10 unchanged sentences
• We have incurred significant net losses since our inception and anticipate that we will continue to incur net losses for the foreseeable future.
−Removed: • A pandemic, epidemic or outbreak of an infectious disease, such as COVID-19, or the perception of its effects, may materially and adversely affect our business, operations and financial condition.
• Drug development is a highly uncertain undertaking.
1 unchanged sentence
• Due to the significant resources required for the development of our programs, and depending on our ability to access capital, we must prioritize development of certain product candidates.
+Added: • A pandemic, epidemic or outbreak of an infectious disease, such as COVID-19, or the perception of its effects, may materially and adversely affect our business, operations and financial condition.
Risks Related to the Discovery, Development and Commercialization of Our Product Candidates
−Removed: • We are heavily dependent on the successful development of our BBB technology and the programs currently in our pipeline, which are in the early stages of development.
+Added: • We are heavily dependent on the successful development of our blood-brain barrier ("BBB") technology and the programs currently in our pipeline, which are in the early stages of development.
There’s no assurance that any of our product candidates will receive regulatory approval.
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patent law could impair our ability to protect our products.
+Added: • Our patent protection could be compromised if we are unable to comply with requirements imposed by government patent agencies.
• Issued patents covering our BBB technology, product candidates and other technologies could be found invalid or unenforceable if challenged.
7 unchanged sentences
• We have engaged in and may in the future engage in acquisitions or strategic partnerships, which may increase our capital requirements, dilute our stockholders, or cause us to incur debt or assume contingent liabilities.
−Removed: • Our internal computer systems, or those used by our collaborators, CROs or other contractors, may fail or suffer security breaches that could compromise the confidentiality, integrity, and availability of such systems and data and expose us to liability.
+Added: • Our internal computer systems, or those used by our collaborators, CROs or other contractors, may fail or suffer security breaches or incidents that could compromise the confidentiality, integrity, and availability of such systems and data and expose us to liability.
• Our business is subject to risks associated with international operations.
10 unchanged sentences
Drug development is a highly uncertain undertaking and involves a substantial degree of risk.
−Removed: We are in Phase 1, 1b or 1/2 clinical trials for our LRRK2, eIF2B, ETV:IDS and RIPK1 programs and have not initiated clinical trials for any of our other current product candidates.
+Added: We are in Phase 1, 1b, 1/2, and 2 clinical trials for our LRRK2, ETV:IDS, eIF2B, RIPK1 and PTV:PGRN programs and have not initiated clinical trials for any of our other current product candidates.
To date, we have not initiated or completed a pivotal clinical trial, obtained marketing approval for any product candidat es, manufactured a commercial scale product, or arranged for a third party to do so on our behalf, or conducted sales and marketing activities necessary for successful product commercialization.
3 unchanged sentences
We have incurred significant net losses since our inception and anticipate that we will continue to incur net losses for the foreseeable future.
−Removed: We have incurred significant net losses since our inception, including net losses of $84.6 million and $215.3 million for the three and nine months ended September 30, 2021, respectively, and $58.2 million and $173.7 million for the three and nine months ended September 30, 2020, respectively .
−Removed: As of September 30, 2021, we had an accumulated deficit of $569.7 million .
+Added: We have incurred significant net losses since our inception, including net losses of $65.2 million for the three months ended March 31, 2022, respectively, and $70.0 million for the three months ended March 31, 2021, respectively .
+Added: As of March 31, 2022, we had an accumulated deficit of $710.2 million .
We have invested significant financial resources in research and development activities, including for our preclinical and clinical product candidates and our TV platform.
14 unchanged sentences
• obtain, maintain, protect and enforce our intellectual property portfolio, including intellectual property obtained through license agreements;
−Removed: • attract, hire and retain qualified personnel;
+Added: • attract, hire and retain qualified personnel and incur increased stock-based compensation, especially in light of a competitive compensation environment;
• provide additional internal infrastructure to support our continued research and development operations and any planned commercialization efforts in the future;
+Added: • implement additional internal systems and infrastructure related to cybersecurity;
• experience any delays or encounter other issues related to our operations;
3 unchanged sentences
In any particular quarter or quarters, our operating results could be below the expectations of securities analysts or investors, which could cause our stock price to decline.
−Removed: A pandemic, epidemic or outbreak of an infectious disease, such as COVID-19, or the perception of its effects, may materially and adversely affect our business, operations and financial condition.
−Removed: Public health outbreaks, such as epidemics or pandemics involving infectious or contagious diseases, such as COVID-19, may significantly disrupt our business.
−Removed: Such outbreaks pose the risk that we or our employees, contractors, suppliers, and other partners may be prevented from conducting business activities for an indefinite period of time due to the spread of the disease, due to shutdowns that may be requested or mandated by federal, state and local governmental authorities or certain employers, or due to the economic consequences associated with the pandemic.
−Removed: Business disruptions could include disruptions or restrictions on our ability to travel, as well as temporary closures of our facilities and the facilities of our partners, clinical trial sites, service providers, suppliers or contract manufacturers.
−Removed: For example, the COVID-19 pandemic caused a temporary disruption in our ability to recruit participants for our clinical trials in the calendar year 2020 and the first quarter of 2021, though recruitment has now returned to pre-pandemic levels.
−Removed: While it is not possible at this time to predict whether another pandemic, epidemic or infectious disease outbreak similar to COVID-19 will materialize, any measures taken by the governments of countries and local authorities in response to such future health crises have the potential to disrupt and delay the initiation of new clinical trials, the progress of our ongoing clinical trials, and could disrupt and delay our preclinical activities, and potentially the manufacture or shipment of both drug substance and finished drug product of our product candidates for preclinical testing and clinical trials and adversely impact our business, financial condition or operating results.
−Removed: The continued impact of the COVID-19 pandemic may materially and adversely affect our business, operations and financial condition.
−Removed: We are actively monitoring, evaluating and responding to developments relating to COVID-19, including new strains of the disease that have emerged in certain locations such as the Delta variant, vaccination status both locally and globally, and other COVID-19 and Delta variant-related protocols and travel restrictions as set forth by the CDC and other state, local and government authorities.
−Removed: In response to the COVID-19 pandemic in 2020, we implemented policies that enabled some of our employees to work remotely, and such policies may continue for an indefinite period.
−Removed: We also implemented various safety protocols for all on-site personnel, including COVID-19 testing procedures and compliance measures for social distancing and use of personal protective equipment and continue to maintain appropriate protocols in accordance with federal, state and local regulation.
−Removed: Our priority is to protect the health and safety of our employees, community, partners and clinical trial participants, while working to ensure the sustainability of our business operations.
−Removed: Although restrictions related to the COVID-19 pandemic were relaxed in many locations in which we do business for a period of time, some of those restrictions have been put back into place as a result of the Delta variant and the associated resurgence in COVID-19 cases.
−Removed: Additional resurgences could occur at any time, which may cause new disruptions to our business going forward.
−Removed: Examples of disruptions to our business from COVID-19 have included:
−Removed: • delays or difficulties in enrolling patients in our clinical trials, particularly elderly subjects, who are at a higher risk of complications from COVID-19;
−Removed: • difficulties interpreting data from our clinical trials due to the possible effects of COVID-19 on subjects enrolled in our clinical trials that contract COVID-19;
−Removed: • delays or difficulties in clinical site initiation, including difficulties in recruiting clinical site investigators and clinical site staff;
−Removed: • diversion of healthcare resources away from the conduct of clinical trials, including the diversion of hospitals serving as our clinical trial sites and hospital staff supporting the conduct of clinical trials;
−Removed: • interruption of key clinical trial activities, such as clinical trial site monitoring, due to limitations on travel imposed or recommended by federal or state governments, employers and others;
−Removed: • delays in receiving approval from local regulatory authorities to initiate our planned clinical trials;
−Removed: • interruption of, or delays in receiving, supplies of our product candidates from our contract manufacturing organizations due to staffing shortages, production slowdowns or stoppages;
−Removed: • delays or difficulties in furthering our preclinical and clinical programs, due to interruptions or limitations in our third party service providers’ business operations;
−Removed: • interruption in global shipping that may affect the transport of clinical trial materials, such as investigational drug product used in our clinical trials;
−Removed: • changes in clinical trial site procedures and requirements as well as regulatory requirements for conducting clinical trials during the COVID-19 pandemic;
−Removed: • delays or interruptions in the operations of or necessary interactions with the U.S.
−Removed: Food and Drug Administration ("FDA") or other regulators;
−Removed: • limitations on employee resources that would otherwise be focused on the conduct of our nonclinical studies and clinical trials, either because of sickness of employees and their families or the desire of employees to avoid contact with large groups of people.
−Removed: Our business is located in the state of California, which was more severely affected by the COVID-19 pandemic than some other parts of the country.
−Removed: On June 11, 2021, the Executive Department of the State of California issued Executive Orders N-07-21 and N-08-21, rescinding previous executive orders requiring various pandemic-related restrictions.
−Removed: Should COVID-19 cases in California significantly increase, however, the relevant counties or state may re-institute a "shelter in place" order at any time or implement other restrictions.
−Removed: Our primary operations are located in South San Francisco and prior to the rescinding of such California state orders, many of our employees have chosen to telecommute.
−Removed: Due to telecommuting patterns, modified schedules and work protocols to enable adequate physical distancing, our laboratory operations have operated with decreased efficiency, which may impact certain of our operations over the near term and long term.
−Removed: Should these developments continue or worsen, our operations and program timelines may be negatively impacted and could result in the incurrence of additional costs.
−Removed: We have clinical trial sites for our clinical studies in the United States, Europe and New Zealand, certain of which may be affected by the Delta variant and any subsequent variants of the coronavirus, and the availability of vaccines at the clinical trial site locations.
−Removed: If healthcare facilities and offices are required to focus limited resources on non-clinical trial matters such as treatment of COVID-19 patients, patient screening, new patient enrollment, and monitoring and data collection could be affected.
−Removed: For example, in 2020, we experienced a pause in enrollment in our DNL151 (BIIB122) Phase 1 and Phase 1b trials, our DNL343 Phase 1 trial, and our ETV:IDS program observational biomarker study.
−Removed: In all cases, recruitment resumed within several months;
−Removed: however, further pauses or delays could occur depending on the success of the vaccine rollout, the efficacy of vaccination, which is not yet fully understood, and any lingering social or economic unrest that continues to result from the COVID-19 pandemic.
−Removed: In June 2020, the FDA issued guidance on manufacturing practice considerations for responding to COVID-19 infection in employees in drug and biologic products manufacturing, including recommendations for manufacturing controls to prevent contamination of the products.
−Removed: Should the FDA issue additional guidance with respect to COVID-19 protocols as relates to the implementation of our clinical trials, the costs of such clinical trials may increase.
−Removed: Further, we may be required to develop and implement additional clinical trial policies and procedures designed to help protect subjects from the COVID-19 virus, the Delta variant, and any new variants of the coronavirus that may emerge in the future.
−Removed: To the extent the COVID-19 pandemic continues to adversely affect our business, operations and financial condition, it may also have the effect of heightening many of the risks described in this “Risk Factors” section.
Drug development is a highly uncertain undertaking and involves a substantial degree of risk.
13 unchanged sentences
• addressing any competing technological and market developments;
+Added: • receiving milestone and other payments under our current and any future collaboration arrangements;
• maintaining, protecting, expanding and enforcing our portfolio of intellectual property rights, including patents, trade secrets and know-how;
• attracting, hiring and retaining qualified personnel;
+Added: • addressing any delays in our clinical trials or other impacts resulting from the ongoing COVID-19 pandemic.
Because of the numerous risks and uncertainties associated with drug development, we are unable to predict the timing or amount of our expenses, or when we will be able to generate any meaningful revenue or achieve or maintain profitability, if ever.
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We currently fund our operations primarily with the proceeds from our follow-on offering completed in January 2020, and payments received from our Takeda Collaboration Agreement, Sanofi Collaboration Agreement and Biogen Collaboration Agreement.
−Removed: We currently have five clinical-stage programs, DNL151 (BIIB122), DNL343, DNL310, DNL758 (SAR443122) and DNL788 (SAR443820), and have several other product candidates in preclinical development, as well as early-stage research projects.
+Added: We currently have six clinical-stage programs, BIIB122/DNL151, DNL310, DNL343, SAR443820/DNL788, SAR443122/DNL758, and TAK-594/DNL593 and have several other product candidates in preclinical development, as well as early-stage research projects.
Developing our product candidates is expensive, and we expect to continue to spend substa ntial amounts as we fund our early-stage research projects, and continue to advance our programs through preclinical and clinical development.
Even if we are successful in developing our product candidates, obtaining regulatory approvals and launching and commercializing any product candidate will require substantial additional funding.
−Removed: As of September 30, 2021, we had $1.36 billion in cash, cash equivalents and marketable securities.
+Added: As of March 31, 2022, we had $1.21 billion in cash, cash equivalents and marketable securities.
We believe that our existing cash, cash equivalents and marketable securities will be sufficient to fund our projected operations through at least the next 12 months.
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As a result, we may fail to capitalize on viable commercial products or profitable market opportunities, be required to forego or delay pursuit of opportunities with other product candidates or other diseases and disease pathways that may later prove to have greater commercial potential than those we choose to pursue, or relinquish valuable rights to such product candidates through collaboration, licensing or other royalty arrangements in cases in which it would have been advantageous for us to invest additional resources to retain sole development and commercialization rights.
+Added: A pandemic, epidemic or outbreak of an infectious disease, such as COVID-19, or the perception of its effects, may materially and adversely affect our business, operations and financial condition.
+Added: Public health outbreaks, such as epidemics or pandemics involving infectious or contagious diseases, such as COVID-19, may significantly disrupt our business.
+Added: Such outbreaks pose the risk that we or our employees, contractors, suppliers, and other partners may be prevented from conducting business activities for an indefinite period of time due to the spread of the disease, due to shutdowns that may be requested or mandated by federal, state and local governmental authorities or certain employers, or due to the economic consequences associated with the pandemic.
+Added: Business disruptions could include disruptions or restrictions on our ability to travel, as well as temporary closures of our facilities and the facilities of our partners, clinical trial sites, service providers, suppliers or contract manufacturers.
+Added: For example, the COVID-19 pandemic caused a temporary disruption in our ability to recruit participants for our clinical trials in the calendar year 2020 and the first quarter of 2021, though recruitment has now returned to pre-pandemic levels.
+Added: While it is not possible at this time to predict whether another pandemic, epidemic or infectious disease outbreak similar to COVID-19 will materialize, any measures taken by the governments of countries and local authorities in response to such future health crises have the potential to disrupt and delay the initiation of new clinical trials, the progress of our ongoing clinical trials, and could disrupt and delay our preclinical activities, and potentially the manufacture or shipment of both drug substance and finished drug product of our product candidates for preclinical testing and clinical trials and adversely impact our business, financial condition or operating results.
+Added: The continued impact of the COVID-19 pandemic may materially and adversely affect our business, operations and financial condition.
+Added: We are actively monitoring, evaluating and responding to developments relating to COVID-19, including new strains of the disease that have emerged, vaccination status both locally and globally, and other COVID-19 related protocols and travel restrictions as set forth by the CDC and other state, local and government authorities.
+Added: In response to the COVID-19 pandemic in 2020, we implemented policies that enabled some of our employees to work remotely, and such policies may continue for an indefinite period.
+Added: We also implemented various safety protocols for all on-site personnel, including COVID-19 testing procedures and compliance measures for social distancing and use of personal protective equipment and continue to maintain appropriate protocols in accordance with federal, state and local regulation.
+Added: Our priority is to protect the health and safety of our employees, community, partners and clinical trial participants, while working to ensure the sustainability of our business operations.
+Added: Although restrictions related to the COVID-19 pandemic were lifted in many of our locations for a period of time, new resurgences could occur at any time, which may cause disruptions to our business going forward.
+Added: Examples of disruptions to our business from COVID-19 have included:
+Added: • delays or difficulties in enrolling patients in our clinical trials, particularly elderly subjects, who are at a higher risk of complications from COVID-19;
+Added: • difficulties interpreting data from our clinical trials due to the possible effects of COVID-19 on subjects enrolled in our clinical trials that contract COVID-19;
+Added: • delays or difficulties in clinical site initiation, including difficulties in recruiting clinical site investigators and clinical site staff;
+Added: • diversion of healthcare resources away from the conduct of clinical trials, including the diversion of hospitals serving as our clinical trial sites and hospital staff supporting the conduct of clinical trials;
+Added: • interruption of key clinical trial activities, such as clinical trial site monitoring, due to limitations on travel imposed or recommended by federal or state governments, employers and others;
+Added: • delays in receiving approval from local regulatory authorities to initiate our planned clinical trials;
+Added: • interruption of, or delays in receiving, supplies of our product candidates from our contract manufacturing organizations due to staffing shortages, production slowdowns or stoppages;
+Added: • delays or difficulties in furthering our preclinical and clinical programs, due to interruptions or limitations in our third party service providers’ business operations;
+Added: • interruption in global shipping that may affect the transport of clinical trial materials, such as investigational drug products used in our clinical trials;
+Added: • changes in clinical trial site procedures and requirements as well as regulatory requirements for conducting clinical trials during the COVID-19 pandemic;
+Added: • delays or interruptions in the operations of or necessary interactions with the U.S.
+Added: Food and Drug Administration ("FDA") or other regulators;
+Added: • limitations on employee resources that would otherwise be focused on the conduct of our nonclinical studies and clinical trials, either because of sickness of employees and their families or the desire of employees to avoid contact with large groups of people;
+Added: Our business is located in California, which was more severely affected by the COVID-19 pandemic than some other parts of the country.
+Added: In June 2021, certain pandemic-related restrictions were lifted in California;
+Added: however, should COVID-19 cases significantly increase, the relevant counties or state may re-institute pandemic-related restrictions.
+Added: Our primary operations are located in South San Francisco and many of our employees have chosen to telecommute.
+Added: Due to telecommuting patterns, modified schedules and work protocols to enable adequate physical distancing, our laboratory operations have operated with decreased efficiency, which may impact certain of our operations over the near term and long term.
+Added: Should these developments continue or worsen, our operations and program timelines may be negatively impacted and could result in the incurrence of additional costs.
+Added: We have clinical trial sites for our clinical studies in the United States and Europe, any of which may be affected by subsequent variants of the coronavirus, and the availability of vaccines at the clinical trial site locations.
+Added: If healthcare facilities and offices are required to focus limited resources on non-clinical trial matters such as treatment of COVID-19 patients, patient screening, new patient enrollment, and monitoring and data collection could be affected.
+Added: For example, in 2020, we experienced a pause in enrollment in our BIIB122/DNL151 Phase 1 and Phase 1b trials, our DNL343 Phase 1 trial, and our ETV:IDS program observational biomarker study.
+Added: In all cases, recruitment resumed within several months;
+Added: however, further pauses or delays could occur in our clinical trials, including as a result of social or economic unrest caused by the ongoing COVID-19 pandemic.
+Added: In March 2020, the FDA issued guidance, which the FDA subsequently updated, on conducting clinical trials during the pandemic, which describes a number of considerations for sponsors of clinical trials impacted by the pandemic, including the requirement to include in the clinical trial report contingency measures implemented to manage the trial and any disruption of the trial as a result of the COVID-19 pandemic, among others.
+Added: In June 2020, the FDA issued guidance on manufacturing practice considerations for responding to COVID-19 infection in employees in drug and biologic products manufacturing, including recommendations for manufacturing controls to prevent contamination of the products.
+Added: Other COVID-19 related industry guidance documents published by the FDA include updates to previous guidance related to Good Manufacturing Practices, guidance on remote interactive evaluations of drug manufacturing and bioresearch monitoring facilities, and guidance on drug product manufacturing and supply chain inspections, among others.
+Added: Should the FDA issue additional guidance with respect to COVID-19 protocols as relates to the implementation of our clinical trials, the costs of such clinical trials may increase.
+Added: Further, we may be required to develop and implement additional clinical trial policies and procedures designed to help protect subjects from the COVID-19 virus, and any variants of the coronavirus that may emerge in the future.
+Added: The extent to which the COVID-19 pandemic impacts our business, preclinical studies and clinical trials will depend on future developments, which are highly uncertain and cannot be predicted with certainty.
+Added: To the extent the COVID-19 pandemic continues to adversely affect our business, operations and financial condition, it may also have the effect of heightening many of the risks described in this “Risk Factors” section.
Risks Related to the Discovery, Development and Commercialization of Our Product Candidates
24 unchanged sentences
Further, we canno t be certain that any of our product candidates will be successful in clinical trials.
−Removed: For instance, in June 2020, together with our collaboration partner Sanofi, we paused clinical activities with DNL747 to accelerate development of DNL788 (SAR443820), in part due to DNL747 preclinical chronic toxicity studies.
+Added: For instance, in June 2020, together with our collaboration partner Sanofi, we paused clinical activities with DNL747 to accelerate development of SAR443820/DNL788, in part due to DNL747 preclinical chronic toxicity studies.
We may in the future advance product candidates into clinical trials and terminate such trials prior to their completion.
53 unchanged sentences
• changes in regulatory requirements and guidance that require amending or submitting new clinical protocols;
+Added: • changes in the approval policies or regulations of the FDA or comparable foreign regulatory authorities;
• changes in the standard of care on which a clinical development plan was based, which may require new or additional trials;
3 unchanged sentences
• delays in manufacturing, testing, releasing, validating, or importing/exporting sufficient stable quantities of our product candidates for use in clinical trials or the inability to do any of the foregoing;
−Removed: • delays associated with the COVID-19 global pandemic.
+Added: • delays associated with the ongoing COVID-19 pandemic.
Any inability to successfully initiate or complete clinical trials could result in additional costs to us or impair our ability to generate revenue.
3 unchanged sentences
Such authorities may suspend or terminate a clinical trial due to a number of factors, including failure to conduct the clinical trial in accordance with regulatory requirements or our clinical protocols, inspection of the clinical trial operations or trial site by the FDA, EMA or other regulatory authorities resulting in the imposition of a clinical hold, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from using a product candidate, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial.
+Added: For example, on January 13, 2022, we announced that the DNL919 (ATV:TREM2) IND application had been placed on clinical hold by the FDA.
+Added: We received a formal clinical hold letter and are moving forward to address the FDA’s observations related to the preclinical toxicology assessment and to provide the information requested to initiate clinical studies, including proposed changes to the clinical trial protocol, the informed consent form, and the investigator brochure.
DNL201, a former LRRK2 inhibitor product candidate, completed a Phase 1b clinical trial in Parkinson's disease patients with and without the genetic LRRK2 mutation.
1 unchanged sentence
The partial clinical hold was removed in December 2017 based on additional clinical and preclinical data provided to the FDA.
−Removed: In our completed Phase 1b clinical trial of DNL201 in patients with Parkinson’s disease, there was one SAE considered unrelated to drug, and at the high dose, there was one severe AE (headache) leading to dose reduction and one study withdrawal (headache and nausea).
−Removed: Our clinical-stage product candidates are DNL151 (BIIB122) for Parkinson's disease, DNL343 for ALS and FTD, DNL310 for Hunter syndrome, DNL758 (SAR443122) for system inflammatory diseases and DNL788 (SAR443820) for neurological diseases .
−Removed: In the nonclinical safety studies for these product candidates, toxicities were observed at high doses in rat and/or cynomolgus monkey above doses and exposures that will be tested in the clinic.
−Removed: We cannot assure you that DNL151 (BIIB122), DNL343, DNL310, DNL758 (SAR443122) and DNL788 (SAR443820), or our other product candidates will not be subject to new, partial or full clinical holds in the future.
+Added: Refer to “Item 1.
+Added: Business—Our Programs” for a more detailed discussion of adverse effects ("AEs") and significant adverse effects ("SAEs") observed in our reported clinical trials for DNL151 and DNL310.
+Added: We cannot assure you that the clinical hold on DNL919 will be lifted, or that BIIB122/DNL151, DNL310, DNL343, SAR443820/DNL788, SAR443122/DNL758, and TAK-594/DNL593 or our other product candidates will not be subject to new, partial or full clinical holds in the future.
We may in the future advance product candidates into clinical trials and terminate such trials prior to their completion, which could adversely affect our business.
−Removed: Further, after the commencement of clinical trials, we may pause the advancement of lead molecules in favor of a backup molecule with a superior safety or efficacy profile, such as we did in our RIPK1 program, switching our focus from DNL747 to DNL788 (SAR443820).
+Added: Further, after the commencement of clinical trials, we may pause the advancement of lead molecules in favor of a backup molecule with a superior safety or efficacy profile, such as we did in our RIPK1 program, switching our focus from DNL747 to SAR443820/DNL788.
Delays in the completion of any clinical trial of our product candidates will increase our costs, slow down our product candidate development and approval process and delay or potentially jeopardize our ability to commence product sales and generate revenue.
3 unchanged sentences
We may experience difficulties in patient enrollment and retention in our clinical trials for a variety of reasons, including:
−Removed: • inability or delay in enrollment of patients due to a variety of reasons, including outbreaks and public health crises, such as the COVID-19 global pandemic;
+Added: • inability or delay in enrollment of patients due to a variety of reasons, including outbreaks and public health crises, such as the ongoing COVID-19 pandemic;
• the size and nature of the patient population;
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There are a number of large pharmaceutical and biotechnology companies that are currently pursuing the development of products for the treatment of the neurodegenerative disease indications for which we have research programs, including Alzheimer’s disease, Parkinson’s disease and ALS.
−Removed: Companies that we are aware are developing therapeutics in the neurodegenerative disease area include companies with significant financial resources, such as AbbVie, Alector, AstraZeneca, Biogen, Bristol-Myers Squibb, Eli Lilly, E-Scape Bio, GlaxoSmithKline, Ionis, JCR Pharmaceuticals, Johnson & Johnson, Novartis, Prevail Therapeutics, Roche, Sanofi and Takeda.
+Added: Companies that we are aware are developing therapeutics in the neurodegenerative disease area include companies with significant financial resources, such as AbbVie, Alector, AstraZeneca, Biogen, Bristol-Myers Squibb, Eli Lilly, E-Scape Bio, GlaxoSmithKline, Ionis, JCR Pharmaceuticals, Johnson & Johnson, Novartis, Prevail Therapeutics, Roche (including Genentech, its wholly owned subsidiary), Sanofi and Takeda.
In addition to competition from other companies targeting neurodegenerative indications, any products we may develop may also face competition from other types of therapies, such as gene-editing therapies.
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The same risks would apply to our internal manufacturing facilities and capabilities, which we are actively building.
−Removed: In addition, building internal manufacturing capacity carries significant risks in terms of being able to plan, design and execute on a complex project to build manufacturing facilities in a timely and cost-efficient manner, and our efforts to scale our internal manufacturing capabilities may not succeed.
+Added: We recently entered into an operating lease for approximately 65,000 square feet of laboratory, office and warehouse premises in Salt Lake City, Utah and have initiated the build-out of our Utah site to expand our clinical manufacturing capabilities for biologic therapeutics including the manufacture of materials for toxicology studies and drug substance for early human clinical studies.
+Added: In addition, building internal manufacturing capacity carries significant risks in terms of being able to plan, design and execute on a complex project to build manufacturing facilities in a timely and cost-efficient manner, and our current and future efforts to scale our internal manufacturing capabilities may not succeed.
In addition, the manufacturing process, including any material modifications in the manufacturing process for any products that we may develop is subject to FDA, EMA and foreign regulatory authority approval processes, and continuous oversight, and we will need to contract with manufacturers who can meet all applicable FDA, EMA and foreign regulatory authority requirements, including complying with current good manufacturing practices ("cGMPs"), on an ongoing basis.
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The regulations that govern marketing approvals, pricing, and reimbursement for new drugs 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.
+Added: In the United States, recently enacted or potential future 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 drug before it can be marketed.
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Adverse events or other undesirable side effects caused by our product candidates could cause us or regulatory authorities to interrupt, delay, or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA, EMA or other comparable foreign regulatory authorities.
−Removed: Our most advanced product candidates, DNL151 (BIIB122), DNL343, DNL310, DNL758 (SAR443122) and DNL788 (SAR443820) are currently our only clinical stage product candidates.
+Added: Our most advanced product candidates, BIIB122/DNL151, DNL310, DNL343, SAR443820/DNL788, SAR443122/DNL758 and TAK-594/DNL593 are currently our only clinical stage product candidates.
In our completed Phase 1b clinical trial of former product candidate DNL201 in patients with Parkinson’s disease, there was one SAE considered unrelated to drug, and at the high dose, there was one severe AE (headache) leading to dose reduction and one study withdrawal (headache and nausea).
−Removed: Adverse events and other side effects may result from higher dosing, repeated dosing and/or longer-term exposure to DNL151 (BIIB122), DNL343 and/or DNL310 and could lead to delays and/or termination of the development of these product candidates.
+Added: Adverse events and other side effects may result from higher dosing, repeated dosing and/or longer-term exposure to our product candidates and could lead to delays and/or termination of the development of these product candidates.
+Added: On January 13, 2022, we announced that the DNL919 (ATV:TREM2) IND application had been placed on clinical hold by the FDA.
+Added: We received a formal clinical hold letter and are moving forward to address the FDA’s observations related to the preclinical toxicology assessment and to provide the information requested to initiate clinical studies, including proposed changes to the clinical trial protocol, the informed consent form, and the investigator brochure.
In 2020, we paused clinical studies with DNL747 in our RIPK1 program.
15 unchanged sentences
We cannot predict whether our product candidates will cause toxicities in humans that would preclude or lead to the revocation of regulatory approval based on nonclinical studies or early-stage clinical trials.
−Removed: We may in the future conduct clinical trials for our product candidates outside the United States, and the FDA, EMA and applicable foreign regulatory authorities may not accept data from such trials.
−Removed: We may in the future choose to conduct one or more of our clinical trials outside the United States, including in Europe.
+Added: We currently conduct clinical trials for our product candidates outside the United States, and may in the future conduct clinical trials outside of the United States, and the FDA, EMA and applicable foreign regulatory authorities may not accept data from such trials.
+Added: We currently conduct one or more of our clinical trials outside the United States, including in Europe, and may continue to do so in the future.
The acceptance of data from clinical trials conducted outside the United States or another jurisdiction by the FDA, EMA or applicable foreign regulatory authority may be subject to certain conditions.
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If regulatory sanctions are applied or if regulatory approval is withdrawn, the value of our company and our operating results will be adversely affected.
−Removed: We plan to seek orphan drug designation for some product candidates, but we may be unable to obtain such designations or to maintain the benefits associated with orphan drug status, including market exclusivity, which may cause our revenue, if any, to be reduced.
+Added: We have received orphan drug designation from the FDA for DNL310, and plan to seek orphan drug designation for additional product candidates, but we may be unable to obtain such designations or to maintain the benefits associated with orphan drug status, including market exclusivity, which may cause our revenue, if any, to be reduced.
Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biologic intended to treat a rare disease or condition, defined as a disease or condition with a patient population of fewer than 200,000 in the United States, or a patient population greater than 200,000 in the United States when there is no reasonable expectation that the cost of developing and making available the drug or biologic in the United States will be recovered from sales in the United States for that drug or biologic.
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Furthermore, the FDA can waive orphan exclusivity if we are unable to manufacture sufficient supply of our product.
−Removed: We may seek Fast Track designation from the FDA for one or more of our product candidates.
−Removed: Even if one or more of our product candidates receive Fast Track designation, we may be unable to obtain or maintain the benefits associated with the Fast Track designation.
−Removed: Recently, the FDA granted Fast Track designation to DNL788 (SAR443820).
+Added: We have received Fast Track designation from the FDA for DNL788 and may seek Fast Track designation from the FDA for additional product candidates.
+Added: Even if one or more of our product candidates receives Fast Track designation, we may be unable to obtain or maintain the benefits associated with the Fast Track designation.
+Added: The FDA has granted Fast Track designation to SAR443820/DNL788.
Fast Track designation is designed to facilitate the development and expedite the review of therapies to treat serious conditions and fill an unmet medical need.
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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: This includes aggregate reductions of Medicare payments to providers of 2% per fiscal year, which went into effect in 2013, and will remain in effect through 2030, with the exception of a temporary suspension implemented under various COVID-19 relief legislation from May 1, 2020 through December 31, 2021, unless additional Congressional action is taken.
+Added: This includes aggregate reductions of Medicare payments to providers of 2% per fiscal year, which went into effect in 2013, and will remain in effect through 2031, with the exception of a temporary suspension implemented under various COVID-19 relief legislation from May 1, 2020 through March 31, 2022, unless additional Congressional action is taken.
+Added: Under the current legislation, the actual reduction in Medicare payments will vary from 1% in 2022 to up to 4% in the final fiscal year of this sequester.
The American Taxpayer Relief Act of 2012 further reduced Medicare payments to several providers, including hospitals and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
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Any denial in coverage or reduction in reimbursement from Medicare or other government-funded programs may result in a similar denial or reduction in payments from private payors, which may prevent us from being able to generate sufficient revenue, attain profitability or commercialize our product candidates, if approved.
+Added: In addition, increased scrutiny by the U.S.
+Added: Congress of the FDA’s approval process may significantly delay or prevent marketing approval, as well as subject us to more stringent product labeling and post-marketing testing and other requirements.
Our employees, independent contractors, consultants, commercial partners and vendors may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements.
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• the federal Physician Payment Sunshine Act, created under the ACA, and its implementing regulations, which require manufacturers of drugs, devices, biologicals and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program to report annually to the U.S.
−Removed: Department of Health and Human Services under the Open Payments Program, information related to payments or other transfers of value made to physicians, as defined by law, and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.
−Removed: Effective January 1, 2022, for data collected in 2021 and reported to CMS in 2022, these reporting and transparency requirements have been extended to include payments and transfers of value made during the previous year to certain non-physician covered recipients, including physician assistants, nurse practitioners and other mid-level practitioners;
+Added: Department of Health and Human Services under the Open Payments Program, information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain non-physician healthcare professionals (such as physician assistants and nurse practitioners, among others), and teaching hospitals, as well as information regarding ownership and investment interests held by physicians and their immediate family members;
• federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers;
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We heavily rely on external security and infrastructure vendors to manage our information technology systems and data centers.
−Removed: We face a number of risks relative to protecting this critical information, including loss of access risk, inappropriate use or disclosure, inappropriate modification, and the risk of our being unable to adequately monitor, audit and modify our controls over our critical information.
−Removed: This risk extends to the third-party vendors and subcontractors we use to manage this sensitive data.
+Added: We face a number of risks relative to protecting this critical information, including the loss of access, inappropriate use or disclosure, inappropriate modification, and the risk of our being unable to adequately monitor, audit and modify our controls over our critical information.
+Added: This risk extends to third-party vendors and subcontractors we use to manage this sensitive data.
A wide variety of provincial, state, national, and international laws, and regulations apply to the collection, use, retention, protection, disclosure, transfer and other processing of personal data.
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GDPR regulations may impose additional responsibility and liability in relation to the personal data that we process and we may be required to put in place additional mechanisms to ensure compliance with the new data protection rules.
−Removed: Beginning in 2021, the UK will be a “third country” under the GDPR.
−Removed: We may, however, incur liabilities, expenses, costs, and other operational losses under GDPR as well as applicable EU Member States and the United Kingdom privacy laws.
+Added: Additionally, the UK has implemented legislation that substantially implements the GDPR, with penalties for noncompliance of up to the greater of £17.5 million or four percent of worldwide revenues.
+Added: Aspects of UK data protection laws and regulations remain unclear.
+Added: On June 28, 2021, the European Commission announced a decision of "adequacy" concluding that the UK ensures an equivalent level of data protection to the GDPR, which provides some relief regarding the legality of continued personal data flows from the European Economic Area ("EEA") to the UK.
+Added: Some uncertainty remains, however, as this adequacy determination must be renewed after four years and may be modified or revoked in the interim.
+Added: We cannot fully predict how UK data protection laws or regulations may develop in the medium to longer term nor the effects of divergent laws and guidance regarding how data transfer to and from the UK will be regulated.
+Added: We may incur liabilities, expenses, costs, and other operational losses under the GDPR as well as privacy and data protection laws of Switzerland, the United Kingdom, and applicable EU Member States.
+Added: We may find it necessary or appropriate to make additional changes to the ways we or our service providers collect, disclose, transfer, and otherwise process data within the EEA, Switzerland and the UK.
This may be onerous and may interrupt or delay our development activities, and adversely affect our business, financial condition, results of operations and prospects.
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These laws and regulations are not necessarily preempted by HIPAA, particularly if a state affords greater protection to individuals than HIPAA.
−Removed: Where state laws are more protective, we have to comply with the stricter provisions.
+Added: Where state laws are more protective, we must comply with the stricter provisions.
In addition to fines and penalties imposed upon violators, some of these state laws also afford private rights of action to individuals who believe their personal information has been misused.
−Removed: For example, California recently enacted legislation, the California Consumer Privacy Act ("CCPA"), that will, among other things, require covered companies to provide new disclosures to California consumers, and afford such consumers new abilities to opt-out of certain sales of personal information, that became effective on January 1, 2020.
−Removed: The CCPA was amended several times throughout 2018 and 2019, and it is unclear whether further modifications will be made to this legislation or how it will be interpreted.
−Removed: Some observers have noted the CCPA could be the beginning of a trend toward more stringent privacy legislation throughout the United States, as evidenced by the recent Virginia Consumer Data Protection Act, enacted March 2021, and the Colorado Privacy Act, enacted June 2021.
+Added: For example, California has enacted legislation, the California Consumer Privacy Act ("CCPA"), that, among other things, requires covered companies to provide new disclosures to California consumers, and afford such consumers new abilities to opt-out of certain sales of personal information.
+Added: The CCPA became effective on January 1, 2020.
+Added: Some observers have noted the CCPA could be the beginning of a trend toward more stringent privacy legislation throughout the United States, as evidenced by the recent Virginia Consumer Data Protection Act, enacted March 2021, the Colorado Privacy Act, enacted June 2021, and the Utah Consumer Privacy Act, enacted March 2022.
The CCPA, as amended and expanded by the California Privacy Rights Act ("CPRA"), requires covered companies to provide new disclosures to individuals and consumers in California, and afford such individuals and consumers new data protection rights, including the ability to opt-out of certain sales of personal information.
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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.
−Removed: In addition, if we are unable to properly protect the privacy and security of protected health information, we could be found to have breached our contracts.
−Removed: Our actual or perceived failure to adequately comply with applicable laws and regulations relating to privacy and data protection, or to protect personal data and other data we process or maintain, could result in regulatory enforcement actions against us, including fines, imprisonment of company officials and public censure, claims for damages by affected individuals, other lawsuits or reputational and damage, all of which could materially affect our business, financial condition, results of operations and growth prospects.
+Added: In addition, if we are unable to properly protect the privacy and security of protected health information, we could be alleged or found to have breached our contracts.
+Added: Our actual or perceived failure to adequately comply with applicable laws and regulations or other actual or asserted obligations relating to privacy and data protection, or to protect personal data and other data we process or maintain, could result in regulatory enforcement actions against us, including fines, imprisonment of company officials and public censure, claims for damages by affected individuals, other lawsuits or reputational and damage, all of which could materially affect our business, financial condition, results of operations and growth prospects.
If we or any contract manufacturers and suppliers we engage fail to comply with environmental, health, and safety laws and regulations, we could become subject to fines or penalties or incur costs that could have a material adverse effect on the success of our business.
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Disruptions at the FDA and other government agencies may also slow 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, including from December 22, 2018 until January 25, 2019, the U.S.
+Added: For example, in 2018 and 2019, the U.S.
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.
−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: Further, in our operations as a public company, future government shutdowns could impact our ability to access the public markets and obtain the funding necessary 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: 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 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 Good Manufacturing Practices.
+Added: However, the FDA may not be able to continue its current inspection 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 may not be able 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 or other regulatory authorities to timely review and process our regulatory submissions, or to provide feedback on our clinical development plans, which could have a material adverse effect on our business.
+Added: Further, in our operations as a public company, future government shutdowns or other disruptions to normal operations could impact our ability to access the public markets and obtain the funding necessary to properly capitalize and continue our operations.
Risks Related to Our Reliance on Third Parties
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Any performance failure on the part of our distributors, including with the shipment of any drug supplies, could delay clinical development or marketing approval of any product candidates we may develop or commercialization of our medicines, producing additional losses and depriving us of potential product revenue.
−Removed: We currently contract with third parties for the manufacture of materials for our research programs, preclinical studies and clinical trials and expect to continue to do so for commercialization of some or all product candidates that we may develop.
+Added: We currently contract with third parties for the manufacture of the significant majority of the materials for our research programs, preclinical studies and clinical trials and expect to continue to do so for commercialization of some or all product candidates that we may develop.
This reliance on third parties may increase the risk that we will not have sufficient quantities of such materials, product candidates, or any medicines that we may develop and commercialize, or that such supply will not be available to us at an acceptable cost, which could delay, prevent, or impair our development or commercialization efforts.
−Removed: We do not have any operational manufacturing facilities.
+Added: Although we have initiated the build-out of our Utah site to expand our clinical manufacturing capabilities for biologic therapeutics, we do not have any operational manufacturing facilities.
We currently rely on third-party manufacturers for the manufacture of our materials for preclinical studies and clinical trials and expect to continue to do so for some or all of our materials for preclinical studies, clinical trials and for commercial supply of any product candidates that we may develop.
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• the inability to produce required volume in a timely manner and to quality standards.
−Removed: Third-party manufacturers may not be able to comply with cGMP regulations or similar regulatory requirements outside the United States.
−Removed: Our failure, or the failure of our third-party manufacturers, to comply with applicable regulations could result in clinical holds on our trials, sanctions being imposed on us, including fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, license revocations, seizures or recalls of product candidates or medicines, operating restrictions, and criminal prosecutions, any of which could significantly and adversely affect supplies of our medicines and harm our business, financial condition, results of operations and growth prospects.
+Added: Third-party manufacturers may not be able to comply with U.S.
+Added: export control regulations, cGMP regulations or similar regulatory requirements outside the United States.
+Added: Our failure, or the failure of our third-party manufacturers, to comply with applicable regulations could result in a need to replace current third-party manufacturers including the possibility of supply delays, clinical holds on our trials, sanctions being imposed on us, including fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, license revocations, seizures or recalls of product candidates or medicines, operating restrictions, and criminal prosecutions, any of which could significantly and adversely affect supplies of our medicines and harm our business, financial condition, results of operations and growth prospects.
Any medicines that we may develop may compete with other product candidates and products for access to manufacturing facilities.
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Any performance failure on the part of our existing or future manufacturers could delay clinical development or marketing approval.
−Removed: We do not currently have arrangements in place for redundant supply for any of our product candidates.
+Added: We do not currently have arrangements in place for redundant supply for many components of our product candidates.
If any one of our current contract manufacturers cannot perform as agreed, we may be required to replace that manufacturer and may incur added costs and delays in identifying and qualifying any such replacement.
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We cannot be certain that our suppliers will continue to provide us with the quantities of these raw materials that we require or satisfy our anticipated specifications and quality requirements.
−Removed: Any supply interruption in limited or sole sourced raw materials could materially harm our ability to manufacture our product candidates until a new source of supply, if any, could be identified and qualified.
+Added: Further, we have in the past and may in the future experience delayed shipments of raw materials due to interruptions relating to the aforementioned events.
We may be unable to find a sufficient alternative supply channel in a reasonable time or on commercially reasonable terms.
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Given that the development of our technology and product candidates is at an early stage, our intellectual property portfolio with respect to certain aspects of our technology and product candidates is also at an early stage.
−Removed: In addition, we cannot be certain that any patents we own or in-license in the United States adequately cover the Fc domain portion of our BBB platform technology that binds to transferrin receptor, or adequately cover the antibodies, enzymes or proteins being developed in our ATV:TREM2, ETV:IDS or PTV:PGRN programs.
+Added: In addition, we cannot be certain that any patents we own or in-license in the United States adequately cover the Fc domain portion of our BBB platform technology that binds to transferrin receptor, or adequately cover the antibodies, enzymes or proteins being developed in our ATV:TREM2, ETV:IDS, ETV:SGSH, or PTV:PGRN programs.
We have filed or intend to file patent applications on these aspects of our technology and product candidates;
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With respect to both in-licensed and owned intellectual property, we cannot predict whether the patent applications we and our licensors are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient protection from competitors or other third parties.
−Removed: The patent prosecution process is expensive, time-consuming, and complex, and we may not be able to file, prosecute, maintain, enforce, or license all necessary or desirable patent applications at a reasonable cost or in a timely manner.
+Added: The patent prosecution process is expensive, time-consuming, and complex, and we may not be able to file, prosecute, maintain, enforce, or license all necessary or desirable patent applications at a reasonable cost or in a timely manner, including delays as a result of the COVID-19 pandemic impacting our or our licensors' operations.
It is also possible that we will fail to identify patentable aspects of our research and development output in time to obtain patent protection.
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We are heavily reliant upon licenses to certain patent rights and proprietary technology from third parties that are important or necessary to the development of our BBB platform technology and product candidates.
−Removed: For example, in June 2016, we entered into a license agreement with Genentech pursuant to which we received an exclusive license to certain of Genentech’s intellectual property relating to our LRRK2 program, including our DNL151 (BIIB122) product candidate.
+Added: For example, in June 2016, we entered into a license agreement with Genentech pursuant to which we received an exclusive license to certain of Genentech’s intellectual property relating to our LRRK2 program, including our BIIB122/DNL151 product candidate.
Our agreements with F-star and other license agreements may not provide exclusive rights to use certain licensed intellectual property and technology in all relevant fields of use and in all territories in which we may wish to develop or commercialize our technology and products in the future.
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The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents, trade secrets, and other intellectual property protection, particularly those relating to biotechnology products, which could make it difficult for us to stop the infringement of our patents or marketing of competing products in violation of our intellectual property and proprietary rights generally.
+Added: In Europe, no earlier than October 1, 2022, European applications will soon have the option, upon grant of a patent, of becoming a Unitary Patent which will be subject to the jurisdiction of the Unitary Patent Court ("UPC").
+Added: This will be a significant change in European patent practice.
+Added: As the UPC is a new court system, there is no precedent for the court, increasing the uncertainty.
Proceedings to enforce our intellectual property and proprietary rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly, could put our patent applications at risk of not issuing, and could provoke third parties to assert claims against us.
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Accordingly, our efforts to enforce our intellectual property and proprietary rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or license.
+Added: Geopolitical actions in the United States and in foreign countries could increase the uncertainties and costs surrounding the prosecution or maintenance of our patent applications or those of any current or future licensors and the maintenance, enforcement or defense of our issued patents or those of any current or future licensors.
+Added: For example, the United States and foreign government actions related to Russia's invasion of Ukraine may limit or prevent filing, prosecution, and maintenance of patent applications in Russia.
+Added: Government actions may also prevent maintenance of issued patents in Russia.
+Added: These actions could result in abandonment or lapse of our patents or patent applications, resulting in partial or complete loss of patent rights in Russia.
+Added: If such an event were to occur, it could have a material adverse effect on our business.
+Added: In addition, a decree was adopted by the Russian government in March 2022, allowing Russian companies and individuals to exploit inventions owned by patentees that have citizenship or nationality in, are registered in, or have predominately primary place of business or profit-making activities in the United States and other countries that Russia has deemed unfriendly without consent or compensation.
+Added: Consequently, we may be unable to prevent third parties from practicing our inventions in Russia or from selling or importing products made using our inventions in and into Russia.
+Added: Accordingly, our competitive position may be impaired, and our business, financial condition, results of operations and prospects may be adversely affected.
Many countries have compulsory licensing laws under which a patent owner may be compelled to grant licenses to third parties.
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In such an event, potential competitors might be able to enter the market with similar or identical products or technology, which could have a material adverse effect on our business, financial condition, results of operations and growth prospects.
+Added: Geopolitical actions in the United States and in foreign countries could prevent us from continuing to make these periodic payments in certain locations.
+Added: For example, the United States and foreign government actions related to Russia's invasion of Ukraine may limit our ability to make or prevent us from making these payments in Russia.
+Added: These actions could result in abandonment or lapse of our patents or patent applications, resulting in partial or complete loss of patent rights in Russia.
+Added: If such an event were to occur, it could have a material adverse effect on our business.
Changes in U.S.
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We will need to grow the size and capabilities of our organization, and we may experience difficulties in managing this growth.
−Removed: As of September 30, 2021, we had 360 emplo yees, all of whom were full-time.
+Added: As of March 31, 2022, we had approximately 380 emplo yees, all of whom were full-time.
As our development plans and strategies develop, we must add a significant number of additional managerial, operational, financial, and other personnel.
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Our management may also have to divert a disproportionate amount of its attention away from day-to-day activities in order to manage these growth activities.
−Removed: Our ability to successfully manage our expected growth is uncertain given the fact that all of our executive officers have joined us since February 2015.
−Removed: This lack of long-term experience working together as a company may adversely impact our senior management team’s ability to effectively manage our business and growth.
We currently rely, and for the foreseeable future will continue to rely, in substantial part on certain independent organizations, advisors and consultants to provide certain services.
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Despite the implementation of security measures, our internal computer systems and those of our CROs and other contractors and consultants may be vulnerable to damage from computer viruses or unauthorized access, or breached, due to operator error, malfeasance or other system disruptions.
−Removed: As the cyber-threat landscape evolves, these attacks are growing in frequency, sophistication and intensity, and are becoming increasingly difficult to detect.
+Added: As the cyber-threat landscape evolves, attacks are growing in frequency, sophistication and intensity, and are becoming increasingly difficult to detect.
These threats can come from a variety of sources, ranging in sophistication from an individual hacker to a state-sponsored attack.
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Such attacks could include the use of key loggers or other harmful and virulent malware, including ransomware or other denials of service, and can be deployed through malicious websites, the use of social engineering and/or other means.
−Removed: We and our third-party vendors may not be able to anticipate all types of security threats, and we may not be able to implement preventive measures effective against all such security threats.
+Added: We and our third-party contractors and consultants may not be able to anticipate all types of security threats, and we may not be able to implement preventive measures effective against all such security threats.
The techniques used by cyber criminals change frequently, may not be recognized until launched, and can originate from a wide variety of sources.
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Likewise, we rely on our third-party research institution collaborators for research and development of our product candidates and other third parties for the manufacture of our product candidates and to conduct clinical trials, and similar events relating to their computer systems could also have a material adverse effect on our business.
−Removed: Cyber-attacks, breaches, interruptions or other data security incidents could result in legal claims or proceedings, liability under federal or state laws that protect the privacy of personal information, regulatory penal-ties, significant remediation costs, disrupt key business operations and divert attention of management and key information technology resources.
+Added: Cyber-attacks, breaches, interruptions or other data security incidents could result in legal claims or proceedings, liability under federal or state laws that protect the privacy of personal information, regulatory penalties, significant remediation costs, disrupt key business operations and divert attention of management and key information technology resources.
In the United States, notice of breaches must be made to affected individuals, the U.S.
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Business disruptions could seriously harm our future revenue and financial condition and increase our costs and expenses.
−Removed: Our operations, and those of our third-party research institution collaborators, CROs, CDMOs, suppliers, and other contractors and consultants, could be subject to earthquakes, power shortages, telecommunications failures, water shortages, floods, hurricanes, typhoons, fires, extreme weather conditions, medical epidemics such as COVID-19, and other natural or man-made disasters or business interruptions, for which we are partly uninsured.
+Added: Our operations, and those of our third-party research institution collaborators, CROs, CDMOs, suppliers, and other contractors and consultants, could be subject to earthquakes, power shortages, telecommunications failures, water shortages, floods, hurricanes, typhoons, fires, extreme weather conditions, health epidemics such as COVID-19, and other natural or man-made disasters or business interruptions, for which we are partly uninsured.
In addition, we rely on our third-party research institution collaborators for conducting research and development of our product candidates, and they may be affected by government shutdowns or withdrawn funding.
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Accordingly, our future results could be harmed by a variety of factors, including:
−Removed: • economic weakness, including inflation, or political instability in particular non-U.S.
+Added: • economic weakness, including inflation, or political instability in certain non-U.S.
economies and markets;
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• potential liability under the FCPA, UK Bribery Act or comparable foreign laws;
−Removed: • business interruptions resulting from geo-political actions, including war and terrorism, natural disasters including earthquakes, typhoons, floods and fires, or health epidemics such as COVID-19;
+Added: • business interruptions resulting from geopolitical actions, including war, such as Russia's invasion of Ukraine, and terrorism, natural disasters including earthquakes, typhoons, floods and fires, or health epidemics such as COVID-19;
• cyberattacks, which are growing in frequency, sophistication and intensity, and are becoming increasingly difficult to detect.
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We, and indirectly, our stockholders, will bear the cost of issuing and servicing all such securities.
−Removed: Because our decision to issue debt or equity securities in any future offering will depend on market conditions and other factors beyond our control, we cannot predict or estimate the amount, timing or nature of any future offerings.
+Added: Because our decision to issue debt or equity securities in any future offering will depend on market conditions and other factors beyond our control, particularly in the current market we cannot predict or estimate the amount, timing or nature of any future offerings.
To the extent that we raise additional capital through the sale of equity or debt securities, your ownership interest will be diluted, and the terms may include liquidation or other preferences that adversely affect your rights as a stockholder.
The incurrence of indebtedness would result in increased fixed payment obligations and could involve restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire, sell or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business.
−Removed: On March 12, 2019, we filed a shelf registration statement on Form S-3 (File No.
−Removed: 333-230232) with the Securities and Exchange Commission, which became effective upon filing.
−Removed: In January 2020, we sold 9.0 million shares of common stock in a follow-on offering pursuant to this registration statement.
−Removed: The shelf registration continues to allow us to sell, from time to time, an unspecified number of shares of common stock;
+Added: In January 2020, we sold 9.0 million shares of common stock in an underwritten follow-on offering pursuant to a shelf registration statement filed in March 2019.
+Added: We filed a second shelf registration statement on February 28, 2022 and simultaneously entered into an equity distribution agreement with Goldman Sachs & Co.
+Added: LLC, SVB Securities LLC, and Cantor Fitzgerald & Co., as sales agents, to establish an at-the-market facility pursuant to which we may offer and sell from time to time up to $400.0 million shares of our common stock.
+Added: Further, the shelf registration allows us to sell, from time to time, an unspecified number of additional shares of common stock;
shares of preferred stock;
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and units representing two or more of the foregoing securities.
+Added: Our decision to issue debt or equity securities in any future offering will depend on market conditions and other factors beyond our control, and therefore we cannot predict or estimate the amount, timing, or nature of any future offerings.
+Added: To the extent that we raise additional capital through the sale of equity or debt securities, your ownership interest will be diluted, and the terms may include liquidation or other preferences that adversely affect your rights as a stockholder.
+Added: The incurrence of indebtedness would result in increased fixed payment obligations and could involve restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire, sell or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business.
+Added: In addition, any sales of our common stock or other securities under our shelf registration statement, including pursuant to at-the-market offerings, could put downward pressure on our stock price.
Additionally, collaborations we enter into with third parties may provide capital in the near term but limit our potential cash flow and revenue in the future.
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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.