9 unchanged sentences
As of December 31, 2021, we had an accumulated deficit of $857.7 million.
−Removed: We have financed our operations primarily through public offerings of our common stock, private placements of our preferred stock, our collaboration with Juno Therapeutics, Inc., a wholly-owned subsidiary of Bristol-Myers Squibb Company (“Juno Therapeutics”), and payments under our strategic alliance with Allergan Pharmaceuticals International Limited (which was acquired by AbbVie Inc.
+Added: We have financed our operations primarily through public offerings of our common stock, our collaboration with Bristol Myers Squibb Company (“BMS”) through its wholly owned subsidiary, Juno Therapeutics, Inc.
+Added: (“Juno Therapeutics”) , and payments under our strategic alliance with Allergan Pharmaceuticals International Limited (which was acquired by AbbVie Inc.
in May 2020 and is referred to together with its affiliates as “Allergan”), which was terminated in August 2020.
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We anticipate that our expenses will increase substantially if and as we:
−Removed: ● progress the clinical development of EDIT-101 to treat Leber congenital amaurosis (“LCA”) 10 (“LCA10”);
−Removed: ● continue our current research programs and our preclinical and clinical development of product candidates from our current research programs, including EDIT-301, our experimental medicine to treat sickle cell disease and beta-thalassemia;
+Added: ● progress the clinical development of EDIT-101 to treat Leber congenital amaurosis (“LCA”) 10 (“LCA10”), including expanding trial enrollment to explore dose response and support establishment of registrational trial endpoints;
+Added: ● progress the clinical development of EDIT-301 to treat sickle cell disease and prepare for and initiate the clinical development of EDIT-301 to treat transfusion-dependent beta-thalassemia;
+Added: ● continue our current research programs and our preclinical and clinical development of product candidates from our current research programs, including EDIT-103, our experimental medicine to treat rhodopsin-associated autosomal dominant retinitis pigmentosa, and EDIT-202, our experimental medicine to treat solid tumors;
● seek to identify additional research programs and additional product candidates;
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● continue to operate as a public company.
−Removed: We are in the early stages of the clinical development of EDIT-101 and expect that it will be many years, if ever, before we have a product candidate ready for commercialization.
−Removed: As a result of the termination of our agreements with Allergan in August 2020, we are now obligated to fund all of the costs related to developing and commercializing the LCA10 program in the United States, including the costs of the clinical development of EDIT-101.
+Added: We are in the early stages of the clinical development of EDIT-101 and EDIT-301 and expect that it will be many years, if ever, before we have a product candidate ready for commercialization.
To become and remain profitable, we must develop and eventually commercialize a medicine or medicines with significant market potential.
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If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, reduce, or eliminate our research and product development programs or future commercialization efforts.
−Removed: We expect that our existing cash, cash equivalents, and marketable securities at December 31, 2020 and anticipated interest income will enable us to fund our operating expenses and capital expenditure requirements into 2023.
+Added: We expect that our existing cash, cash equivalents, and marketable securities at December 31, 2021 and anticipated interest income will enable us to fund our operating expenses and capital expenditure requirements through 2023.
Our future capital requirements will depend on many factors, including:
−Removed: ● the costs of progressing the clinical development of EDIT-101 to treat LCA10 and EDIT-301 to treat sickle cell disease;
● the scope, progress, results, and costs of drug discovery, preclinical development, laboratory testing, and clinical or natural history study trials for the product candidates we develop;
+Added: ● the costs of progressing the clinical development of EDIT-101 to treat LCA10, including expanding trial enrollment to explore dose response and support establishment of registrational trial endpoints;
+Added: ● the costs of progressing the clinical development of EDIT-301 to treat sickle cell disease and preparing for and initiating the clinical development of EDIT-301 to treat transfusion-dependent beta-thalassemia;
● the costs of preparing, filing, and prosecuting patent applications, maintaining and enforcing our intellectual property and proprietary rights, and defending intellectual property-related claims;
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● the costs of future activities, including product sales, medical affairs, marketing, manufacturing, and distribution, for any product candidates for which we receive regulatory approval;
−Removed: ● the success of our collaboration with Juno Therapeutics;
−Removed: ● whether Juno Therapeutics exercises any of its options to extend the research program term and/or to certain of the research programs under our collaboration;
+Added: ● the success of our collaboration with BMS;
+Added: ● whether BMS exercises any of its options to extend the research program term and/or to additional research programs under our collaboration;
● our ability to establish and maintain additional collaborations on favorable terms, if at all;
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Adequate additional financing may not be available to us on acceptable terms, or at all.
−Removed: Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or product candidates.
+Added: Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish
+Added: rights to our technologies or product candidates.
Until such time, if ever, as we can generate substantial product revenues, we expect to finance our cash needs through a combination of public or private equity offerings, debt financings, collaborations, strategic alliances, and licensing arrangements.
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We were founded and commenced operations in the second half of 2013.
−Removed: Our operations to date have been limited to organizing and staffing our company, business planning, raising capital, acquiring and developing our technology, identifying potential product candidates, undertaking preclinical studies and preparing to undertake clinical trials.
+Added: Our operations to date have been limited to organizing and staffing our company, business planning, raising capital, acquiring and developing our technology, identifying potential product candidates, undertaking preclinical studies and initiating clinical trials.
Except for EDIT-101 and EDIT-301, all of our research programs are still in the preclinical or research stage of development, and the risk of failure of all of our research programs is high.
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Any of these factors may prevent us from completing our preclinical studies or any clinical trials that we may initiate or commercializing any product candidates we develop on a timely or profitable basis, if at all.
−Removed: Because genome editing is novel and the regulatory landscape that will govern any product candidates we develop is uncertain and may change, we cannot predict the time and cost of obtaining regulatory approval, if we receive it at all, for any product candidates we develop.
−Removed: The regulatory requirements that will govern any novel genome editing product candidates we develop are not entirely clear and may change.
−Removed: Within the broader genomic medicine field, we are aware of a limited number of gene therapy products that have received marketing authorization from the FDA and the EMA.
−Removed: Even with respect to more established products that fit into the categories of gene therapies or cell therapies, the regulatory landscape is still developing.
−Removed: Regulatory requirements governing gene therapy products and cell therapy products have changed frequently and will likely continue to change in the future.
−Removed: Moreover, there is substantial, and sometimes uncoordinated, overlap in those responsible for regulation of existing gene therapy products and cell therapy products.
−Removed: For example, in the United States, the FDA has established the Office of Tissues and Advanced Therapies within its Center for Biologics Evaluation and Research (“CBER”) to consolidate the review of gene therapy and related products, and the Cellular, Tissue and Gene Therapies Advisory Committee to advise CBER on its review.
−Removed: Gene therapy clinical trials are also subject to review and oversight by an institutional biosafety committee (“IBC”), a committee that reviews and oversees the use of biological agents.
−Removed: Although the FDA decides whether individual gene therapy protocols may proceed, the review process and determinations of other reviewing bodies can impede or delay the initiation of a clinical trial, even if the FDA has reviewed the trial and allowed its initiation.
+Added: Regulatory requirements governing genetic medicines, and in particular any novel genetic medicines we may develop, have changed frequently and may continue to change in the future.
+Added: Regulatory requirements governing genetic and cellular medicines, and in particular any novel genetic medicine products we may develop, have changed frequently and may continue to change in the future.
+Added: We are aware of a limited number of genetic medicines that have received marketing authorization from the FDA and EMA.
+Added: Even with respect to more established products in the genetic medicine field, the regulatory landscape is still developing.
+Added: For example, the FDA has established the Office of Tissues and Advanced Therapies (formerly the Office of Cellular, Tissue and Gene Therapies) within CBER to consolidate the review of genetic medicines and related products, and the Cellular, Tissue and Gene Therapies Advisory Committee to advise CBER on its review.
+Added: Genetic medicine clinical trials conducted at institutions that receive funding for recombinant DNA research from the NIH also are potentially subject to review by the Office of Biotechnology Activities’ Recombinant DNA Advisory Committee, or the RAC;
+Added: however, the NIH announced that the RAC will only publicly review clinical trials if the trials cannot be evaluated by standard oversight bodies and pose unusual risks.
The same applies in the European Union.
−Removed: The EMA’s Committee for Advanced Therapies (“CAT”) is responsible for assessing the quality, safety, and efficacy of advanced-
−Removed: therapy medicinal products.
−Removed: The role of the CAT is to prepare a draft opinion on an application for marketing authorization for a gene therapy medicinal candidate that is submitted to the EMA.
−Removed: The EMA may issue new guidelines concerning the development and marketing authorization for gene therapy medicinal products and require that we comply with these new guidelines.
−Removed: Adverse developments in clinical trials conducted by others of gene therapy products, cell therapy products, or products developed through the application of a CRISPR or other genome editing technology may cause the FDA, the EMA, and other regulatory bodies to revise the requirements for approval of any product candidates we develop or limit the use of products utilizing genome editing technologies, either of which could materially harm our business.
+Added: The EMA’s Committee for Advanced Therapies (“CAT”) is responsible for assessing the quality, safety and efficacy of advanced-therapy medicinal products.
+Added: The role of the CAT is to prepare a draft opinion on an application for marketing authorization for a genetic medicinal candidate that is submitted to the CHMP before CHMP adopts its final opinion.
+Added: In the European Union, the development and evaluation of a genetic medicinal product must be considered in the context of the relevant European Union guidelines.
+Added: The EMA may issue new guidelines concerning the development and marketing authorization for genetic medicinal products and require that we comply with these new guidelines.
+Added: As a result, the procedures and standards applied to genetic medicines and cell therapy products may be applied to any product candidates we may develop, but that remains uncertain at this point.
+Added: These regulatory review committees and advisory groups and the new guidelines they promulgate may lengthen the regulatory review process, require us to perform additional studies, increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of any product candidates we may develop or lead to significant post-approval limitations or restrictions.
+Added: As we advance any product candidates we may develop, we will be required to consult with these regulatory and advisory groups and comply with applicable guidelines.
+Added: If we fail to do so, we may be required to delay or discontinue development of these product candidates.
+Added: Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential product to market could decrease our ability to generate sufficient product revenue to maintain our business.
+Added: Although the FDA decides whether individual genetic medicine protocols may proceed, the RAC public review process, if undertaken, can delay the initiation of a clinical trial, even if the FDA has reviewed the trial design and details and approved its initiation.
+Added: Conversely, the FDA can put an IND on a clinical hold even if the RAC has provided a favorable review or an exemption from in-depth, public review.
+Added: If we were to engage an NIH-funded institution to conduct a clinical trial, that institution’s IBC as well as its IRB would need to review the proposed clinical trial to assess the safety of the trial.
+Added: In addition, adverse developments in clinical trials of genetic medicine products conducted by
+Added: others may cause the FDA or other oversight bodies to change the requirements for approval of any product candidates we may develop.
+Added: Similarly, the EMA may issue new guidelines concerning the development and marketing authorization for genetic medicine products and require that we comply with these new guidelines.
+Added: As we are initially seeking to identify and develop product candidates to treat diseases using novel technologies, there is heightened risk that the FDA, the EMA or other regulatory authority may not consider the clinical trial endpoints that we propose to provide clinically meaningful results.
+Added: Even if the endpoints are deemed clinically meaningful, we may not achieve these endpoints to a degree of statistical significance, particularly because many of the diseases we are targeting with our platform have small patient populations, making development of large and rigorous clinical trials more difficult.
+Added: Adverse developments in post-marketing experience or in clinical trials conducted by others of genetic medicines or cell therapy products may cause the FDA, the EMA, and other regulatory bodies to revise the requirements for development or approval of any product candidates we may develop or limit the use of products utilizing non-viral genetic medicinal technologies, either of which could materially harm our business.
In addition, the clinical trial requirements of the FDA, the EMA, and other regulatory authorities and the criteria these regulators use to determine the safety and efficacy of a product candidate vary substantially according to the type, complexity, novelty and intended use and market of the potential products.
−Removed: The regulatory approval process for novel product candidates such as ours can be more expensive and take longer than for other, better known, or more extensively studied pharmaceutical or other product candidates.
−Removed: Regulatory agencies administering existing or future regulations or legislation may not allow production and marketing of products utilizing genome editing technology in a timely manner or under technically or commercially feasible conditions.
+Added: The regulatory approval process for novel product candidates such as the product candidates we may develop can be more expensive and take longer than for other, better known or more extensively studied pharmaceutical or other product candidates.
+Added: Regulatory agencies administering existing or future regulations or legislation may not allow production and marketing of products utilizing non-viral genetic medicine technology in a timely manner or under technically or commercially feasible conditions.
In addition, regulatory action or private litigation could result in expenses, delays or other impediments to our research programs or the commercialization of resulting products.
−Removed: Adverse public perception of genomic medicines, and genome editing in particular, may negatively impact regulatory approval of, or demand for, our potential products.
−Removed: Our potential therapeutic products involve editing the human genome.
−Removed: The clinical and commercial success of our potential products will depend in part on public understanding and acceptance of the use of genome editing therapy for the prevention or treatment of human diseases.
−Removed: Public attitudes may be influenced by claims that genome editing is unsafe, unethical, or immoral, and, consequently, our products may not gain the acceptance of the public or the medical community.
−Removed: Adverse public attitudes may adversely impact our ability to enroll clinical trials.
−Removed: Moreover, our success will depend upon physicians prescribing, and their patients being willing to receive, treatments that involve the use of product candidates we develop in lieu of, or in addition to, existing treatments with which they are already familiar and for which greater clinical data may be available.
−Removed: In addition, genome editing technology is subject to public debate and heightened regulatory scrutiny due to ethical concerns relating to the application of genome editing technology to human embryos or the human germline.
−Removed: For example, academic scientists in several countries, including the United States, have reported on their attempts to edit the genome of human embryos as part of basic research and, in November 2018, Dr.
−Removed: Jiankui He, a Chinese biophysics researcher who was an associate professor in the Department of Biology of the Southern University of Science and Technology in Shenzhen, China, announced he had created the first human genetically edited babies, twin girls and helped create a second gene-edited pregnancy.
−Removed: The announcement was negatively received by the public, in particular by those in the scientific community.
−Removed: In the United States, germline editing for clinical application has been expressly prohibited since enactment of a December 2015 U.S.
−Removed: FDA ban on such activity.
−Removed: Prohibitions are also in place in the United Kingdom, across most of Europe, in China, and many other countries around the world.
−Removed: In the United States, the NIH has announced that it would not fund any use of genome editing technologies in human embryos, noting that there are multiple existing legislative and regulatory prohibitions against such work, including the Dickey-Wicker Amendment, which prohibits the use of appropriated funds for the creation of human embryos for research purposes or for research in which human embryos are destroyed.
−Removed: Laws in the United Kingdom prohibit genetically modified embryos from being implanted into women, but embryos can be altered in research labs under license from the Human Fertilisation and Embryology Authority.
−Removed: Basic research on embryos is more tightly controlled in many other European countries.
−Removed: Although we do not use our technologies to edit human embryos or the human germline, such public debate about the use of genome editing technologies in human embryos and heightened regulatory scrutiny could prevent or delay our development of product candidates.
−Removed: More restrictive government regulations or negative public opinion would have a negative effect on our business or financial condition and may delay or impair our development and commercialization of product candidates or demand for any products we may develop.
+Added: In addition, ethical, social and legal concerns about genetic medicine, genetic testing and genetic research could result in additional regulations or prohibiting the processes we may use.
+Added: Federal and state agencies, congressional committees and foreign governments have expressed their intentions to further regulate biotechnology.
+Added: More restrictive regulations or claims that any product candidates we may develop are unsafe or pose a hazard could prevent us from commercializing any products.
+Added: New government requirements may be established that could delay or prevent regulatory approval of any product candidates we may develop under development.
+Added: It is impossible to predict whether legislative changes will be enacted, regulations, policies or guidance changed, or interpretations by agencies or courts changed, or what the impact of such changes, if any, may be.
+Added: As we advance any product candidates we may develop through clinical development, we will be required to consult with these regulatory and advisory groups, and comply with applicable guidelines.
+Added: These regulatory review committees and advisory groups and any new guidelines they promulgate may lengthen the regulatory review process, require us to perform additional studies, increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of any product candidates we may develop or lead to significant post-approval limitations or restrictions.
+Added: Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential product to market could decrease our ability to generate sufficient product revenue.
We may not be successful in our efforts to identify, develop, or commercialize potential product candidates.
The success of our business depends primarily upon our ability to identify, develop, and commercialize products based on our genome editing platform.
−Removed: Other than EDIT-101 to treat LCA10 and EDIT-301 to treat sickle cell disease, all of our product development programs are still in the preclinical or research stage of development.
−Removed: Our research programs, including those subject to our collaboration with Juno Therapeutics, may fail to identify potential product candidates for clinical development for a number of reasons.
+Added: Other than EDIT-101 and EDIT-301, all of our product development programs are still in the preclinical or research stage of development.
+Added: Our research programs, including those subject to our collaboration with BMS, may fail to identify potential product candidates for clinical development for a number of reasons.
Our research methodology may be unsuccessful in identifying potential product candidates, or our potential product candidates may be shown to have harmful side effects or may have other characteristics that may make the products impractical to manufacture, unmarketable, or unlikely to receive marketing approval.
−Removed: If any of these events occur, we may be forced to abandon our development efforts for a program or programs, which would have a material adverse effect on our business, financial condition, results of operations, and prospects.
+Added: If any of these events occur, we may be forced to abandon our development efforts for a program or programs,
+Added: which would have a material adverse effect on our business, financial condition, results of operations, and prospects.
Research programs to identify new product candidates require substantial technical, financial, and human resources.
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Any of these factors could reduce or eliminate our commercial opportunity, and could have a material adverse effect on our business, financial condition, results of operations, and prospects.
−Removed: We depend heavily on the success of EDIT-101.
+Added: We depend heavily on the success of EDIT-101 and EDIT-301.
Except for EDIT-101 and EDIT-301, all of our product development programs are at the preclinical or research stage.
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If we are unable to commercialize any product candidates we develop or experience significant delays in doing so, our business will be materially harmed.
−Removed: We have invested a significant portion of our efforts and financial resources in the identification and development of EDIT-101 to treat LCA10.
−Removed: Our ability to generate product revenues, which we do not expect will occur for many years, if ever, will depend heavily on the successful development and eventual commercialization of EDIT-101 for the treatment of LCA10 and other product candidates that we may identify in the future.
−Removed: As a result of the termination of our collaboration with Allergan in August 2020, we are now obligated to fund all of the costs related to developing and commercializing the LCA10 program in the United States, including the costs of the clinical development of EDIT-101, and will need to expand our clinical development organization.
−Removed: Previously, we relied on Allergan to conduct the Phase 1/2 clinical trial of EDIT-101 and we do not have significant experience conducting Phase 1/2 clinical trials.
−Removed: The success of product candidates we identify and develop will depend on many factors, including the following:
+Added: We have invested a significant portion of our efforts and financial resources in the identification and development of EDIT-101 and EDIT-301.
+Added: Our ability to generate product revenues, which we do not expect will occur for many years, if ever, will depend heavily on our successful development and eventual commercialization of EDIT-101 and EDIT-301 and other product candidates that we have identified or may identify in the future.
+Added: The success of product candidates we identify and develop will depend on many factors, including our ability to successfully:
● identify product candidates and complete research and preclinical and clinical development of any product candidates we may identify;
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● address competing technological and market developments;
−Removed: ● implement internal systems and infrastructure, as needed;
+Added: ● implement and maintain internal systems and infrastructure, as needed;
● negotiate favorable terms in any collaboration, licensing, or other arrangements into which we may enter and performing our obligations in such arrangements;
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If serious adverse events, undesirable side effects, or unexpected characteristics are identified during the development of any product candidates we develop, we may need to abandon or limit our further clinical development of those product candidates.
−Removed: Other than in connection with the EDIT-101 Phase 1/2 clinical trial, for which we began dosing patients in 2020 and is in the early stages of assessing safety, we have not evaluated any product candidates in human clinical trials, and our proposed delivery modes, combined with CRISPR technology, have a limited history, if any, of being tested clinically.
−Removed: It is impossible to predict when or if any product candidates we develop will ultimately prove safe in humans, including EDIT-101.
+Added: Other than in connection with the EDIT-101 Phase 1/2 clinical trial, for which we began dosing patients in 2020, we have not evaluated any product candidates in human clinical trials, and our proposed delivery modes, combined with CRISPR technology, have a limited history, if any, of being tested clinically.
+Added: It is impossible to predict when or if any product candidates we develop will ultimately prove safe in humans, including EDIT-101 and EDIT-301.
In the genomic medicine field, there have been several significant adverse events from gene therapy treatments in the past, including reported cases of leukemia and death.
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We cannot be certain that off-target editing will not occur in any of our clinical studies.
−Removed: There is also the potential risk of delayed adverse events following exposure to
−Removed: genome editing therapy due to the potential for persistent biological activity of the genetic material or other components of products used to carry the genetic material.
+Added: There is also the potential risk of delayed adverse events following exposure to genome editing therapy due to the potential for persistent biological activity of the genetic material or other components of products used to carry the genetic material.
If any product candidates we develop are associated with serious adverse events, or undesirable side effects, or have characteristics that are unexpected, we may need to abandon their development or limit development to certain uses or subpopulations in which the serious adverse events, undesirable side effects or other characteristics are less prevalent, less severe, or more acceptable from a risk-benefit perspective, any of which would have a material adverse effect on our business, financial condition, results of operations, and prospects.
If any of the product candidates we develop or the delivery modes we rely on cause undesirable side effects, it could delay or prevent their regulatory approval, limit the commercial potential, or result in significant negative consequences following any potential marketing approval.
−Removed: Our product candidates that we are testing or may test in clinical trials, including EDIT-101, or that are developed may be associated with off-target editing or other serious adverse events, undesirable side effects, or unexpected characteristics.
−Removed: In addition to serious adverse events or side effects caused by any product candidate we develop and test, the administration process or related procedures also can cause undesirable side effects.
+Added: Our product candidates that we are testing or may test in clinical trials, including EDIT-101 and EDIT-301, or that are developed may be associated with off-target editing or other serious adverse events, undesirable side effects, or unexpected characteristics.
+Added: In addition to serious adverse events or side effects caused by any product candidate we
+Added: develop and test, the administration process or related procedures also can cause undesirable side effects.
If any such events occur, our clinical trials could be suspended or terminated.
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Our proposed delivery modes, combined with our product candidates, have a limited history of being evaluated in human clinical trials.
−Removed: Any of our product candidates may fail to show the desired safety and efficacy in later stages of clinical development despite having successfully advanced through initial clinical trials.
+Added: Any of our product candidates, including EDIT-101 to treat LCA10, may fail to show the desired safety and efficacy in later stages of clinical development despite having successfully advanced through initial clinical trials.
There is a high failure rate for drugs and biologics proceeding through clinical trials.
A number of companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in later stage clinical trials even after achieving promising results in earlier stage clinical trials.
+Added: For example, ProQR Therapeutics N.V.
+Added: recently announced its failure to meet the primary endpoint of its Phase 2/3 clinical trial to treat LCA10 despite previously announcing positive results observed in the Phase 1/2 portion of the clinical trial.
Data obtained from preclinical and clinical activities are subject to varying interpretations, which may delay, limit, or prevent regulatory approval.
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No genome editing therapeutic product has been approved in the United States or in Europe.
−Removed: If clinical trials of any product candidates we may identify and develop fail to demonstrate safety and efficacy to the satisfaction of regulatory authorities or do not otherwise produce positive results, we may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of such product candidates.
+Added: If clinical trials of any product candidates we identify and develop fail to demonstrate safety and efficacy to the satisfaction of regulatory authorities or do not otherwise produce positive results, we may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of such product candidates.
Before obtaining marketing approval from regulatory authorities for the sale of any of our product candidates, we must complete preclinical development and then conduct extensive clinical trials to demonstrate the safety and efficacy in humans of any such product candidates.
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Product development costs will also increase if we or our collaborators experience delays in testing or marketing approvals.
−Removed: We do not know whether any clinical trials will begin as planned, will need to be restructured, or will be completed on schedule, or at all.
+Added: We do not know whether clinical trials will begin as planned, will need to be restructured, or will be completed on schedule, or at all.
Significant clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize any product candidates we develop, could allow our competitors to bring products to market before we do, and could impair our ability to successfully commercialize any product candidates we develop, any of which may harm our business, financial condition, results of operations, and prospects.
−Removed: If we experience delays or difficulties in the enrollment of patients in clinical trials, our receipt of necessary regulatory approvals could be delayed or prevented.
+Added: If we experience delays or difficulties in the enrollment of patients in clinical trials, our receipt of necessary
+Added: regulatory approvals could be delayed or prevented.
We or our collaborators may not be able to initiate or continue clinical trials for any of our product candidates if we are unable to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA or analogous regulatory authorities outside the United States, or as needed to provide appropriate statistical power for a given trial.
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In addition, if patients are unwilling to participate in our genome editing trials because of negative publicity from adverse events related to the biotechnology, gene therapy, or genome editing fields, competitive clinical trials for similar patient populations, clinical trials in competing products, or for other reasons, the timeline for recruiting patients, conducting studies, and obtaining regulatory approval of any product candidates we develop may be delayed.
+Added: For example, the recent announcement by ProQR Therapeutics N.V.
+Added: of its failure to meet the primary endpoint of its Phase 2/3 clinical trial to treat LCA10 may result in reluctance of potential patients to enroll in other genome editing trials targeting LCA10, such as our ongoing Phase I/II clinical trial for EDIT-101.
Moreover, some of our competitors may have ongoing clinical trials for product candidates that would treat the same indications as any product candidates we develop, and patients who would otherwise be eligible for our clinical trials may instead enroll in clinical trials of our competitors’ product candidates.
−Removed: For example, ProQR Therapeutics N.V.
−Removed: has already enrolled LCA10 patients in its clinical trial, which may limit the number of potential patients available to enroll in the ongoing Phase 1/2 clinical trial for EDIT-101.
Patient enrollment is also affected by other factors, including:
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Additionally, the process of finding and diagnosing patients may prove costly.
−Removed: We experienced slowed enrollment in the EDIT-101 clinical trial resulting from the impact of the COVID-19 pandemic, including international travel restrictions imposed in response to the pandemic.
−Removed: The ultimate impact of the COVID-19 pandemic on enrollment for our clinical trials, including our trial for EDIT-301, is highly uncertain and we do not yet know the full extent of the delays or impacts on these clinical trials.
+Added: The COVID-19 pandemic, including related restrictions
+Added: imposed by regulatory authorities and constraints on healthcare provider capacity, has previously impacted and may in the future impact our ability to timely enroll trial participants and conduct our studies.
Our ability to successfully initiate, enroll, and complete a clinical trial in any foreign country is subject to numerous risks unique to conducting business in foreign countries, including:
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Because we have limited financial and managerial resources, we focus on research programs and our product candidates for specific indications among many potential options.
−Removed: As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential.
+Added: As a result, we may forgo or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential.
Our resource allocation decisions may cause us to fail to capitalize on viable commercial medicines or profitable market opportunities.
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If any of our product candidates do not achieve an adequate level of acceptance, we may not generate significant product revenues, and we may not become profitable.
+Added: Adverse public perception of genomic medicines, and genome editing in particular, may negatively impact regulatory approval of, or demand for, our potential products.
+Added: Our potential therapeutic products involve editing the human genome.
+Added: The clinical and commercial success of our potential products will depend in part on public understanding and acceptance of the use of genome editing therapy for the prevention or treatment of human diseases.
+Added: Public attitudes may be influenced by claims that genome editing is unsafe, unethical, or immoral, and, consequently, our products may not gain the acceptance of the public or the medical community.
+Added: Adverse public attitudes may adversely impact our ability to enroll clinical trials.
+Added: Moreover, our success will depend upon physicians prescribing, and their patients being willing to receive, treatments that involve the use of product candidates we develop in lieu of, or in addition to, existing treatments with which they are already familiar and for which greater clinical data may be available.
+Added: In addition, genome editing technology is subject to public debate and heightened regulatory scrutiny due to ethical concerns relating to the application of genome editing technology to human embryos or the human germline.
+Added: For example, academic scientists in several countries, including the United States, have reported on their attempts to edit the genome of human embryos as part of basic research and, in November 2018, Dr.
+Added: Jiankui He, a Chinese biophysics researcher who was an associate professor in the Department of Biology of the Southern University of Science and Technology in Shenzhen, China, announced he had created the first human genetically edited babies, twin girls and helped create a second gene-edited pregnancy.
+Added: The announcement was negatively received by the public, in particular by those in the scientific community.
+Added: In the United States, germline editing for clinical application has been expressly prohibited since enactment of a December 2015 U.S.
+Added: FDA ban on such activity.
+Added: Prohibitions are also in place in the United Kingdom, across most of Europe, in China, and many other countries around the world.
+Added: In the United States, the NIH has announced that it would not fund any use of genome editing technologies in human embryos, noting that there are multiple existing legislative and regulatory prohibitions against such work, including the Dickey-Wicker Amendment, which prohibits the use of appropriated funds for the creation of human embryos for research purposes or for research in which human embryos are destroyed.
+Added: Laws in the United Kingdom prohibit genetically modified embryos from being implanted into women, but embryos can be altered in research labs under license from the Human Fertilisation and Embryology Authority.
+Added: Basic research on embryos is more tightly controlled in many other European countries.
+Added: Although we do not use our technologies to edit human embryos or the human germline, such public debate
+Added: about the use of genome editing technologies in human embryos and heightened regulatory scrutiny could prevent or delay our development of product candidates.
+Added: More restrictive government regulations or negative public opinion would have a negative effect on our business or financial condition and may delay or impair our development and commercialization of product candidates or demand for any products we may develop.
If, in the future, we are unable to establish sales and marketing capabilities or enter into agreements with third parties to sell and market any of our product candidates, we may not be successful in commercializing those product candidates if and when they are approved.
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If the commercial launch of a product candidate for which we recruit a sales force and establish marketing and other commercialization capabilities is delayed or does not occur for any reason, we would have prematurely or unnecessarily incurred these commercialization expenses.
−Removed: This may be costly, and our investment would be lost if we cannot retain or reposition our commercialization
+Added: This may be costly, and our investment would be lost if we cannot retain or reposition our commercialization personnel.
Factors that may inhibit our efforts to commercialize our medicines on our own include:
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We will face competition with respect to any of our product candidates now and in the future from major pharmaceutical companies, specialty pharmaceutical companies, and biotechnology companies worldwide.
−Removed: Potential competitors also include academic institutions, government agencies, and other public and private research organizations that conduct research, seek patent protection, and establish collaborative arrangements for research, development, manufacturing, and commercialization.
+Added: Potential competitors also include academic institutions, government agencies, and other public and private research
+Added: organizations that conduct research, seek patent protection, and establish collaborative arrangements for research, development, manufacturing, and commercialization.
There are a number of large pharmaceutical and biotechnology companies that currently market and sell products or are pursuing the development of products for the treatment of the disease indications for which we have research programs.
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Our platform and product focus is the development of therapies using CRISPR technology.
−Removed: 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.
−Removed: (“ToolGen”), TRACR Hematology and Vertex Pharmaceuticals.
+Added: 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.
−Removed: 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.
−Removed: These companies include Beam Therapeutics, Prime Medicine, bluebird bio, Cellectis, Poseida Therapeutics, Precision Biosciences and Sangamo Therapeutics.
−Removed: Additional companies developing gene therapy products include Abeona Therapeutics, Adverum Biotechnologies, AGTC Therapeutics, Audentes Therapeutics, Homology Medicines, REGENXBIO, Sarepta Therapeutics, Solid Biosciences, Spark Therapeutics, uniQure and Voyager Therapeutics.
+Added: There are additional companies developing therapies using related CRISPR genome editing technologies, including other CRISPR nucleases, base editing, prime editing and gene writing.
+Added: 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.
+Added: There are also companies developing therapies using transcription activator-like effector nucleases, meganucleases, Mega-TALs and zinc finger nucleases.
+Added: These companies include 2Seventy Bio, Allogene Therapeutics, bluebird bio, Cellectis, Precision Biosciences, and Sangamo Therapeutics.
+Added: 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.
+Added: 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.
−Removed: For example, ProQR Therapeutics N.V.
−Removed: is conducting a clinical trial for its experimental treatment using antisense oligonucleotide technology
Many of our competitors may have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals, and marketing approved products than we do.
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The regulations that govern marketing approvals, pricing, and reimbursement for new medicines vary widely from country to country.
−Removed: In the United States, recently enacted legislation may significantly change the approval requirements in ways that could involve additional costs and cause delays in obtaining approvals.
Some countries require approval of the sale price of a medicine before it can be marketed.
In many countries, the pricing review period begins after marketing or product licensing approval is granted.
−Removed: In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted.
+Added: foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted.
As a result, we might obtain marketing approval for a medicine in a particular country, but then be subject to price regulations that delay our commercial launch of the medicine, possibly for lengthy time periods, and negatively impact the revenues we are able to generate from the sale of the medicine in that country.
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Moreover, eligibility for reimbursement does not imply that any medicine will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale, and distribution.
−Removed: reimbursement levels for new medicines, if applicable, may also not be sufficient to cover our costs and may not be made permanent.
+Added: Interim reimbursement levels for new medicines, if applicable, may also not be sufficient to cover our costs and may not be made permanent.
Reimbursement rates may vary according to the use of the medicine and the clinical setting in which it is used, may be based on reimbursement levels already set for lower cost medicines and may be incorporated into existing payments for other services.
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We expect that coverage and reimbursement by government and private payors will be essential for most patients to be able to afford these treatments.
−Removed: Accordingly, sales of any such product candidates will depend substantially, both domestically and abroad, on the extent to which the costs of any product candidates we develop will be paid by health maintenance, managed care, pharmacy benefit, and similar healthcare management organizations, or will be reimbursed by government authorities, private health coverage insurers, and other third-party payors.
+Added: Accordingly, sales of any such product candidates will
+Added: depend substantially, both domestically and abroad, on the extent to which the costs of any product candidates we develop will be paid by health maintenance, managed care, pharmacy benefit, and similar healthcare management organizations, or will be reimbursed by government authorities, private health coverage insurers, and other third-party payors.
Coverage and reimbursement by a third-party payor may depend upon several factors, including the third-party payor’s determination that use of a product is:
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In the event of contamination or injury resulting from our use of hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources.
−Removed: Under certain environmental laws, we could be held
−Removed: responsible for costs relating to any contamination at our current or past facilities and at third-party facilities.
+Added: Under certain environmental laws, we could be held responsible for costs relating to any contamination at our current or past facilities and at third-party facilities.
We also could incur significant costs associated with civil or criminal fines and penalties.
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Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials, this insurance may not provide adequate coverage against potential liabilities.
−Removed: We do not carry specific biological or hazardous waste insurance coverage, and our commercial general liability and umbrella liability policies (under which we currently have an aggregate of $12.0 million in coverage) specifically exclude coverage for damages and fines arising from biological or hazardous waste exposure or contamination.
+Added: We do not carry specific biological or hazardous waste insurance coverage, and our commercial general liability and umbrella liability policies specifically exclude coverage for damages and fines arising from biological or hazardous waste exposure or contamination.
Accordingly, in the event of contamination or injury, we could be held liable for damages or be penalized with fines in an amount exceeding our resources, and our clinical trials or regulatory approvals could be suspended, which could have a material adverse effect on our business, financial condition, results of operations, and prospects.
1 unchanged sentence
Liabilities they incur pursuant to these laws and regulations could result in significant costs or an interruption in operations, which could have a material adverse effect on our business, financial condition, results of operations, and prospects.
−Removed: Genomic medicines are novel, and our product candidates may be complex and difficult to manufacture.
+Added: Genomic medicines are novel, and our product candidates can be complex and difficult to manufacture.
We could experience production problems that result in delays in our development or commercialization programs, limit the supply of our products, or otherwise harm our business.
−Removed: Our product candidates will likely require processing steps that are more complex than those required for most chemical pharmaceuticals.
+Added: Our product candidates can require processing steps that are more complex than those required for most chemical pharmaceuticals.
Moreover, unlike chemical pharmaceuticals, the physical and chemical properties of a biologic such as our product candidates generally cannot be fully characterized.
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Problems with the manufacturing process, even minor deviations from the normal process, could result in product defects or manufacturing failures that result in lot failures, product recalls, product liability claims, or insufficient inventory.
−Removed: If we successfully develop product candidates, we may encounter problems achieving adequate quantities and quality of clinical-grade materials that meet FDA, EMA or other comparable applicable foreign standards or specifications with consistent and acceptable production yields and costs.
+Added: If we successfully
+Added: develop product candidates, we may encounter problems achieving adequate quantities and quality of clinical-grade materials that meet FDA, EMA or other comparable applicable foreign standards or specifications with consistent and acceptable production yields and costs.
In addition, the FDA, the EMA, and other regulatory authorities may require us to submit samples of any lot of any approved product together with the protocols showing the results of applicable tests at any time.
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Such raw materials are difficult to procure and may be subject to contamination or recall.
−Removed: A material shortage, contamination, recall, or restriction on the use of biologically derived substances in the manufacture of any product candidates we develop could adversely impact or disrupt the commercial manufacturing or the production of clinical material, which could materially harm our development timelines and our
−Removed: business, financial condition, results of operations, and prospects.
+Added: A material shortage, contamination, recall, or restriction on the use of biologically derived substances in the manufacture of any product candidates we develop could adversely impact or disrupt the commercial manufacturing or the production of clinical material, which could materially harm our development timelines and our business, financial condition, results of operations, and prospects.
Any problems in our manufacturing process or the facilities with which we contract could make us a less attractive collaborator for potential partners, including larger pharmaceutical companies and academic research institutions, which could limit our access to additional attractive development programs.
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If a present or future collaborator of ours were to be involved in a business combination, the continued pursuit and emphasis on our product development or commercialization program under such collaboration could be delayed, diminished, or terminated.
−Removed: For example, in March 2017, we entered into a strategic alliance with Allergan focused on discovering, developing, and commercializing new gene editing medicines for a range of ocular disorders, which collaboration was terminated in August 2020.
−Removed: As a result of the termination of the collaboration and the related co-development and commercialization agreement, we are now obligated to fund all of the costs related to developing and commercializing the LCA10 program in the United States, including the costs of the clinical development of EDIT-101, which will increase our expenses significantly.
If our collaborations do not result in the successful development and commercialization of products, or if one of our collaborators terminates its agreement with us, we may not receive any milestone or royalty payments under such collaborations.
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We may also be restricted under existing collaboration agreements from entering into future agreements on certain terms with potential collaborators or allies.
−Removed: For example, under our amended and restated collaboration with Juno Therapeutics, we may not use directly or indirectly, or license others to use, genome editing technology in connection
−Removed: with any research, development, manufacture, commercialization or other exploration of certain T cells, subject to certain exceptions, as more fully described in “Part I—Business—Our Collaborations and Licensing Strategy” of this Annual Report on Form 10-K.
+Added: For example, under our amended and restated collaboration with Juno Therapeutics, we may not use directly or indirectly, or license others to use, genome editing technology in connection with any research, development, manufacture, commercialization or other exploration of certain T cells, subject to certain exceptions, as more fully described in “Part I—Business—Our Collaborations and Licensing Strategy” of this Annual Report on Form 10-K.
Collaborations are also complex and time-consuming to negotiate and document.
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Any of these third parties may terminate their engagements with us at any time.
−Removed: If we need to enter into alternative arrangements, it would delay our product development activities.
+Added: If we need to enter into alternative arrangements, our product development activities would be delayed.
Additionally, the activities performed by these third parties may be delayed or suspended in light of the ongoing COVID-19 pandemic, which may impact our ability to successfully develop and test our product candidates and research programs in a timely manner.
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Furthermore, these third parties may also have relationships with other entities, some of which may be our competitors.
−Removed: If these third parties do not successfully carry out their contractual duties, meet expected deadlines, or conduct our clinical trials in accordance with regulatory requirements or our stated protocols, we will not be able to obtain, or may be delayed in obtaining, marketing approvals for any product candidates we develop and will not be able to, or may be delayed in our efforts to, successfully commercialize our medicines.
+Added: If these third parties do not successfully carry out their contractual duties, meet expected deadlines, or conduct our clinical trials in accordance with regulatory requirements or our stated protocols, we will not be able to obtain, or may be delayed in obtaining, marketing approvals for any product candidates we develop and will not be able
+Added: to, or may be delayed in our efforts to, successfully commercialize our medicines.
We also expect to rely on other third parties to store and distribute drug supplies for our clinical trials.
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Our success depends in large part on our ability to obtain and maintain patent protection in the United States and other countries with respect to our CRISPR platform technology and any proprietary product candidates and technology we develop.
−Removed: We seek to protect our proprietary position by in-licensing intellectual property relating to our platform technology and filing patent applications in the United States and abroad related to our technologies and product candidates that are important to our business.
+Added: We seek to protect our proprietary position by in-licensing intellectual property relating to our
+Added: platform technology and filing patent applications in the United States and abroad related to our technologies and product candidates that are important to our business.
If we or our licensors and/or collaborators are unable to obtain or maintain patent protection with respect to our CRISPR platform technology and any proprietary products and technology we develop, our business, financial condition, results of operations, and prospects could be materially harmed.
No consistent policy regarding the scope of claims allowable in the field of genome editing, including CRISPR technology, has emerged in the United States.
−Removed: The scope of patent protection outside of the United States is also
+Added: The scope of patent protection outside of the United States is also uncertain.
Changes in either the patent laws or their interpretation in the United States and other countries may diminish our ability to protect our inventions, obtain, maintain, and enforce our intellectual property rights and, more generally, could affect the value of our intellectual property or narrow the scope of our owned and licensed patents.
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Moreover, some of our owned and in-licensed patents and patent applications are, and may in the future be, co-owned with third parties.
−Removed: If we are unable to obtain an exclusive license to any such third party co-owners’ interest in such patents or patent applications, such co-owners may be able to license their rights to other third parties, including our competitors, and our competitors could market competing products and
+Added: If we are unable to obtain an exclusive license to any such third party co-owners’ interest in such patents or patent applications, such co-owners may be able to license their rights to other third parties, including our competitors, and our competitors could market competing products and technology.
In addition, we or our licensors may need the cooperation of any such co-owners of our owned and in-licensed patents in order to enforce such patents against third parties, and such cooperation may not be provided to us or our licensors.
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Broad does not and does not purport to grant any rights in NIH’s interest in these patent applications under our agreement.
−Removed: If other third parties have ownership rights to our in-licensed patents and patent applications, they may be able to license such patents and patent applications to our competitors, and our competitors could market competing products and technology.
+Added: If other third parties have ownership rights to our in-licensed patents and patent applications, they may be able to license such patents and patent applications to our
+Added: competitors, and our competitors could market competing products and technology.
This could have a material adverse effect on our competitive position, business, financial conditions, results of operations, and prospects.
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patents and a U.S.
−Removed: patent application that are co-owned by Broad and the Massachusetts Institute of Technology (“MIT”), and in some cases Harvard, and in-licensed by us were involved in a first interference with a U.S.
−Removed: patent application that is co-owned by the University of California, the University of Vienna, and Emmanuelle Charpentier.
−Removed: An interference is a proceeding before the Patent Trial and Appeal Board of the USPTO (“PTAB”) to determine priority of invention of the subject matter of patent claims filed by different parties.
+Added: patent application directed to CRISPR/Cas9 that are co-owned by the Broad and the Massachusetts Institute of Technology (“MIT”), and in some cases Harvard (collectively referred to as “Broad”), and in-licensed by us were involved in a first interference with a U.S.
+Added: patent application that is co-owned by the University of California, the University of Vienna, and Emmanuelle Charpentier (collectively referred to “CVC”).
+Added: An interference is a proceeding in the USPTO before the Patent Trial and Appeal Board of the USPTO (“PTAB”) to determine priority of invention of the subject matter of patent claims filed by different parties.
In this first interference, the PTAB made a judgment of no interference-in-fact in favor of the Broad, which was upheld on appeal.
3 unchanged sentences
On June 24, 2019, the PTAB declared a second interference between certain pending U.S.
−Removed: patent applications that are co-owned by the University of California, the University of Vienna, and Emmanuelle Charpentier and certain U.S.
+Added: patent applications that are co-owned by CVC and certain U.S.
patents and a U.S.
−Removed: patent application that are co-owned by Broad and MIT, and in some cases Harvard, and in-licensed by us.
+Added: patent application that are co-owned by Broad and in-licensed by us.
Most of the Broad U.S.
patents and the patent application that are involved in the second interference were also part of the first interference.
−Removed: The invention that was considered in the first interference was related to a method that involves contacting a target DNA in a eukaryotic cell with certain defined CRISPR/Cas9 components for the purpose of cleaving or editing a target DNA molecule or modulating transcription of at least one gene encoded thereon.
−Removed: The second interference is directed to a different invention, namely a eukaryotic cell that comprises a target DNA and certain defined CRISPR/Cas9 components including a single molecule guide RNA that are capable of cleaving or editing the target DNA molecule.
−Removed: On September 10, 2020, the PTAB granted Broad’s motion for priority benefit while denying the University of California, the University of Vienna, and Emmanuelle Charpentier priority benefit to their two earliest provisional patent applications.
−Removed: As a result, Broad entered the priority phase of the interference as “Senior Party” while the University of California, the University of Vienna, and Emmanuelle Charpentier remained the “Junior Party” for purposes of determining which entity was the first to invent the inventions at issue.
+Added: The invention that was considered in the first interference related to a method involving contacting a target DNA in a eukaryotic cell with certain defined CRISPR/Cas9 components for the purpose of cleaving or editing that target DNA molecule or modulating transcription of at least one gene encoded thereon.
+Added: The second interference is directed to a different invention, namely a eukaryotic cell comprising a target DNA and certain defined CRISPR/Cas9 components including a single molecule guide RNA that are capable of cleaving or editing the target DNA molecule.
+Added: On September 10, 2020, the PTAB granted Broad’s motion for priority benefit while denying CVC priority benefit to their two earliest provisional patent applications.
+Added: As a result, Broad entered the priority phase of the interference as “Senior Party” while CVC remained the “Junior Party” for purposes of determining which entity was the first to invent the inventions at issue.
We cannot predict with any certainty how long it will take before the PTAB issues a decision at the conclusion of the priority phase.
−Removed: On December 14, 2020, the PTAB, declared a third interference between a pending U.S.
−Removed: patent application that is owned by ToolGen and certain U.S.
+Added: On December 14, 2020, the PTAB, declared two new interferences involving a pending U.S.
+Added: patent application that is owned by ToolGen, Inc.
+Added: (the “ToolGen application”).
+Added: One of the two interferences is between the ToolGen application and certain U.S.
patents and U.S.
−Removed: patent applications that are co-owned by Broad and MIT, and in some cases Harvard, and in-licensed by us.
+Added: patent applications that are co-owned by Broad and in-licensed by us.
Most of the Broad U.S.
−Removed: patents and patent applications that are involved in the interference with ToolGen are also part of the second interference with the University of California, the University of Vienna, and Emmanuelle Charpentier .
−Removed: On the same day, the PTAB also declared a fourth interference between the same pending U.S.
−Removed: patent application that is owned by ToolGen and the U.S.
−Removed: patent applications that are co-owned by the University of California, the University of Vienna, and Emmanuelle Charpentier and involved in the second interference with Broad.
−Removed: These two declarations of interference involving ToolGen’s patent application describe the interfering subject matter as related to a mammalian cell with a CRISPR/Cas system that comprises a codon optimized nucleic acid encoding a Cas9 polypeptide with a nuclear localization signal and a single-molecule guide RNA that are together capable of forming a Cas9/RNA complex that mediates double stranded cleavage of a target nucleic acid sequence.
−Removed: As a result of these declarations of interference, parallel adversarial proceedings in the USPTO before the PTAB have been initiated.
−Removed: We cannot predict with any certainty how long each interference proceeding will actually take.
+Added: patents and patent applications that are involved in the interference with ToolGen are also part of the second interference with CVC.
+Added: The other ToolGen interference is between the same ToolGen application and the U.S.
+Added: patent applications that are co-owned by CVC and involved in the second interference with Broad.
+Added: The claims in ToolGen’s patent application relate to a mammalian cell with a CRISPR/Cas system comprising a codon optimized nucleic acid encoding a Cas9 polypeptide with a nuclear localization signal and a single-molecule guide RNA that, together, are capable of forming a Cas9/RNA complex that mediates double stranded cleavage of a target nucleic acid sequence.
+Added: On June 21, 2021, the PTAB declared two new patent interferences involving a pending U.S.
+Added: patent application owned by Sigma-Aldrich (the “Sigma-Aldrich application”).
+Added: One of the two new patent interferences is between the Sigma-Aldrich application and certain U.S.
+Added: patents and U.S.
+Added: patent applications that are co-owned by Broad and in-licensed by us.
+Added: The second new patent interference is between the same Sigma-Aldrich application and the U.S.
+Added: patent applications that are co-owned by CVC.
+Added: Most of the Broad U.S.
+Added: patents and patent applications that are involved in the
+Added: interference with Sigma-Aldrich are also part of the concurrent interferences with CVC and ToolGen.
+Added: The claims in Sigma-Aldrich’s application relate to a method for modifying a chromosomal sequence in a eukaryotic cell by integrating a donor sequence into that chromosomal sequence.
+Added: These methods use a CRISPR/Cas9 system comprising a Cas9 polypeptide with a nuclear localization signal, a guide RNA, and a donor sequence that, together, are capable of mediating double stranded cleavage and repair of a target nucleic acid sequence leading to integration of the donor sequence into the chromosomal sequence.
+Added: As a result of these declarations of interference, five parallel adversarial proceedings in the USPTO before the PTAB have been initiated – the patent interferences between Broad and CVC, Broad and ToolGen, CVC and ToolGen, Broad and Sigma-Aldrich, and CVC and Sigma-Aldrich.
+Added: We cannot predict with any certainty how long each interference proceeding will take.
It is also possible that other third parties may seek to become a party to these interferences.
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For example, a request for ex parte re-examination was filed with the USPTO on February 16, 2016 against a U.S.
−Removed: patent that we have in-licensed from Broad, which is part of the second and third interferences .
−Removed: The request for ex parte re-examination was granted on May 9, 2016 thereby initiating a re-examination procedure between the USPTO and Broad, acting on behalf of itself and MIT.
+Added: patent that we have in-licensed from Broad, which is involved in certain of the interferences.
+Added: The request for ex parte re-examination was granted on May 9, 2016 thereby initiating a re-examination procedure between the USPTO and The Broad Institute, acting on behalf of itself and MIT.
The PTAB has suspended the re-examination noting that it has jurisdiction over any file that involves a patent involved in an interference.
It is uncertain when the PTAB will lift the suspension.
−Removed: If Broad is unsuccessful during the re-examination, the patent in question may be revoked or narrowed, which could have a material adverse effect on the scope of our rights under such patent.
+Added: If The Broad Institute is unsuccessful during the re-examination, the patent in question may be revoked or narrowed, which could have a material adverse effect on the scope of our rights under such patent.
We or our licensors may also be subject to claims that former employees, collaborators, or other third parties have an interest in our owned or in-licensed patents or patent applications, or other intellectual property rights as an inventor or co-inventor.
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Certain other European patents that we have in-licensed from Broad were maintained with amended patent claims.
−Removed: Certain of these decisions have been appealed by both Broad and the opposing party, and it is uncertain when or in what manner the Boards of Appeal will act on these appeals.
+Added: Certain of these decisions have been appealed by both Broad and the opposing party(s), and it is uncertain when or in what manner the Boards of Appeal will act on these appeals.
The Opposition Division has also initiated opposition proceedings against certain other European patents that we have in-licensed from Broad.
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If we or our licensors are unsuccessful in any patent related disputes, including interference proceedings, patent oppositions, re-examinations, or other priority, inventorship, or validity disputes to which we or they are subject (including any of the proceedings discussed above), we may lose valuable intellectual property rights through the loss of one or more patents owned or licensed or our owned or licensed patent claims may be narrowed, invalidated, or held unenforceable.
−Removed: In addition, if we or our licensors are unsuccessful in any inventorship disputes to which we or they are subject, we may lose valuable intellectual property rights, such as exclusive ownership of, or the exclusive right to use, our owned or in-licensed patents and patent applications.
+Added: In addition, if we or our licensors are unsuccessful in any inventorship disputes to which we or they are
+Added: subject, we may lose valuable intellectual property rights, such as exclusive ownership of, or the exclusive right to use, our owned or in-licensed patents and patent applications.
If we or our licensors are unsuccessful in any interference proceeding or other priority or inventorship dispute, we may be required to obtain and maintain licenses from third parties, including parties involved in any such interference proceedings or other priority or inventorship disputes.
−Removed: Such licenses may not be available on commercially reasonable terms or at all, or may be non-exclusive.
+Added: Such licenses may not be available on commercially reasonable terms or may be non-exclusive or may not be available at all.
If we are unable to obtain and maintain such licenses, we may need to cease the development, manufacture, and commercialization of one or more of the product candidates we develop.
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Obtaining and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment, and other requirements imposed by government patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.
−Removed: Periodic maintenance fees, renewal fees, annuity fees, and various other government fees on patents and applications will be due to be paid to the USPTO and various government patent agencies outside of the United States over the lifetime of our owned or licensed patents and applications.
+Added: Periodic maintenance fees, renewal fees, annuity fees, and various other government fees on patents and applications will be due to be paid to the USPTO and various government patent agencies outside of the United States
+Added: over the lifetime of our owned or licensed patents and applications.
In certain circumstances, we rely on our licensing partners to pay these fees due to U.S.
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In addition, the agreements under which we currently license intellectual property or technology from third parties are complex, and certain provisions in such agreements may be susceptible to multiple interpretations.
−Removed: The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology, or increase what we believe to be our financial or other obligations under the relevant agreement, including the amount, if any, that may become due and payable to our licensors in connection with sublicense income.
+Added: The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology, or increase what we believe to be our financial or other
+Added: obligations under the relevant agreement, including the amount, if any, that may become due and payable to our licensors in connection with sublicense income.
If these events were to occur, they could have a material adverse effect on our business, financial condition, results of operations, and prospects.
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We are subject to and may in the future become party to, or threatened with, adversarial proceedings or litigation regarding intellectual property rights with respect to our technology and any product candidates we develop, including interference, re-examination, post-grant review, inter partes review, and derivation proceedings before the USPTO and similar proceedings in foreign jurisdictions such as oppositions before the EPO.
−Removed: Third parties may assert infringement claims
−Removed: against us based on existing patents or patents that may be granted in the future, regardless of their merit.
+Added: Third parties may assert infringement claims against us based on existing patents or patents that may be granted in the future, regardless of their merit.
We are aware of certain third party patents and patent applications in this landscape that may be asserted to encompass our CRISPR/Cas9 technology.
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Many of our employees, consultants, and advisors are currently or were previously employed at universities or other biotechnology or pharmaceutical companies, including our competitors or potential competitors.
−Removed: Although we try to ensure that our employees, consultants, and advisors do not use the proprietary information or know-how of others in
−Removed: their work for us, we may be subject to claims that we or these individuals have used or disclosed intellectual property, including trade secrets or other proprietary information, of any such individual’s current or former employer.
+Added: Although we try to ensure that our employees, consultants, and advisors do not use the proprietary information or know-how of others in their work for us, we may be subject to claims that we or these individuals have used or disclosed intellectual property, including trade secrets or other proprietary information, of any such individual’s current or former employer.
Litigation may be necessary to defend against these claims.
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The Hatch-Waxman Amendments permit a patent extension term of up to five years as compensation for patent term lost during the FDA regulatory review process.
−Removed: A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, only one patent may be extended and only those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended.
+Added: A patent term extension cannot extend the remaining term of a patent beyond a total of
+Added: 14 years from the date of product approval, only one patent may be extended and only those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended.
However, we may not be granted an extension because of, for example, failing to exercise due diligence during the testing phase or regulatory review process, failing to apply within applicable deadlines, failing to apply prior to expiration of relevant patents, or otherwise failing to satisfy applicable requirements.
Moreover, the applicable time period or the scope of patent protection afforded could be less than we request.
−Removed: If we are unable to obtain patent term extension or term of any such extension is less than we request, our competitors may obtain approval of competing products following our patent
−Removed: expiration, and our business, financial condition, results of operations, and prospects could be materially harmed.
+Added: If we are unable to obtain patent term extension or term of any such extension is less than we request, our competitors may obtain approval of competing products following our patent expiration, and our business, financial condition, results of operations, and prospects could be materially harmed.
Risks Related to Regulatory Approval and Other Legal Compliance Matters
13 unchanged sentences
Any marketing approval we ultimately obtain may be limited or subject to restrictions or post-approval commitments that render the approved medicine not commercially viable.
−Removed: Finally, disruptions at the FDA and other agencies may prolong the time necessary for new drugs to be reviewed and/or approved by necessary government agencies, which would adversely affect our business.
−Removed: For example, over the last several years, the U.S.
−Removed: government has shut down several times and certain regulatory agencies, such as the FDA, have had to furlough critical employees and stop critical activities.
−Removed: If a prolonged government shutdown occurs, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business.
−Removed: The Trump Administration also took several executive actions that could impose significant burdens on, or otherwise materially delay, the FDA’s ability to engage in routine regulatory and oversight activities.
If we experience delays in obtaining approval or if we fail to obtain approval of any of our product candidates, the commercial prospects for those product candidates may be harmed, and our ability to generate revenues will be materially impaired.
−Removed: Fast track and Priority Review designation by the FDA may not actually lead to a faster development or regulatory review or approval process, and does not assure FDA approval of our product candidates.
−Removed: If a product candidate is intended for the treatment of a serious or life threatening condition and the product candidate demonstrates the potential to address unmet medical need for this condition, the sponsor may apply for FDA fast track designation.
−Removed: Further, if the FDA determines that a product candidate offers major advances in treatment or provides a treatment where no adequate therapy exists, the FDA may designate the product candidate for priority review.
+Added: We may seek certain designations for our product candidates, including Breakthrough Therapy, Fast Track and Priority Review designations in the US, and PRIME Designation in the EU, but we might not receive such designations, and even if we do, such designations may not lead to a faster development or regulatory review or approval process.
+Added: We may seek certain designations for one or more of our product candidates that could expedite review and
+Added: approval by the FDA.
+Added: A Breakthrough Therapy product is defined as a product that is intended, alone or in combination with one or more other products, to treat a serious 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.
+Added: For products that have been designated as Breakthrough Therapies, interaction and communication between the FDA and the sponsor of the trial can help to identify the most efficient path for clinical development while minimizing the number of patients placed in ineffective control regimens.
+Added: The FDA may also 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.
+Added: 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.
+Added: 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.
+Added: We may also seek a priority review designation for one or more of our product candidates.
+Added: If the FDA determines that a product candidate offers major advances in treatment or provides a treatment where no adequate therapy exists, the FDA may designate the product candidate for priority review.
A priority review designation means that the goal for the FDA to review an application is six months, rather than the standard review period of ten months.
−Removed: We may request fast track and priority review designations for certain of our product candidates.
−Removed: The FDA has broad discretion with respect to whether or not to grant fast track and priority review status to a product candidate, so even if we believe a particular product candidate is eligible for such designation or status, the FDA may decide not to grant it.
−Removed: Moreover, a fast track or priority review designation does not necessarily mean a faster regulatory review process or necessarily confer any advantage with respect to approval compared to conventional FDA procedures.
−Removed: As a result, while we may seek and receive these designations for our product candidates, we may not experience a faster development process, review or approval compared to conventional FDA procedures.
−Removed: In addition, the FDA may withdraw these designations if it believes that the designation is no longer supported by data from our clinical development program.
+Added: These designations are within the discretion of the FDA.
+Added: Accordingly, even if we believe that one of our product candidates meets the criteria for these designations, the FDA may disagree and instead determine not to make such designation.
+Added: Further, even if we receive a designation, the receipt of such designation for a product candidate may not result in a faster development or regulatory review or approval process compared to products considered for approval under conventional FDA procedures and does not assure ultimate approval by the FDA.
+Added: In addition, even if one or more of our product candidates qualifies for these designations, the FDA may later decide that the product candidates no longer meet the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.
+Added: In the EU, we may seek PRIME designation for some of our product candidates in the future.
+Added: PRIME is a voluntary program aimed at enhancing the EMA’s role to reinforce scientific and regulatory support in order to optimize development and enable accelerated assessment of new medicines that are of major public health interest with the potential to address unmet medical needs.
+Added: The program focuses on medicines that target conditions for which there exists no satisfactory method of treatment in the EU or even if such a method exists, it may offer a major therapeutic advantage over existing treatments.
+Added: PRIME is limited to medicines under development and not authorized in the EU and the applicant intends to apply for an initial marketing authorization application through the centralized procedure.
+Added: To be accepted for PRIME, a product candidate must meet the eligibility criteria in respect of its major public health interest and therapeutic innovation based on information that is capable of substantiating the claims.
+Added: The benefits of a PRIME designation include the appointment of a CHMP rapporteur to provide continued support and help to build knowledge ahead of a marketing authorization application, early dialogue and scientific advice at key development milestones, and the potential to qualify products for accelerated review, meaning reduction in the review time for an opinion on approvability to be issued earlier in the application process.
+Added: PRIME enables an applicant to request parallel EMA scientific advice and health technology assessment advice to facilitate timely market access.
+Added: Even if we receive PRIME designation for any of our product candidates, the designation may not result in a materially faster development process, review or approval compared to conventional EMA procedures.
+Added: Further, obtaining PRIME designation does not assure or increase the likelihood of EMA’s grant of a marketing authorization.
+Added: If approved, our product candidates that are licensed and regulated as biologics may face competition from biosimilars approved through an abbreviated regulatory pathway.
+Added: The Biologics Price Competition and Innovation Act of 2009, (“BPCIA”), was enacted as part of the Patient Protection and Affordable Care Act, (“ACA”), to establish an abbreviated pathway for the approval of biosimilar and interchangeable biological products.
+Added: The regulatory pathway establishes legal authority for the FDA to review and approve biosimilar biologics, including the possible designation of a biosimilar as “interchangeable” based on its
+Added: similarity to an approved biologic.
+Added: Under the BPCIA, a reference biological product is granted 12 years of data exclusivity from the time of first licensure of the product, and the FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first licensure of the reference product In addition, the licensure of a biosimilar product may not be made effective by the FDA until 12 years from the date on which the reference product was first licensed.
+Added: During this 12-year period of exclusivity, another company may still develop and receive approval of a competing biologic, so long as its BLA does not reply on the reference product, sponsor’s data or submit the application as a biosimilar application.
+Added: The law is complex and is still being interpreted and implemented by the FDA.
+Added: As a result, its ultimate impact, implementation, and meaning are subject to uncertainty, and any new policies or processes adopted by the FDA could have a material adverse effect on the future commercial prospects for our biological products.
+Added: We believe that any of the product candidates we develop as a biological product under a BLA should qualify for the 12-year period of exclusivity.
+Added: However, there is a risk that this exclusivity could be shortened due to congressional action or otherwise, or that the FDA will not consider the subject product candidates to be reference products for competing products, potentially creating the opportunity for biosimilar competition sooner than anticipated.
+Added: Moreover, the extent to which a biosimilar, once approved, will be substituted for any one of the reference products in a way that is similar to traditional generic substitution for non-biological products will depend on a number of marketplace and regulatory factors that are still developing.
+Added: Nonetheless, the approval of a biosimilar to our product candidates would have a material adverse impact on our business due to increased competition and pricing pressure.
We may not be able to obtain orphan drug exclusivity for one or more of our product candidates, and even if we do, that exclusivity may not prevent the FDA or the EMA from approving other competing products.
8 unchanged sentences
In particular, the concept of what constitutes the "same drug"
−Removed: 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.
+Added: for purposes of orphan drug exclusivity remains in flux in the context of gene therapies.
+Added: In September 2021, the FDA issued final guidance describing its current thinking on when a gene therapy product is the “same” as another product for purposes of orphan exclusivity.
+Added: Under the guidance, if either the transgene or vector differs between two gene therapy products in a manner that does not reflect “minor” differences, the two products would be considered different drugs for orphan drug exclusivity purposes.
+Added: 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.
In addition, even after an orphan drug is approved, the FDA can subsequently approve the same product for the same condition if the FDA concludes that the later product is clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care.
1 unchanged sentence
On August 3, 2017, Congress passed the FDA Reauthorization Act of 2017 (“FDARA”).
−Removed: FDARA, among other things, codified the FDA’s pre-existing regulatory interpretation, to require that a drug sponsor demonstrate the clinical superiority of an orphan drug that is otherwise the same as a previously approved drug for the same rare disease in order to receive orphan drug exclusivity.
+Added: FDARA, among other things, codified the FDA’s pre-existing regulatory interpretation, to require that a drug sponsor demonstrate the clinical superiority of an orphan drug that is otherwise the same as a previously approved drug for the same rare disease in order
+Added: to receive orphan drug exclusivity.
The new legislation reverses prior precedent holding that the Orphan Drug Act unambiguously requires that the FDA recognize the orphan exclusivity period regardless of a showing of clinical superiority.
+Added: Further, under Omnibus legislation signed by President Trump on December 27, 2020, the requirement for a product to show clinical superiority applies to drugs and biologics that received orphan drug designation before enactment of FDARA in 2017, but have not yet been approved or licensed by the FDA.
The FDA may further reevaluate the Orphan Drug Act and its regulations and policies.
−Removed: We do not know if, when, or how the FDA may change the orphan drug regulations and policies in the future, and it is uncertain how any
−Removed: changes might affect our business.
+Added: This may be particularly true in light of a decision from the Court of Appeals for the 11th Circuit in September 2021 finding that, for the purpose of determining the scope of exclusivity, the term “same disease or condition” 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.” We do not know if, when, or how the FDA may change the orphan drug regulations and policies in the future, and it is uncertain how any changes might affect our business.
Depending on what changes the FDA may make to its orphan drug regulations and policies, our business could be adversely impacted.
8 unchanged sentences
We may not be able to file for marketing approvals and may not receive necessary approvals to commercialize our medicines in any jurisdiction, which would materially impair our ability to generate revenue.
−Removed: Additionally, we could face heightened risks with respect to seeking marketing approval in the United Kingdom as a result of the recent withdrawal of the United Kingdom from the European Union, commonly referred to as Brexit.
−Removed: Pursuant to the formal withdrawal arrangements agreed between the United Kingdom and the European Union, the United Kingdom withdrew from the European Union, effective December 31, 2020.
−Removed: On December 24, 2020, the United Kingdom and European Union entered into a Trade and Cooperation Agreement.
−Removed: The agreement sets out certain procedures for approval and recognition of medical products in each jurisdiction.
−Removed: Since the regulatory framework for pharmaceutical products in the United Kingdom covering the quality, safety, and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales, and distribution of pharmaceutical products is derived from European Union directives and regulations, Brexit could materially impact the future regulatory regime that applies to products and the approval of product candidates in the United Kingdom.
−Removed: Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, would prevent us from commercializing any product candidates in the United Kingdom and/or the European Union and restrict our ability to generate revenue and achieve and sustain profitability.
−Removed: If any of these outcomes occur, we may be forced to restrict or delay efforts to seek regulatory approval in the United Kingdom and/or European Union for any product candidates, which could significantly and materially harm our business.
+Added: Additionally, the United Kingdom left the European Union on January 31, 2020, commonly referred to as Brexit, and a transition period to December 31, 2020, was established to allow the United Kingdom and the European Union to negotiate the United Kingdom’s withdrawal.
+Added: As a result, effective January 1, 2021, the United Kingdom is no longer part of the European Single Market and European Union Customs Union.
+Added: A co-operation agreement was signed between the United Kingdom and the European Union in December 2020, which was applied provisionally beginning on January 1, 2021 and entered into force on May 1, 2021.
+Added: The agreement addresses trade, economic arrangements, law enforcement, judicial cooperation and a governance framework including procedures for dispute resolution, among other things.
+Added: As both parties continue to work on the rules for implementation, significant political and economic uncertainty remains about how the precise terms of the relationship between the parties will differ from the terms before withdrawal.
+Added: Since the regulatory framework for pharmaceutical products in the United Kingdom covering the quality, safety, and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales, and distribution of pharmaceutical products is derived from European Union directives and regulations, the consequences of Brexit and the impact the future regulatory regime that applies to products and the approval of product candidates in the United Kingdom remains unclear.
+Added: As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency, or the MHRA, became responsible for supervising medicines and medical devices in Great Britain, comprising England, Scotland and Wales under domestic law, whereas Northern Ireland will continue to be subject to European Union rules under the Northern Ireland Protocol.
+Added: The MHRA will rely on the Human Medicines Regulations 2012 (SI 2012/1916) (as amended), or the HMR, as the basis for regulating medicines.
+Added: The HMR has incorporated into the domestic law of the body of European Union law instruments governing medicinal products that pre-existed prior to the United Kingdom’s withdrawal from the European Union.
+Added: Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, may force us to restrict or delay efforts to seek regulatory approval in the United Kingdom for our product candidates, which could significantly and materially harm our business.
Even if we, or any collaborators we may have, obtain marketing approvals for any of our product candidates, the terms of approvals and ongoing regulation of our products could require the substantial expenditure of resources and may limit how we, or they, manufacture and market our products, which could materially impair our ability to generate revenue.
3 unchanged sentences
Accordingly, assuming we, or any collaborators we may have, receive marketing approval for one or more of our product candidates, we, and such collaborators, and our and their contract manufacturers will continue to expend time, money, and effort in all areas of regulatory compliance, including manufacturing, production, product surveillance, and quality control.
−Removed: If we and such collaborators are not able to comply with post-approval regulatory requirements, we
−Removed: and such collaborators could have the marketing approvals for our products withdrawn by regulatory authorities and our, or such collaborators’, ability to market any future products could be limited, which could adversely affect our ability to achieve or sustain profitability.
+Added: If we and such collaborators are not able to comply with post-approval regulatory requirements, we and such collaborators could have the marketing approvals for our products withdrawn by regulatory authorities and our, or such collaborators’, ability to market any future products could be limited, which could adversely affect our ability to achieve or sustain profitability.
Further, the cost of compliance with post-approval regulations may have a negative effect on our business, operating results, financial condition, and prospects.
+Added: Inadequate funding for the FDA, the SEC and other government agencies, including from government shut downs, or other disruptions to these agencies’ operations, could hinder their ability to hire and retain key leadership and other personnel, prevent new products and services from being developed or commercialized in a timely manner or otherwise prevent those agencies from performing normal business functions on which the operation of our business may rely, which could negatively impact our business.
+Added: The ability of the FDA to review and approve new products can be affected by a variety of factors, including government budget and funding levels, ability to hire and retain key personnel and accept the payment of user fees, and statutory, regulatory and policy changes.
+Added: Average review times at the agency have fluctuated in recent years as a result.
+Added: Disruptions at the FDA and other agencies may also slow the time necessary for new product candidates to be reviewed and/or approved by necessary government agencies, which would adversely affect our business.
+Added: In addition, government funding of the SEC and other government agencies on which our operations may rely, including those that fund research and development activities, is subject to the political process, which is inherently fluid and unpredictable.
+Added: Disruptions at the FDA and other agencies may also slow the time necessary for new product candidates to be reviewed and/or approved by necessary government agencies, which would adversely affect our business.
+Added: For example, over the last several years the U.S.
+Added: government has shut down several times and certain regulatory agencies, such as the FDA and the SEC, have had to furlough critical FDA, SEC and other government employees and stop critical activities.
+Added: If a prolonged government shutdown occurs, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business.
+Added: Further, future government shutdowns could impact our ability to access the public markets and obtain necessary capital in order to properly capitalize and continue our operations.
+Added: Separately, in response to the COVID-19 pandemic, since March 2020 when foreign and domestic inspections of facilities were largely placed on hold, the FDA has been working to resume routine surveillance, bioresearch monitoring and pre-approval inspections on a prioritized basis.
+Added: The FDA has developed a rating system to assist in determining when and where it is safest to conduct prioritized domestic inspections.
+Added: As of May 2021, certain inspections, such as foreign preapproval, surveillance, and for-cause inspections that are not deemed mission-critical, remain temporarily postponed.
+Added: In April 2021, the FDA issued guidance for industry formally announcing plans to employ remote interactive evaluations, using risk management methods, to meet user fee commitments and goal
+Added: dates and in May 2021 announced plans to continue progress toward resuming standard operational levels.
+Added: Should FDA determine that an inspection is necessary for approval and an inspection cannot be completed during the review cycle due to restrictions on travel, and the FDA does not determine a remote interactive evaluation to be adequate, the FDA has stated that it generally intends to issue a complete response letter or defer action on the application until an inspection can be completed.
+Added: In 2020 and 2021, a number of companies announced receipt of complete response letters due to the FDA’s inability to complete required inspections for their applications.
+Added: As of May 26, 2021, the FDA noted it was continuing to ensure timely reviews of applications for medical products during the ongoing COVID-19 pandemic in line with its user fee performance goals and conducting mission critical domestic and foreign inspections to ensure compliance of manufacturing facilities with FDA quality standards.
+Added: However, the FDA may not be able to continue its current pace and review timelines could be extended, including where a pre-approval inspection or an inspection of clinical sites is required and due to the ongoing COVID-19 pandemic and travel restrictions, the FDA is unable to complete such required inspections during the review period.
+Added: Regulatory authorities outside the U.S.
+Added: may adopt similar restrictions or other policy measures in response to the COVID-19 pandemic and may experience delays in their regulatory activities.
+Added: If a prolonged government shutdown or other disruption occurs, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business.
+Added: Future shutdowns or other disruptions could also affect other government agencies such as the SEC, which may also impact our business by delaying review of our public filings, to the extent such review is necessary, and our ability to access the public markets.
Any product candidate for which we obtain marketing approval could be subject to restrictions or withdrawal from the market, and we may be subject to substantial penalties if we fail to comply with regulatory requirements or if we experience unanticipated problems with our medicines, when and if any of them are approved.
18 unchanged sentences
Any government investigation of alleged violations of law could require us to expend significant time and resources in response and could generate negative publicity.
−Removed: The occurrence of any event or penalty described above may inhibit our ability to commercialize any product candidates we develop and adversely affect our business, financial
−Removed: condition, results of operations, and prospects.
+Added: The occurrence of any event or penalty described above may inhibit our ability to commercialize any product candidates we develop and adversely affect our business, financial condition, results of operations, and prospects.
Our relationships with healthcare providers, physicians, and third-party payors will be subject to applicable anti-kickback, fraud and abuse, and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm, and diminished profits and future earnings.
6 unchanged sentences
● the federal false statements statute, which prohibits knowingly and willfully falsifying, concealing, or covering up a material fact or making any materially false statement in connection with the delivery of or payment for healthcare benefits, items, or services;
−Removed: ● the federal transparency requirements under the federal Physician Payment Sunshine Act, which requires manufacturers of drugs, devices, biologics, and medical supplies to report to the Department of Health and Human Services information related to payments and other transfers of value to physicians and teaching hospitals, and ownership and investment interests held by physicians and other healthcare providers and their immediate family members and applicable group purchasing organizations;
+Added: ● the federal transparency requirements under the federal Physician Payment Sunshine Act, which requires manufacturers of drugs, devices, biologics, and medical supplies to report to the Department of Health and
+Added: Human Services information related to payments and other transfers of value to physicians, other healthcare providers and teaching hospitals, and ownership and investment interests held by physicians, other healthcare providers and other healthcare providers and their immediate family members and applicable group purchasing organizations;
● analogous state laws and regulations, such as state anti-kickback and false claims laws, which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers, and certain state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government in addition to requiring drug manufacturers to report information related to payments to physicians and other health care providers or marketing expenditures.
Because of the breadth of these laws and the narrowness of the statutory exceptions and safe harbors available, it is possible that some of our business activities could be subject to challenge under one or more of such laws.
−Removed: If our operations are found to be in violation of any of the laws described above or any other government regulations that apply to us, we may be subject to penalties, including civil and criminal penalties, damages, fines, exclusion from participation
−Removed: in government health care programs, such as Medicare and Medicaid, imprisonment, and the curtailment or restructuring of our operations, any of which could adversely affect our business, financial condition, results of operations, and prospects.
+Added: If our operations are found to be in violation of any of the laws described above or any other government regulations that apply to us, we may be subject to penalties, including civil and criminal penalties, damages, fines, exclusion from participation in government health care programs, such as Medicare and Medicaid, imprisonment, and the curtailment or restructuring of our operations, any of which could adversely affect our business, financial condition, results of operations, and prospects.
The provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order, or use of medicinal products is prohibited in the European Union.
12 unchanged sentences
In the United States and some foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could, among other things, prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability, or the ability of any future collaborators, to profitably sell any products for which we, or they, obtain marketing approval.
−Removed: We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we, or any future collaborators, may receive for any approved products.
−Removed: In the United States, the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (the “Medicare Modernization Act”), changed the way Medicare covers and pays for pharmaceutical products.
−Removed: The legislation expanded Medicare coverage for drug purchases by the elderly and introduced a new reimbursement methodology based on average sales prices for physician administered drugs.
−Removed: In addition, this legislation provided authority for limiting the number of drugs that will be covered in any therapeutic class.
−Removed: Cost reduction initiatives and other provisions of this legislation could decrease the coverage and price that we receive for any approved products.
−Removed: While the Medicare Modernization Act applies only to drug benefits for Medicare beneficiaries, private payors often follow Medicare coverage policy and payment limitations in setting their own reimbursement rates.
−Removed: Therefore, any reduction in reimbursement that results from the Medicare Modernization Act may result in a similar reduction in payments from private payors.
−Removed: The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Affordability Reconciliation Act (the “PPACA”), which became law in 2010, contains provisions of importance to our business, including, without limitation, our ability to commercialize and the prices we may obtain for any of our product candidates and that are approved for sale, the following:
−Removed: ● an annual, non-deductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents;
−Removed: ● an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program;
−Removed: ● expansion of federal healthcare fraud and abuse laws, including the False Claims Act and the Anti-Kickback Statute, new government investigative powers and enhanced penalties for noncompliance;
−Removed: ● a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% point-of-sale discounts off negotiated prices;
−Removed: ● extension of manufacturers’ Medicaid rebate liability;
−Removed: ● expansion of eligibility criteria for Medicaid programs;
−Removed: ● expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program new requirements to report financial arrangements with physicians and teaching hospitals;
−Removed: ● a new requirement to annually report drug samples that manufacturers and distributors provide to physicians;
−Removed: ● a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.
−Removed: In addition, other legislative changes have been proposed and adopted since the PPACA was enacted.
+Added: We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we, or any future collaborators,
+Added: may receive for any approved products.
+Added: In March 2010, President Obama signed into law the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Affordability Reconciliation Act (collectively the “ACA”).
+Added: In addition, other legislative changes have been proposed and adopted since the ACA was enacted.
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.
−Removed: 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 2029 unless additional Congressional action is taken.
−Removed: The Coronavirus Aid, Relief, and Economic Security Act, or the CARES Act, suspended the 2% Medicare sequester from May 1, 2020 through December 31, 2020, and extended the sequester by one year, through 2030.
+Added: 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 under the Coronavirus Aid, Relief, and Economic Security Act (the “CARES Act”).
+Added: Pursuant to subsequent legislation, however, these Medicare sequester reductions have been suspended through the end of March 2022.
+Added: 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.
−Removed: These new 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.
−Removed: 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.
−Removed: For example, with enactment of the Tax Cuts and Jobs Act of 2017 (the “TCJA”), 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.
+Added: 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 products or product candidates for which we may obtain regulatory approval or the frequency with which any such product is prescribed or used.
+Added: 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.
+Added: For example, with enactment of the Tax Cuts for Jobs Act, or TCJA, in 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.
−Removed: 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.
−Removed: 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.
−Removed: Thereafter, the U.S.
−Removed: Supreme Court agreed to hear this case.
−Removed: Oral argument in the case took place on November 10, 2020.
−Removed: On February 10, 2021, the Biden Administration withdrew the federal government’s support for overturning the ACA.
−Removed: A ruling by the Court is expected sometime this year.
+Added: 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 TCJA, the remaining provisions of the ACA are invalid as well.
+Added: Supreme Court heard this case on November 10, 2020 and on June 17, 2021, dismissed this action after finding that the plaintiffs do not have standing to challenge the constitutionality of the ACA.
Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.
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and policies that reduce affordability of coverage or financial assistance, including for dependents.
−Removed: This Executive Order also directs the U.S.
+Added: This Executive Order also directed the U.S.
Department of Health and Human Services to create a special enrollment period for the Health Insurance Marketplace in response to the COVID-19 pandemic.
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The prices of prescription pharmaceuticals have also been the subject of considerable discussion in the United States.
−Removed: To date, there have been several recent U.S.
−Removed: 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 products.
−Removed: To those ends, President Trump issued several executive orders intended to lower the costs of prescription drug products.
−Removed: Certain of these orders are reflected in recently promulgated regulations, including an interim final rule implementing President Trump’s most favored nation model, but such final rule is currently subject to a nationwide preliminary injunction.
−Removed: It remains to be seen whether these orders and resulting regulations will remain in force during the Biden Administration.
−Removed: 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.
−Removed: 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.
−Removed: 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).
+Added: There have been several recent U.S.
+Added: 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.
+Added: 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.
+Added: These regulations include an interim final rule implementing a most favored nation model for prices that would tie Medicare Part B payments for certain
+Added: physician-administered pharmaceuticals to the lowest price paid in other economically advanced countries, effective January 1, 2021.
+Added: That rule, however, has been subject to a nationwide preliminary injunction and, on December 29, 2021, CMS issued a final rule to rescind it.
+Added: 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.
+Added: 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, or SIP, to import certain prescription drugs from Canada into the United States.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: On July 9, 2021, President Biden signed Executive Order 14063, which focuses on, among other things, the price of pharmaceuticals.
+Added: The Order directs the Department of Health and Human Services, or HHS, to create a plan within 45 days to combat “excessive pricing of prescription pharmaceuticals and enhance domestic pharmaceutical supply chains, to reduce the prices paid by the federal government for such pharmaceuticals, and to address the recurrent problem of price gouging.” On September 9, 2021, HHS released its plan to reduce pharmaceutical prices.
+Added: The key features of that plan are to:
+Added: (a) make pharmaceutical prices more affordable and equitable for all consumers and throughout the health care system by supporting pharmaceutical price negotiations with manufacturers;
+Added: (b) improve and promote competition throughout the prescription pharmaceutical industry by supporting market changes that strengthen supply chains, promote biosimilars and generic drugs, and increase transparency;
+Added: and (c) foster scientific innovation to promote better healthcare and improve health by supporting public and private research and making sure that market incentives promote discovery of valuable and accessible new treatments.
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.
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In particular, sales, marketing, and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, misconduct, kickbacks, self-dealing and other abusive practices.
−Removed: These laws and
−Removed: regulations restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs, and other business arrangements.
−Removed: Such misconduct also could involve the improper use of information obtained in the course of clinical trials or interactions with the FDA or other regulatory authorities, which could result in regulatory sanctions and cause serious harm to our reputation.
+Added: These laws and regulations restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs, and other business arrangements.
+Added: Such misconduct also could involve the improper use of information obtained in the course of clinical trials or interactions with the FDA or other regulatory authorities, which
+Added: could result in regulatory sanctions and cause serious harm to our reputation.
We have adopted a code of conduct applicable to all of our employees, but it is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from government investigations or other actions or lawsuits stemming from a failure to comply with these laws or regulations.
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exchanges for violations of the FCPA’s accounting provisions.
+Added: We are subject to stringent privacy laws, information security laws, regulations, policies and contractual obligations related to data privacy and security and changes in such laws, regulations, policies, contractual obligations and failure to comply with such requirements could subject us to significant fines and penalties, which may have a material adverse effect on our business, financial condition or results of operations.
+Added: We are subject to data privacy and protection laws and regulations that apply to the collection, transmission, storage and use of personally-identifying information, which among other things, impose certain requirements relating to
+Added: the privacy, security and transmission of personal information, including comprehensive regulatory systems in the U.S., EU and U.K.
+Added: The legislative and regulatory landscape for privacy and data protection continues to evolve in jurisdictions worldwide, and there has been an increasing focus on privacy and data protection issues with the potential to affect our business.
+Added: Failure to comply with any of these laws and regulations could result in enforcement action against us, including fines, imprisonment of company officials and public censure, claims for damages by affected individuals, damage to our reputation and loss of goodwill, any of which could have a material adverse effect on our business, financial condition, results of operations or prospects.
+Added: There are numerous U.S.
+Added: federal and state laws and regulations related to the privacy and security of personal information.
+Added: In particular, regulations promulgated pursuant to HIPAA establish privacy and security standards that limit the use and disclosure of individually identifiable health information, or protected health information, and require the implementation of administrative, physical and technological safeguards to protect the privacy of protected health information and ensure the confidentiality, integrity and availability of electronic protected health information.
+Added: Determining whether protected health information has been handled in compliance with applicable privacy standards and our contractual obligations can be complex and may be subject to changing interpretation.
+Added: These obligations may be applicable to some or all of our business activities now or in the future.
+Added: If we are unable to properly protect the privacy and security of protected health information, we could be found to have breached our contracts.
+Added: Further, if we fail to comply with applicable privacy laws, including applicable HIPAA privacy and security standards, we could face civil and criminal penalties.
+Added: HHS enforcement activity can result in financial liability and reputational harm, and responses to such enforcement activity can consume significant internal resources.
+Added: In addition, state attorneys general are authorized to bring civil actions seeking either injunctions or damages in response to violations that threaten the privacy of state residents.
+Added: We cannot be sure how these regulations will be interpreted, enforced or applied to our operations.
+Added: In addition to the risks associated with enforcement activities and potential contractual liabilities, our ongoing efforts to comply with evolving laws and regulations at the federal and state level may be costly and require ongoing modifications to our policies, procedures and systems.
+Added: In 2018, California passed into law the California Consumer Privacy Act (CCPA), which took effect on January 1, 2020 and imposed many requirements on businesses that process the personal information of California residents.
+Added: Many of the CCPA’s requirements are similar to those found in the GDPR, including requiring businesses to provide notice to data subjects regarding the information collected about them and how such information is used and shared, and providing data subjects the right to request access to such personal information and, in certain cases, request the erasure of such personal information.
+Added: The CCPA also affords California residents the right to opt-out of “sales” of their personal information.
+Added: The CCPA contains significant penalties for companies that violate its requirements.
+Added: On November 3, 2020, California voters passed a ballot initiative for the California Privacy Rights Act, or CPRA, which will significantly expand the CCPA to incorporate additional GDPR-like provisions including requiring that the use, retention, and sharing of personal information of California residents be reasonably necessary and proportionate to the purposes of collection or processing, granting additional protections for sensitive personal information, and requiring greater disclosures related to notice to residents regarding retention of information.
+Added: Most CPRA provisions will take effect on January 1, 2023, though the obligations will apply to any personal information collected after January 1, 2022.
+Added: These provisions may apply to some of our business activities.
+Added: In addition, other states, including Virginia and Colorado, already have passed state privacy laws.
+Added: Other states will be considering these laws in the future.
+Added: These laws may impact our business activities, including our identification of research subjects, relationships with business partners and ultimately the marketing and distribution of our products.
+Added: Similar to the laws in the United States, there are significant privacy and data security laws that apply in Europe and other countries.
+Added: The collection, use, disclosure, transfer, or other processing of personal data, including personal health data, regarding individuals who are located in the European Economic Area (EEA), and the processing of personal data that takes place in the EEA, is regulated by the General Data Protection Regulation, or GDPR, which went into effect in May 2018 and which imposes obligations on companies that operate in our industry with respect to the processing of personal data and the cross-border transfer of such data.
+Added: The GDPR imposes onerous accountability obligations requiring data controllers and processors to maintain a record of their data processing and policies.
+Added: If our or our partners’ or service providers’ privacy or data security measures fail to comply with the GDPR requirements, we may be subject to litigation, regulatory investigations, enforcement notices requiring us to change the way we use
+Added: personal data and/or fines of up to 20 million Euros or up to 4% of the total worldwide annual turnover of the preceding financial year, whichever is higher, as well as compensation claims by affected individuals, negative publicity, reputational harm and a potential loss of business and goodwill.
+Added: The GDPR places restrictions on the cross-border transfer of personal data from the EU to countries that have not been found by the European Commission to offer adequate data protection legislation, such as the United States.
+Added: There are ongoing concerns about the ability of companies to transfer personal data from the EU to other countries.
+Added: In July 2020, the Court of Justice of the European Union (“CJEU”) invalidated the EU-U.S.
+Added: Privacy Shield, one of the mechanisms used to legitimize the transfer of personal data from the EEA to the U.S.
+Added: 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 EEA to the U.S.
+Added: While we were not self-certified under the Privacy Shield, this CJEU decision may lead to increased scrutiny on data transfers from the EEA to the U.S.
+Added: generally and increase our costs of compliance with data privacy legislation as well as our costs of negotiating appropriate privacy and security agreements with our vendors and business partners.
+Added: Following the withdrawal of the U.K.
+Added: from the EU, the U.K.
+Added: Data Protection Act 2018 applies to the processing of personal data that takes place in the U.K.
+Added: and includes parallel obligations to those set forth by GDPR.
+Added: As with other issues related to Brexit, there are open questions about how personal data will be protected in the UK and whether personal information can transfer from the EU to the UK.
+Added: Following the withdrawal of the U.K.
+Added: from the EU, the U.K.
+Added: Data Protection Act 2018 applies to the processing of personal data that takes place in the U.K.
+Added: and includes parallel obligations to those set forth by GDPR.
+Added: While the Data Protection Act of 2018 in the United Kingdom that “implements” and complements the European Union 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.
+Added: The United Kingdom government has already determined that it considers all European Union 27 and EEA member states to be adequate for the purposes of data protection, ensuring that data flows from the United Kingdom to the European Union/EEA remain unaffected.
+Added: In addition, a recent decision from the European Commission appears to deem the UK as being “essentially adequate” for purposes of data transfer from the EU to the UK, although this decision may be re-evaluated in the future.
+Added: Beyond GDPR, there are privacy and data security laws in a growing number of countries around the world.
+Added: While many loosely follow GDPR as a model, other laws contain different or conflicting provisions.
+Added: These laws will impact our ability to conduct our business activities, including both our clinical trials and any eventual sale and distribution of commercial products, through increased compliance costs, costs associated with contracting and potential enforcement actions.
+Added: While we continue to address the implications of the recent changes to data privacy regulations, data privacy remains an evolving landscape at both the domestic and international level, with new regulations coming into effect and continued legal challenges, and our efforts to comply with the evolving data protection rules may be unsuccessful.
+Added: It is possible that these laws may be interpreted and applied in a manner that is inconsistent with our practices.
+Added: We must devote significant resources to understanding and complying with this changing landscape.
+Added: Failure to comply with laws regarding data protection would expose us to risk of enforcement actions taken by data protection authorities in the EEA and elsewhere and carries with it the potential for significant penalties if we are found to be non-compliant.
+Added: Similarly, failure to comply with federal and state laws in the United States regarding privacy and security of personal information could expose us to penalties under such laws.
+Added: Any such failure to comply with data protection and privacy laws could result in government-imposed fines or orders requiring that we change our practices, claims for damages or other liabilities, regulatory investigations and enforcement action, litigation and significant costs for remediation, any of which could adversely affect our business.
+Added: Even if we are not determined to have violated these laws, government investigations into these issues typically require the expenditure of significant resources and generate negative publicity, which could harm our business, financial condition, results of operations or prospects.
Risks Related to Employee Matters, Managing Growth, Public Health and Information Technology
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The loss of the services of any of these persons could impede the achievement of our research, development, and commercialization objectives.
−Removed: Additionally, we are actively trying to recruit a candidate for the role of Chief Scientific Officer.
+Added: Additionally, we are actively trying to recruit a candidate for the role of Chief Medical Officer.
Any inability to fill this position in an expedient manner may have a material adverse effect on our business.
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Our consultants and advisors may be employed by employers other than us and may have commitments under consulting or advisory contracts with other entities that may limit their availability to us.
+Added: In addition, our ability to recruit and retain qualified personnel could be impacted by other factors, such as remote or hybrid working arrangements, including those resulting from the ongoing COVID-19 pandemic, which could impact employees’ productivity and morale, as well as any failure to succeed in preclinical or clinical trials.
+Added: The inability to recruit or the loss of the services of any executive, key employee, consultant or advisor may impede the progress of our research, development and commercialization objectives.
We face risks related to health epidemics, pandemics and other widespread outbreaks of contagious disease, including the COVID-19 pandemic, which could significantly disrupt our operations, impact our financial results or otherwise adversely impact our business.
Significant outbreaks of contagious diseases, and other adverse public health developments, could have a material impact on our business operations and operating results.
−Removed: For example, the spread of COVID-19 has affected segments of the global economy and could affect our operations.
+Added: The ongoing COVID-19 pandemic has continued to evolve with new, more contagious, variants emerging from time to time.
+Added: In response to COVID-19 and these variants, governments have implemented a variety of responses, including government-imposed quarantines, travel restrictions and other public health safety measures.
We have taken steps in line with guidance from the U.S.
Centers for Disease Control and Prevention, the Commonwealth of Massachusetts and the State of Colorado, the jurisdictions in which we primarily operate our business, to protect the health and safety of our employees and the community.
−Removed: In particular, we have implemented a work from home policy, and restricted on-site activities at our facilities in Massachusetts and Colorado to certain manufacturing, laboratory and related support activities.
−Removed: Under our return-to-work plans, we have resumed manufacturing, laboratory, and related support activities at our facilities in Massachusetts and Colorado using shifts and other capacity-limiting measures to comply with social distancing guidelines.
−Removed: We continue to assess the impact of the COVID-19 pandemic to best mitigate risk and continue the operations of our business.
−Removed: As a result of the COVID-19 pandemic or similar public health crises that may arise, we may experience disruptions that could adversely impact our operations, research and development, including preclinical studies, clinical trials and manufacturing activities, including:
+Added: In particular, in March 2020, we implemented a work from home policy, and restricted on-site activities at our facilities in Massachusetts and Colorado to certain manufacturing, laboratory and related support activities.
+Added: Under our return to onsite work plans, we gradually resumed these activities and fully reopened our facilities in the third quarter of 2021 using a hybrid work model.
+Added: However, in response to the recent spread of the Omicron variant, for January and a portion of February we temporarily reimposed the work from home policy and on-site activity restrictions.
+Added: We continue to assess the impact of the COVID-19 pandemic to best mitigate risk and continue the operations of our business, with focus on prioritizing the health and safety of our employees and maintaining safe and reliable operations of our facilities.
+Added: As a result of the COVID-19 pandemic or similar public health crises that may arise, or related healthcare staffing shortages, supply chain restrictions, or other issues, we may experience disruptions that could adversely impact our operations, research and development, including preclinical studies, clinical trials and manufacturing activities, including:
● delays or disruptions in clinical trials that we may be conducting, including patient screening, patient enrollment, patient dosing, clinical trial site activation, and study monitoring;
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● business disruptions caused by potential workplace, laboratory and office closures and an increased reliance on employees working from home, disruptions to or delays in ongoing laboratory experiments and operations, staffing shortages, travel limitations, cyber security and data accessibility, or communication or mass transit disruptions, any of which could adversely impact our business operations or delay necessary interactions with local regulators, ethics committees, manufacturing sites, research or clinical trial sites and other important agencies and contractors.
−Removed: For example and in light of the ongoing COVID-19 pandemic, we previously delayed the development of our research program to treat autosomal dominant retinitis pigmentosa 4.
−Removed: We also experienced slowed enrollment in the EDIT-101 clinical trial as a result of the COVID-19 pandemic and may experience further slowdowns.
−Removed: In addition, the trading prices for our common stock and other biopharmaceutical companies have been highly volatile as a result of the COVID-19 pandemic.
+Added: Our clinical trials for EDIT-101 and EDIT-301, as well as timely completion of preclinical activities and initiation of planned clinical trials for other product candidates is dependent upon the availability of, for example, preclinical and clinical trial sites, researchers and investigators, regulatory agency personnel, and materials, which may be adversely affected by the COVID-19 pandemic and related government responses.
+Added: For example, in late 2020 we experienced slowed enrollment in the EDIT-101 clinical trial as a result of the COVID-19 pandemic, including international travel restrictions imposed in response to the pandemic.
+Added: We have also experienced some delays in obtaining materials for certain of our programs, but these delays have not significantly impacted our operations to date.
+Added: In addition, the trading prices for our common stock and other biopharmaceutical companies have been highly volatile in part as a result of the COVID-19 pandemic.
As a result, we may face difficulties raising additional capital through sales of our common stock or such sales may be on unfavorable terms.
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Security breaches and other disruptions to our information technology structure could compromise our information, disrupt our business and expose us to liability, which would cause our business and reputation to suffer.
−Removed: In the ordinary course of our business, we collect, process and store sensitive data, including intellectual property, as well as our proprietary business information and that of our suppliers and business partners, employee data, and we may collect personally identifiable information of clinical trial participants in connection with clinical trials.
+Added: In the ordinary course of our business, we collect, process and store sensitive data, including intellectual property, as well as our proprietary business information and that of our suppliers and business partners, employee data,
+Added: and we may collect personally identifiable information of clinical trial participants in connection with clinical trials.
We also rely to a large extent on information technology systems to operate our business, including our financial systems.
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Despite our security measures, our information technology infrastructure (and those of our partners, vendors and third-party providers) may be vulnerable to attacks by hackers or breached due to employee error, malfeasance or other disruptions.
−Removed: We, our partners, vendors, and other third-party providers could be susceptible to third party attacks on our, and their, information security systems, which attacks are of ever-increasing levels of sophistication and are made by groups and individuals with a wide range of motives and expertise, including organized criminal groups, hacktivists,
−Removed: nation states and others.
+Added: We, our partners, vendors, and other third-party providers could be susceptible to third party attacks on our, and their, information security systems, which attacks are of ever-increasing levels of sophistication and are made by groups and individuals with a wide range of motives and expertise, including organized criminal groups, hacktivists, nation states and others.
+Added: Furthermore, in response to the COVID-19 pandemic, we have implemented a hybrid work model, which may place our information technology infrastructure and data at increased risk as more of our employees work from home utilizing network connections outside our premises.
We have invested in information technology security measures and the protection of confidential and sensitive information, but there can be no assurance that our efforts will prevent system failures, accidents or security breaches.
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Risks Related to Our Common Stock
−Removed: An active trading market for our common stock may not be sustained.
−Removed: Although our common stock is listed on The Nasdaq Global Select Market, an active trading market for our common stock may not be sustained.
−Removed: If an active market for our common stock does not continue, it may be difficult for our stockholders to sell their shares.
−Removed: An inactive trading market for our common stock may also impair our ability to raise capital to continue to fund our operations by selling shares and may impair our ability to acquire other companies or technologies by using our shares as consideration..
The market price of our common stock may be volatile, which could result in substantial losses for our stockholders.
Our stock price has been, and is likely to remain, volatile.
+Added: For example, since January 1, 2021, the trading price of our common stock on the Nasdaq Global Select Market has ranged from a low of $16.37 to a high of $99.95 through January 31, 2022.
Some of the factors that may cause the market price of our common stock to fluctuate include:
● the success of existing or new competitive products or technologies;
−Removed: ● the timing and results of clinical trials for EDIT-101 and any preclinical studies and clinical trials of any other product candidates that we develop;
+Added: ● the timing and results of clinical trials for EDIT-101 and EDIT-301 and any preclinical studies and clinical trials of any other product candidates that we develop;
● commencement or termination of collaborations for our product development and research programs;
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● the other factors described in this “Risk Factors” section.
+Added: In addition, the trading prices for our common stock and other biopharmaceutical companies have been highly volatile as a result of the COVID-19 pandemic.
+Added: The extent to which the COVID-19 pandemic may impact our business, preclinical studies and ongoing and planned clinical trials will depend on future developments, which are highly uncertain and cannot be predicted with confidence, such as the emergence of new variants of the disease, the ability of governments to vaccinate their populations and the effectiveness of existing vaccines to address any new variants, the ultimate containment of the disease, the modification or lifting of travel restrictions and other actions implemented to contain the outbreak or address its impact, such as social distancing and quarantines or lock-downs in the United States and other countries, business closures or business disruptions, and the ultimate effectiveness of other actions taken in the United States and other countries to contain and address the disease.
+Added: A resurgence or other negative developments relating to the pandemic may require us to again restrict access to our offices and laboratories for an extended period of time, or to pause or suspend preclinical research and our clinical trials;
+Added: and, further, may cause delays or restrictions at healthcare facilities or disrupt our manufacturing and supply chain or those of our third-party suppliers and manufacturers.
In recent years, the stock market in general, and the market for pharmaceutical and biotechnology companies in particular, has experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to changes in the operating performance of the companies whose stock is experiencing those price and volume fluctuations.
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Provisions in our restated certificate of incorporation and amended and restated bylaws or Delaware law may discourage, delay, or prevent a merger, acquisition, or other change in control that stockholders may consider favorable, including transactions in which you might otherwise receive a premium for your shares of our common stock.
−Removed: These provisions may also prevent or frustrate attempts by our stockholders to replace or remove our management.
+Added: provisions may also prevent or frustrate attempts by our stockholders to replace or remove our management.
These provisions include:
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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.