug exclusivity, if they express different transgenes or have or use different vectors, so long as those differences are not “minor .” The FDA will determine whether two vectors from the same viral class are the same on a case-by-case basis and may consider additional key features in assessing sameness.

If a product designated as an orphan drug ultimately receives marketing approval for an indication broader than what was designated in its orphan drug application, it may not be entitled to exclusivity.

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The FDA cannot, however, approve the same product made by another manufacturer for the same indication during the market exclusivity period unless it has the consent of the sponsor or the sponsor is unable to provide sufficient quantities.

In September 2021, the Court of Appeals for the 11th Circuit held that, for the purpose of determining the scope of market exclusivity, the term “same disease or condition” in the statute means the designated “rare disease or condition” and could not be interpreted by the FDA to mean the “indication or use.” Thus, the court concluded, orphan drug exclusivity applies to the entire designated disease or condition rather than the “indication or use.” It is unclear how this court decision will be implemented by the FDA.

Pediatric Exclusivity

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The BPCIA established a regulatory scheme authorizing the FDA to approve biosimilars and interchangeable biosimilars.

A biosimilar is a biological product that is highly similar to an existing FDA-licensed “reference product.” As of January 1, 2021, the FDA has approved 29 biosimilar products for use in the United States.

No interchangeable biosimilars, however, have been approved.

The FDA has issued several guidance documents outlining an approach to review and approval of biosimilars.

Additional guidances are expected to be finalized by the FDA in the near term.

A biosimilar is a biological product that is highly similar to an existing FDA-licensed “reference product.” To date, the FDA has approved a number of biosimilars and the first interchangeable biosimilar product was approved on July 30, 2021, and a second product previously approved as a biosimilar was designated as interchangeable in October 2021.

The FDA has also issued numerous guidance documents outlining its approach to reviewing and licensing biosimilars and interchangeable biosimilars under the PHSA, including a draft guidance issued in November 2020 that seeks to provide additional clarity to manufacturers of interchangeable biosimilars.

Under the BPCIA, a manufacturer may submit an application for licensure of a biologic product that is “biosimilar to” or “interchangeable with” a previously approved biological product or “reference product.” In order for the FDA to approve a biosimilar product, it must find that there are no clinically meaningful differences between the reference product and proposed biosimilar product in terms of safety, purity, and potency.

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The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products.

At this juncture, it is unclear whether products deemed “interchangeable” by the FDA will, in fact, be readily substituted by pharmacies, which are governed by state pharmacy law.

Since the passage of the BPCIA, many states have passed laws or amendments to laws, including laws governing pharmacy practices, which are state-regulated, to regulate the use of biosimilars.

There have been recent government proposals to reduce the 12-year reference product exclusivity period, but none has been enacted to date.

At the same time, since passage of the BPCIA, many states have passed laws or amendments to laws, which address pharmacy practices involving biosimilar products.

Patent Term Restoration and Extension

A patent claiming a new biologic product, its method of use or its method of manufacture may be eligible for a limited patent term extension under the Hatch-Waxman Act, which permits a patent restoration of up to five years for patent term lost during product development and FDA regulatory review.

The restoration period granted on a patent covering a product is typically one-half the time between the effective date of a clinical investigation involving human beings is begun and the submission date of an application, plus the time between the submission date of an application and the ultimate approval date.

patent term lost during product development and FDA regulatory review.

The restoration period granted on a patent covering a product is typically one-half the time between the effective date of the IND and the submission date of an application, plus the time between the submission date of an application and the ultimate approval date.

Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date.

Only one patent applicable to an approved product is eligible for the extension, and the application for the extension must be submitted prior to the expiration of the patent in question.

A patent that covers multiple products for which approval is sought can only be extended in connection with one of the

A patent that covers multiple products for which approval is sought can only be extended in connection with one of the approvals.

The USPTO reviews and approves the application for any patent term extension or restoration in consultation with the FDA.

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The guidance provides that depending on the details of the study plan and subjects, a sponsor may seek to submit an IND alone, or both an IND and an IDE.

In April 2020, the FDA issued additional guidance which describes considerations for the development and labeling of companion diagnostic devices to support the indicated uses of multiple drug or biological oncology products, when appropriate.

This guidance builds upon existing policy regarding the labeling of companion diagnostics.

In its 2014 guidance, the FDA stated that if evidence is sufficient to conclude that the companion diagnostic is appropriate for use with a specific group of therapeutic products, the companion diagnostic’s intended use/indications for use should name the specific group of therapeutic products, rather than specific products.

The 2020 guidance expands on the policy statement in the 2014 guidance by recommending that companion diagnostic developers consider a number of factors when determining whether their test could be developed, or the labeling for approved companion diagnostics could be revised through a supplement, to support a broader labeling claim such as use with a specific group of oncology therapeutic products (rather than listing an individual therapeutic product(s)).

Under the FDCA, in vitro diagnostics, including companion diagnostics, are regulated as medical devices.

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The PMA process, including the gathering of clinical and preclinical data and the submission to and review by the FDA, can take several years or longer.

It involves a rigorous premarket review during which the applicant must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and information about the device and its components regarding, among other things, device design, manufacturing and labeling.

PMA applications are subject to an application fee.

It involves a rigorous premarket review during which the sponsor must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and information about the device and its components regarding, among other things, device design, manufacturing and labeling.

applications are subject to an application fee.

For federal fiscal year 2022, the standard fee is $374,858 and the small business fee is $93,714.

A clinical trial is typically required for a PMA application and, in a small percentage of cases, the FDA may require a clinical study in support of a 510(k) submission.

A manufacturer that wishes to conduct a clinical study involving the device is subject to the FDA’s IDE regulation.

The IDE regulation distinguishes between significant and non-significant risk device studies and the procedures for obtaining approval to begin the study differ accordingly.

Also, some types of studies are exempt from the IDE regulations.

A significant risk device presents a potential for serious risk to the health, safety, or welfare of a subject.

Significant risk devices are devices that are substantially important in diagnosing, curing, mitigating, or treating disease or in preventing impairment to human health.

Studies of devices that pose a significant risk require both FDA and an IRB approval prior to initiation of a clinical study.

Non-significant risk devices are devices that do not pose a significant risk to the human subjects.

A non-significant risk device study requires only IRB approval prior to initiation of a clinical study.

After a device is placed on the market, it remains subject to significant regulatory requirements.

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Device manufacturers must also establish registration and device listings with the FDA.

A medical device manufacturer’s manufacturing

processes and those of its suppliers are required to comply with the applicable portions of the Quality System Regulation, which covers the methods and documentation of the design, testing, production, processes, controls, quality assurance, labeling, packaging and shipping of medical devices.

A medical device manufacturer’s manufacturing processes and those of its suppliers are required to comply with the applicable portions of the Quality System Regulation, which covers the methods and documentation of the design, testing, production, processes, controls, quality assurance, labeling, packaging and shipping of medical devices.

Domestic facility records and manufacturing processes are subject to periodic unscheduled inspections by the FDA.

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The clinical trial application must be accompanied by an investigational medicinal product dossier with supporting information prescribed by Directive 2001/20/EC and Directive 2005/28/EC and corresponding national laws of the member states and further detailed in applicable guidance documents.

In April 2014, the EU adopted a new Clinical Trials Regulation (EU) No 536/2014, which is set to replace the current Clinical Trials Directive 2001/20/EC.

The new Clinical Trials Regulation will become directly applicable to and binding in all 28 EU Member States without the need for any national implementing legislation.

It will overhaul the current system of approvals for clinical trials in the EU.

Specifically, the new legislation aims at simplifying and streamlining the approval of clinical trials in the EU.

Under the new coordinated procedure for the approval of clinical trials, the sponsor of a clinical trial will be required to submit a single application for approval of a clinical trial to a reporting EU Member State (RMS) through an EU Portal.

The submission procedure will be the same irrespective of whether the clinical trial is to be conducted in a single EU Member State or in more than one EU Member State.

The Regulation was published on June 16, 2014 but has not yet become effective.

As of January 1, 2020, the website of the European Commission reported that the implementation of the Clinical Trials Regulation was dependent on the development of a fully functional clinical trials portal and database, which would be confirmed by an independent audit, and that the new legislation would come into effect six months after the European Commission publishes a notice of this confirmation.

The website indicated that the audit was expected to commence in December 2020.

In late 2020, the EMA indicated that it plans to focus on the findings of a system audit;

improving the usability, quality and stability of the clinical trial information system;

and knowledge transfer to prepare users and their organizations for the new clinical trial system.

The EMA has indicated that the system will go live in December 2021.

In April 2014, the new Clinical Trials Regulation, (EU) No 536/2014, or the Clinical Trials Regulation, was adopted.

The Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the EU.

The main characteristics of the regulation include:

a streamlined application procedure via a single-entry point, the “EU portal”;

a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors;

and a harmonized procedure for the assessment of applications for clinical trials, which is divided in two parts.

Part I is assessed by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted (Member States concerned).

Part II is assessed separately by each Member State concerned.

Strict deadlines have been established for the assessment of clinical trial applications.

The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national law of the concerned EU Member State.

However, overall related timelines will be defined by the Clinical Trials Regulation.

The Clinical Trials Regulation came into application in all the EU Member States on January 31, 2022, repealing Clinical Trials Directive 2001/20/EC.

According to the transitional provisions, if a clinical trial continues for more than three years from the day on which the Clinical Trials Regulation became applicable, the Clinical Trials Regulation will at that time begin to apply to the clinical trial.

Parties conducting certain clinical studies must, as in the U.S., post clinical trial information in the European Union at the EudraCT website:

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PRIME Designation in the EU

In March 2016, the European Medicines Agency (“EMA”) launched an initiative to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist.

In March 2016, the EMA launched an initiative to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist.

The PRIority Medicines (“PRIME”) scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the centralized procedure.

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Specifically, the grant of marketing authorization in the European Union for products containing viable human tissues or cells such as gene therapy medicinal products is governed by Regulation 1394/2007/EC on advanced therapy medicinal products, read in combination with Directive 2001/83/EC of the European Parliament and of the Council, commonly known as the Community code on medicinal products.

Regulation 1394/2007/EC lays down specific rules concerning the authorization, supervision, and pharmacovigilance of gene therapy medicinal products, somatic cell therapy medicinal products, and tissue engineered products.

Manufacturers of advanced therapy medicinal products must demonstrate the quality, safety, and efficacy of their products to EMA which provides an opinion regarding the

application for marketing authorization.

Regulation 1394/2007/EC lays down specific rules

concerning the authorization, supervision, and pharmacovigilance of gene therapy medicinal products, somatic cell therapy medicinal products, and tissue engineered products.

Manufacturers of advanced therapy medicinal products must demonstrate the quality, safety, and efficacy of their products to EMA which provides an opinion regarding the application for marketing authorization.

The European Commission grants or refuses marketing authorization in light of the opinion delivered by EMA.

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Even if a compound is considered to be a new chemical entity so that the innovator gains the prescribed period of data exclusivity, another company may market another version of the product if such company obtained marketing authorization based on an MAA with a complete independent data package of pharmaceutical tests, preclinical tests and clinical trials.

Patent Term Extensions in the European Union and Other Jurisdictions

The European Union also provides for patent term extension through Supplementary Protection Certificates, or SPCs.

The rules and requirements for obtaining an SPC are similar to those in the United States.

An SPC may extend the term of a patent for up to five years after its originally scheduled expiration date and can provide up to a maximum of fifteen years of marketing exclusivity for a drug.

These periods can be extended for six additional months if pediatric exclusivity is obtained, which is described in detail below.

Although SPCs are available throughout the European Union, sponsors must apply on a country-by-country basis.

Similar patent term extension rights exist in certain other foreign jurisdictions outside the European Union.

Periods of Authorization and Renewals

A marketing authorization is valid for five years, in principle, and it may be renewed after five years on the basis of a reevaluation of the risk-benefit balance by the EMA or by the competent authority of the authorizing member state.

To that end, the marketing authorization holder must provide the EMA or the competent authority with a

consolidated version of the file in respect of quality, safety and efficacy, including all variations introduced since the marketing authorization was granted, at least six months before the marketing authorization ceases to be valid.

To that end, the marketing authorization holder must provide the EMA or the competent authority with a consolidated version of the file in respect of quality, safety and efficacy, including all variations introduced since the marketing authorization was granted, at least six months before the marketing authorization ceases to be valid.

Once renewed, the marketing authorization is valid for an unlimited period, unless the European Commission or the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal period.

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Finally, the marketing and promotion of authorized products, including industry-sponsored continuing medical education and advertising directed toward the prescribers of drugs and/or the general public, are strictly regulated in the European Union under Directive 2001/83EC, as amended.

Reimbursement and Pricing of Prescription Pharmaceuticals

In the E.U., similar political, economic and regulatory developments to those in the United States may affect our ability to profitably commercialize our product candidates, if approved.

In markets outside of the U.S.

and the E.U., reimbursement and healthcare payment systems vary significantly by country and many countries have instituted price ceilings on specific products and therapies.

In many countries, including those of the E.U., the pricing of prescription pharmaceuticals is subject to governmental control and access.

In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product.

To obtain reimbursement or pricing approval in some countries, pharmaceutical firms may be required to conduct a clinical trial that compares the cost-effectiveness of the product to other available therapies.

Orphan Drug Designation and Exclusivity

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This pediatric reward is subject to specific conditions and is not automatically available when data in compliance with the PIP are developed and submitted.

Patent Term Extensions in the European Union and Other Jurisdictions

The European Union also provides for patent term extension through Supplementary Protection Certificates, or SPCs.

The rules and requirements for obtaining an SPC are similar to those in the United States.

An SPC may extend the term of a patent for up to five years after its originally scheduled expiration date and can provide up to a maximum of fifteen years of marketing exclusivity for a drug.

These periods can be extended for six additional months if pediatric exclusivity is obtained, which is described in detail below.

Although SPCs are available throughout the European Union, sponsors must apply on a country-by-country basis.

Similar patent term extension rights exist in certain other foreign jurisdictions outside the European Union.

Brexit and the Regulatory Framework in the United Kingdom

On June 23, 2016, the electorate in the United Kingdom voted in favor of leaving the EU, commonly referred to as Brexit.

Following protracted negotiations, the United Kingdom left the EU on January 31, 2020.

Under the withdrawal agreement, there is a transitional period until December 31, 2020 (extendable by up to two years).

On December 24, 2020, the United Kingdom and the European Union entered into a Trade and Cooperation Agreement.

The agreement sets out certain procedures for approval and recognition of medical products in each jurisdiction.

Since the regulatory framework for pharmaceutical products in the United Kingdom covering quality, safety and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales and distribution of pharmaceutical products is derived from EU directives and regulations, Brexit could materially impact the future regulatory regime which applies to products and the approval of product candidates in the UK, as the UK legislation now has the potential to diverge from EU legislation.

It remains to be seen how Brexit will impact regulatory requirements for product candidates and products in the UK in the long-term.

The MHRA has recently published detailed guidance for industry and organizations to follow from January 1, 2021 now the transition period is over, which will be updated as the UK’s regulatory position on medicinal products evolves over time.

Furthermore, while the Data Protection Act of 2018 in the United Kingdom that “implements” and complements the European Union’s General Data Protection Regulation, or GDPR, has achieved Royal Assent on May 23, 2018 and is now effective in the United Kingdom, it is still unclear whether transfer of data from the European Economic Area, or EEA, to the United Kingdom will remain lawful under GDPR.

The United Kingdom’s withdrawal from the EU took place on January 31, 2020.

The EU and the U.K.

reached an agreement on their new partnership in the Trade and Cooperation Agreement, (“the Agreement”), which was applied provisionally beginning on January 1, 2021 and which entered into force on May 1, 2021.

The Agreement focuses primarily on free trade by ensuring no tariffs or quotas on trade in goods, including healthcare products such as medicinal products.

Thereafter, the EU and the U.K.

will form two separate markets governed by two distinct regulatory and legal regimes.

As such, the Agreement seeks to minimize barriers to trade in goods while accepting that border checks will become inevitable as a consequence that the U.K.

is no longer part of the single market.

As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency (“MHRA”), became responsible for supervising medicines and medical devices in Great Britain, comprising England, Scotland and Wales under domestic law whereas Northern Ireland continues to be subject to EU rules under the Northern Ireland Protocol.

The MHRA will rely on the Human Medicines Regulations 2012 (SI 2012/1916) (as amended), or the HMR, as the basis for regulating medicines.

The HMR has incorporated into the domestic law the body of EU law instruments governing medicinal products that pre-existed prior to the U.K.’s withdrawal from the EU.

Furthermore, while the Data Protection Act of 2018 in the United Kingdom that “implements” and complements the European Union’s General Data Protection Regulation (“ GDPR”), has achieved Royal Assent on May 23, 2018 and is now effective in the United Kingdom, it is still unclear whether transfer of data from the European Economic Area, (“EEA”), to the United Kingdom will remain lawful under GDPR.

The Trade and Cooperation Agreement provides for a transitional period during which the United Kingdom will be treated like an European Union member state in relation to processing and transfers of personal data for four months from January 1, 2021.

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General Data Protection Regulation

The collection, use, disclosure, transfer, or other processing of personal data regarding individuals in the EU, including personal health data, is subject to the EU General Data Protection Regulation (“GDPR”), which became effective on May 25, 2018.

The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including requirements relating to processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates, providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal data, providing notification of data breaches, and taking certain measures when engaging third-party processors.

The GDPR also imposes strict rules on the transfer of personal data to countries outside the EU, including the U.S., and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global revenues, whichever is greater.

The collection, use, disclosure, transfer, or other processing of personal data regarding individuals in the EU, including personal health data, is subject to the GDPR, which became effective on May 25, 2018.

security and confidentiality of personal data, providing notification of data breaches, and taking certain measures when engaging third-party processors.

The GDPR also imposes strict rules on the transfer of personal data to countries outside the EU, including the United States, and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global revenues, whichever is greater.

The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.

Compliance with the GDPR will be a rigorous and time-intensive process that may increase the cost of doing business or require companies to change their business practices to ensure full compliance.

In July 2020, the Court of Justice of the European Union, (“CJEU”), invalidated the EU-U.S.

Privacy Shield framework, one of the mechanisms used to legitimize the transfer of personal data from the EU to the United States.

The CJEU decision also drew into question the long-term viability of an alternative means of data transfer, the standard contractual clauses, for transfers of personal data from the EU to the United States.

Following the withdrawal of the U.K.

from the EU, the U.K.

Data Protection Act 2018 applies to the processing of personal data that takes place in the U.K.

and includes parallel obligations to those set forth by GDPR.

Coverage, Pricing, and Reimbursement

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Coverage policies and third-party reimbursement rates may change at any time.

Even if favorable coverage and reimbursement status is attained for one or more products for which a company or its collaborators receive marketing approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

Even if favorable coverage and reimbursement status is attained for one or more products for which a company

or its collaborators receive marketing approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

Outside the United States, ensuring adequate coverage and payment for any product candidates we may develop will face challenges.

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For example, the European Union provides options for its member states to restrict the range of products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

European Union member states may approve a specific price for a product or it may instead adopt a system

of direct or indirect controls on the profitability of the company placing the product on the market.

European Union member states may approve a specific price for a product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the product on the market.

Other member states allow companies to fix their own prices for products, but monitor and control prescription volumes and issue guidance to physicians to limit prescriptions.

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● the federal civil and criminal false claims laws, including the civil False Claims Act, and civil monetary penalties laws, which prohibit individuals or entities from, among other things, knowingly presenting, or causing to be presented, to the federal government, claims for payment that are false, fictitious, or fraudulent or knowingly making, using, or causing to made or used a false record or statement to avoid, decrease, or conceal an obligation to pay money to the federal government;

● t he federal civil monetary penalty and false statement laws and regulations relating to pricing and submission of pricing information for government programs, including penalties for knowingly and intentionally overcharging 340b eligible entities and the submission of false or fraudulent pricing information to government entities;

intentionally overcharging 340b eligible entities and the submission of false or fraudulent pricing information to government entities;

● the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), which created additional federal criminal laws that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;

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● the federal transparency requirements known as the federal Physician Payments Sunshine Act, under the Patient Protection and Affordable Care Act (“PPACA”), as amended by the Health Care Education Reconciliation Act, which requires certain manufacturers of drugs, devices, biologics and medical supplies to report annually to the Centers for Medicare & Medicaid Services (“CMS”) within the U.S.

Department of Health and Human Services, information related to payments and other transfers of value made by that entity to physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;

Department of Health and Human Services, information related to payments and other transfers of value made by that entity to physicians, other healthcare providers and teaching hospitals, as well as ownership and investment interests held by physicians, other healthcare providers and their immediate family members;

● analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws, which may apply to healthcare items or services that are reimbursed by non-governmental third-party payors, including private insurers.

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In August 2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress.

A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.

These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect in April 2013 and will remain in effect through 2030 under the Coronavirus Aid, Relief, and Economic Security Act, or the CARES Act.

A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the

years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.

These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect in April 2013 and will remain in effect through 2031 pursuant to the Coronavirus Aid, Relief and Economic Security Act, or CARES Act.

Under subsequent legislation, these Medicare sequester reductions have been suspended through the end of March 2022.

From April 2022 through June 2022 a 1% sequester cut will be in effect, with the full 2% cut resuming thereafter.

The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

These laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

Since enactment of the ACA, there have been, and continue to be, numerous legal challenges and Congressional actions to repeal and replace provisions of the law.

For example, with enactment of the Tax Cuts and Jobs Act of 2017, which was signed by President Trump on December 22, 2017, Congress repealed the “individual mandate.” The repeal of this provision, which requires most Americans to carry a minimal level of health insurance, became effective in 2019.

Further, on December 14, 2018, a U.S.

District Court judge in the Northern District of Texas ruled that the individual mandate portion of the ACA is an essential and inseverable feature of the ACA, and therefore because the mandate was repealed as part of the Tax Cuts and Jobs Act, the remaining provisions of the ACA are invalid as well.

On December 18, 2019, the Court of Appeals for the Fifth Circuit court affirmed the lower court’s ruling that the individual mandate

portion of the ACA is unconstitutional and it remanded the case to the district court for reconsideration of the severability question and additional analysis of the provisions of the ACA.

Thereafter, the U.S.

Supreme Court agreed to hear this case.

Oral argument in the case took place on November 10, 2020.

On February 10, 2021, the Biden Administration withdrew DOJ’s support for this lawsuit.

A ruling by the Court is expected sometime this year.

Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.

Since enactment of the PPACA, there have been, and continue to be, numerous legal challenges and Congressional actions to repeal and replace provisions of the law.

For example, with enactment of the Tax Cuts and Jobs Act of 2017 (“ the Tax Act”), which was signed by President Trump on December 22, 2017, Congress repealed the “individual mandate.” The repeal of this provision, which requires most Americans to carry a minimal level of health insurance, became effective in 2019.

On December 14, 2018, a U.S.

District Court judge in the Northern District of Texas ruled that the individual mandate portion of the PPACA is an essential and inseverable feature of the PPACA, and therefore because the mandate was repealed as part of the Tax Act, the remaining provisions of the PPACA are invalid as well.

In June 2021, the U.S.

Supreme Court dismissed this action after finding that the plaintiffs do not have standing to challenge the constitutionality of the ACA.

Litigation and legislation over the PPACA are likely to continue, with unpredictable and uncertain results.

The Trump Administration also took executive actions to undermine or delay implementation of the ACA, including directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.

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and policies that reduce affordability of coverage or financial assistance, including for dependents.

The costs of prescription pharmaceuticals have also been the subject of considerable discussion in the United States To date, there have been several recent U.S.

congressional inquiries, as well as proposed and enacted state and federal legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products.

To those ends, President Trump issued five executive orders intended to lower the costs of prescription drug products but it is unclear whether, and to what extent, these orders will remain in force under the Biden Administration.

Further, on September 24, 2020, the Trump Administration finalized a rulemaking allowing states or certain other non-federal government entities to submit importation program proposals to the FDA for review and approval.

Applicants are required to demonstrate that their importation plans pose no additional risk to public health and safety and will result in significant cost savings for consumers.

The FDA has issued draft guidance that would allow manufacturers to import their own FDA-approved drugs that are authorized for sale in other countries (multi-market approved products).

Pharmaceutical Prices

The prices of prescription pharmaceuticals have also been the subject of considerable discussion in the United States.

There have been several recent U.S.

congressional inquiries, as well as proposed and enacted state and federal legislation designed to, among other things, bring more transparency to pharmaceutical pricing, review the relationship between pricing and manufacturer patient programs, and reduce the costs of pharmaceuticals under Medicare and Medicaid.

In 2020, President Trump issued several executive orders intended to lower the costs of prescription products and certain provisions in these orders have been incorporated into regulations.

These regulations include an interim final rule implementing a most favored nation model for prices that would tie Medicare Part B payments for certain physician-administered pharmaceuticals to the lowest price paid in other economically advanced countries, effective January 1, 2021.

That rule, however, has been subject to a nationwide preliminary injunction and, on December 29, 2021, CMS issued a final rule to rescind it.

With issuance of this rule, CMS stated that it will explore all options to incorporate value into payments for Medicare Part B pharmaceuticals and improve beneficiaries' access to evidence-based care.

In addition, in October 2020, HHS and the FDA published a final rule allowing states and other entities to develop a Section 804 Importation Program (“SIP”), to import certain prescription drugs from Canada into the United States.

The final rule is currently the subject of ongoing litigation, but at least six states (Vermont, Colorado, Florida,

Maine, New Mexico, and New Hampshire) have passed laws allowing for the importation of drugs from Canada with the intent of developing SIPs for review and approval by the FDA.

Further, on November 20, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also been delayed by the Biden administration until January 1, 2023.

At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

In addition, regional health care authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other health care programs.

A number of states, for example, require drug manufacturers and other entities in the drug supply chain, including health carriers, pharmacy benefit managers, wholesale distributors, to disclose information about pricing of pharmaceuticals.

In addition, regional healthcare organizations and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription pharmaceutical and other healthcare programs.

These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing.

We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our product candidates or additional pricing pressures.

Federal and State Data Privacy Laws

There are multiple privacy and data security laws that may impact our business activities, in the United States and in other countries where we conduct trials or where we may do business in the future.

These laws are evolving and may increase both our obligations and our regulatory risks in the future.

In the health care industry generally, under the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), the U.S.

Department of Health and Human Services, or HHS, has issued regulations to protect the privacy and security of protected health information, or PHI, used or disclosed by covered entities including certain healthcare providers, health plans and healthcare clearinghouses.

HIPAA also regulates standardization of data content, codes and formats used in healthcare transactions and standardization of identifiers for health plans and providers.

HIPAA also imposes certain obligations on the business associates of covered entities that obtain protected health information in providing services to or on behalf of covered entities.

HIPAA may apply to us in certain circumstances and may also apply to our business partners in ways that may impact our relationships with them.

Our clinical trials are regulated by the Common Rule, which also includes specific privacy-related provisions.

In addition to federal privacy regulations, there are a number of state laws governing confidentiality and security of health information that may be applicable to our business.

In addition to possible federal civil and criminal penalties for HIPAA violations, state attorneys general are authorized to file civil actions for damages or injunctions in federal courts to enforce HIPAA and seek attorney’s fees and costs associated with pursuing federal civil actions.

In addition, state attorneys general (along with private plaintiffs) have brought civil actions seeking injunctions and damages resulting from alleged violations of HIPAA’s privacy and security rules.

State attorneys general also have authority to enforce state privacy and security laws.

New laws and regulations governing privacy and security may be adopted in the future as well.

At the state level, California has enacted legislation that has been dubbed the first “GDPR-like” law in the United States.

Known as the California Consumer Privacy Act (“CCPA”), it creates new individual privacy rights for consumers (as that word is broadly defined in the law) and places increased privacy and security obligations on entities handling personal data of consumers or households.

The CCPA went into effect on January 1, 2020 and requires covered companies to provide new disclosures to California consumers, provide such consumers new ways to opt-out of certain sales of personal information, and allow for a new cause of action for data breaches.

Additionally, effective starting on January 1, 2023, the California Privacy Rights Act, or CPRA, will significantly modify the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal information.

The CPRA also creates a new state agency that will be vested with authority to implement and enforce the CCPA and the CPRA.

The CCPA and CPRA could impact our business activities depending on how it is interpreted and exemplifies the vulnerability of our business

to not only cyber threats but also the evolving regulatory environment related to personal data and individually identifiable health information.

These provisions may apply to some of our business activities.

In addition, other states, including Virginia and Colorado, already have passed state privacy laws and other states will likely be considering similar laws in the near future.

Because of the breadth of these laws and the narrowness of the statutory exceptions and regulatory safe harbors available under such laws, it is possible that some of our current or future business activities, including certain clinical research, sales and marketing practices and the provision of certain items and services to our customers, could be subject to challenge under one or more of such privacy and data security laws.

The heightening compliance environment and the need to build and maintain robust and secure systems to comply with different privacy compliance and/or reporting requirements in multiple jurisdictions could increase the possibility that a healthcare company may fail to comply fully with one or more of these requirements.

If our operations are found to be in violation of any of the privacy or data security laws or regulations described above that are applicable to us, or any other laws that apply to us, we may be subject to penalties, including potentially significant criminal, civil and administrative penalties, damages, fines, contractual damages, reputational harm, diminished profits and future earnings, additional reporting requirements and/or oversight if we become subject to a consent decree or similar agreement to resolve allegations of non-compliance with these laws, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

To the extent that any product candidates we may develop, once approved, are sold in a foreign country, we may be subject to similar foreign laws.

Additional Regulations

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None of our employees are represented by a labor union or covered by a collective bargaining agreement.

We experienced significant growth in the number of our employees in 2020, particularly in our research and development organization.

We anticipate that we will continue to increase headcount in our clinical and development organization as we progress the clinical development of EDIT-101 to treat LCA10 and EDIT-301 to treat sickle cell disease, and further advance our current research programs and our preclinical development activities.

Our values – community, innovation, and results – are built on the foundation that our people and the way we treat one another promote creativity in all aspects of our work and drive us as a team to achieve our mission of translating the promise of gene editing into a broad class of differentiated, transformational medicines for diseases with high unmet need .

Our human capital is integral to our future success.

For that reason, our human capital resources objectives include attracting, retaining, developing and motivating a diverse team of highly skilled employees at all levels.

We value our employees and provide them with competitive salaries and bonuses, opportunities for equity ownership, including stock-based compensation awards and an employee stock purchase plan, development programs that enable continued learning and growth and an employment package that promotes well-being across all aspects of their lives, including health care, retirement planning and paid time off.

We anticipate that we will continue to increase headcount in our clinical and development organization as we progress the clinical development of EDIT-101 to treat LCA10 and EDIT-301 to treat sickle cell disease and TDT, and further advance our current research programs and our preclinical development activities.

At Editas, we seek to unlock the full potential of gene editing technology, and we recognize that our success is driven by our dynamic, passionate and diverse team.

We work together with integrity, guided by our distinct culture, to develop transformative medicines for people living with serious diseases around the world.

At the core of our culture are our values – community, innovation, and results – which are built on the foundation that our people and the way we treat one another promote creativity in all aspects of our work and drive us as a team to achieve our mission of translating the promise of gene editing into a broad class of differentiated, transformational medicines for diseases with high unmet need .

Our Commitment to Diversity, Equity and Inclusion

We strongly believe that our greatest strength comes from the people who make up our team.

Each employee brings diverse perspectives, backgrounds, and thinking styles, and, by embracing and celebrating these differences, we strengthen our culture and further our mission to pioneer a new field of genome editing.

We are committed to preserving and further cultivating our diverse and inclusive workforce, including in our senior management team, to ensure an environment where employees feel empowered to achieve their fullest potential.

As of December 31, 2021, approximately 54% of our full-time employees were women and 51% of our senior management (director level and above) were women.

As of December 31, 2021, approximately 45% of our full-time employees identify as racially/ethnically diverse and 32% of our senior management identify as racially/ethnically diverse.

Recruitment, Retention and Development

Successful execution of our strategy is dependent on attracting, retaining and motivating a diverse team of highly skilled employees at all levels.

We believe a key component of recruiting, retaining and motivating our employees is our total compensation package.

For this reason, we provide employees with competitive compensation, including market-competitive salary and equity awards, along with competitive benefits packages, including medical, dental, vision and life insurance, an employee stock purchase plan, flexible spending accounts, short- and long-term disability and matching contributions to a 401(k) tax-deferred savings plan.

We also provide annual cash incentive bonus opportunities that are tied to both company performance and individual performance to foster a pay-for-performance culture.

We regularly benchmark these total rewards against our industry peers to ensure we remain competitive and attractive to potential new hires.

We believe that continued learning and development, training and other resources are also an essential part of retaining our employees and creating a culture of learning and leadership.

We encourage our employees to participate and take advantage of a variety of learning and development resources, including online skills courses, professional development events, and external training programs based on individual needs.

We have also implemented formal coaching and mentoring programs, which enable employees to connect with, and learn and develop from, individuals across our company.

Communication and Engagement

We recognize that our employees perform best when they know how their work contributes to our overall strategy.

To achieve this, we emphasize open and direct communication through the use of a variety of channels, including quarterly all-company business updates from the senior management team, fireside chats with new members of the board of directors and our executive management team, open forums and company-wide written communications, and postings on our company intranet.

In addition, we regularly conduct employee surveys to gauge employee engagement and solicit feedback, and enhance our understanding of the views of our employees, work environment and culture.

The results from engagement surveys are used to implement programs and processes designed to enhance employee engagement and improve the employee experience.

Health, Wellness and Safety

Employee safety and well-being is of paramount importance to us, particularly in light of the COVID-19 pandemic.

Since March 2020, we have taken a number of additional steps to support our employees and government efforts to curb the COVID-19 pandemic, including creating or implementing some or all of the following from time to time:

● A task force responsible for establishing COVID-19 safety protocols and regularly communicating updates to all employees;

● A work from home policy, urging that all work that can be done from home should be done from home;

● Decreased density and increased physical distancing in our facilities for employees who must work onsite using scheduling adjustments and flexibility;

● Robust cleaning protocols across our facilities;

● Provision of masks to all onsite employees and masking requirements;

● Distribution of at-home COVID-19 test kits to all employees;

● Rigorous procedures to address actual and suspected COVID-19 cases and potential exposure; and

● Prohibition of all non-essential travel for all employees.

Our Corporate Information

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Item 1. Business