Item 1. Business
Overview
We are a leading genome editing company
focused on the development of proprietary, potentially curative therapeutics utilizing a biological tool known as CRISPR/Cas9. We believe that the CRISPR/Cas9 technology has the potential to transform medicine by permanently editing
disease-associated genes or genetic material in the human body with a single treatment course. We intend to leverage our leading scientific expertise, clinical development experience and intellectual property position to unlock broad therapeutic
applications of CRISPR/Cas9 genome editing and develop a potential new class of therapeutic products.
In 2012, one of our co-founders and current
scientific advisors, Dr. Jennifer Doudna, and her colleagues published a paper in the journal
Science
describing the use of CRISPR/Cas9 as a genome editing tool. Genome editing is the precise and targeted modification of the genetic
material of cells or viruses. Since the publication of Dr. Doudnas landmark paper, thousands of research papers have been published on the CRISPR/Cas9 technology. The CRISPR/Cas9 system offers a revolutionary approach for therapeutic
development due to its broad potential to precisely edit the genome. This system can be used to make three general types of edits: knockouts, repairs and insertions. Each of these editing strategies takes advantage of naturally-occurring biological
mechanisms to effect the desired genetic alteration. By addressing the underlying cause of the disease, this approach has the potential to provide curative therapeutic options for patients with genetically-based diseases.
We plan to use the CRISPR/Cas9 system across two broad areas:
in vivo
applications, in which CRISPR/Cas9 therapeutic products are delivered
directly to target cells within the body; and
ex vivo
applications, in which cells are removed from a patients body, modified using CRISPR/Cas9 and then returned to the patient. Initially, our
in vivo
pipeline
includes proprietary programs targeting transthyretin amyloidosis (ATTR), which we are co-developing with Regeneron Pharmaceuticals, Inc. (Regeneron), hepatitis B virus (HBV), alpha-1 antitrypsin deficiency (AATD) and inborn errors of metabolism
(IEMs). Our initial
ex vivo
pipeline includes both proprietary and partnered programs focused on chimeric antigen receptor T cells (CAR-T cells) and hematopoietic stem cells (HSCs), the stem cells from which all of the various
types of blood cells originate, which we are developing in collaboration with Novartis Institutes for BioMedical Research, Inc. (Novartis).
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The following table illustrates our current discovery programs and opportunities as of February 28, 2017:
We believe that the combination of our product focus, therapeutic discovery and development strength, delivery expertise
and intellectual property portfolio makes us well-positioned to translate the potential of the CRISPR/Cas9 system into clinically meaningful genome editing-based therapeutics. To maximize our opportunity to rapidly develop clinically successful
products, we have applied a risk-mitigated approach to selecting our initial indications that we refer to as our sentinel indications. Our approach is defined by four primary criteria:
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the type of edit: knockout, repair or insertion;
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the delivery modality for
in vivo
and
ex vivo
applications;
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the presence of established therapeutic endpoints; and
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the potential for the CRISPR/Cas9 system to provide therapeutic benefits when compared to existing therapeutic options.
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These selection criteria position us to build a diversified pipeline, in which we are not reliant on any single delivery technology or editing approach for
success. In addition, we believe we can apply the learnings from these sentinel indications to inform our selection of subsequent indications and targets of interest. We believe this approach serves to increase our probabilities of success in our
sentinel indications, generate insights that will accelerate the development of additional therapeutic products and broaden the opportunity for potential strategic alliances.
Delivery plays a key role in our
in vivo
therapeutic approach. We have shown in animal models that lipid nanoparticle (LNP) delivery
technology, which involves encapsulating therapeutic agents into microscopic lipid droplets, can systemically deliver CRISPR/Cas9 components to the liver, our initial organ of focus for
in vivo
applications. With our teams
expertise with LNP delivery technology, we expect to readily translate the LNPs in our preclinical development to clinical development in humans. In parallel, we are exploring additional delivery vehicles, including viral delivery vectors, which are
viruses engineered to carry non-viral nucleic acids to patients cells, which we believe may assist us in targeting other organs.
To explore the
scope of gene edits with the CRISPR/Cas9 system, we have chosen four sentinel
in vivo
liver indications employing different editing strategies:
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ATTR program, which utilizes a gene knockout strategy;
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HBV program, which utilizes a knockout strategy to target covalently closed circular DNA (cccDNA);
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AATD program, which utilizes either a gene knockout strategy or a gene repair strategy; and
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PH-1, our lead IEM program, which can utilize a gene knockout strategy and targeted DNA insertion.
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addition to giving us four potential product opportunities, each of these programs will provide us with learnings that we intend to translate to a broader set of disease indications requiring the same types of edits.
Our sentinel
ex vivo
programs in CAR-T cell and HSC applications are being developed with Novartis, where we retain the right to develop and
commercialize rights to certain HSC programs. In CAR-T cell therapy, naturally-occurring immune cells, specifically T cells, are removed from a patients body, modified
ex vivo
by inserting a chimeric antigen receptor (CAR) to
selectively target cancer cells by activating an immune response against them. The CAR is an engineered fusion protein expressed on a cells surface with an antibody-based portion that can recognize certain markers on other cells, such as
cancer cells, and a signaling portion inside the cell that can deliver the desired signals when the antibody portion binds its markers. We believe CRISPR/Cas9 can further enhance CAR-T cells by, for example, generating a universal donor
CAR-T cell or modifying genes that regulate T cell behavior to increase the therapeutic potential of a CAR-T cell therapy. In the HSC programs, we can apply CRISPR/Cas9 to correct defective proteins in HSCs of a given patient for the potential
treatment of blood disorders or primary immune deficiencies. In additional applications, normal HSCs may be engineered
ex vivo
using CRISPR/Cas9 to express a therapeutic protein, which is then administered to patients in need of
that protein. Our sentinel
ex vivo
programs will help inform the broader applicability of CRISPR/Cas9 in an
ex vivo
setting, which we plan to explore through eXtellia, a division of our company focused on the
application of CRISPR/Cas9 gene editing in the fields of immuno-oncology beyond CAR-T cells and autoimmune and inflammatory diseases. We expect eXtellia to focus on relevant immune cells for which we retain proprietary rights, such as T effector
cells, including engineered T cells, natural killer (NK) cells and tumor infiltrating lymphocytes (TILs) for immuno-oncology applications, T regulatory cells (Tregs) for autoimmune disorders and other cell types, including induced pluripotent
stem cells, mesenchymal stem cells and muscle satellite stem cells for tissue-targeted treatments. Our
ex vivo
delivery approach is a clinically proven delivery method called electroporation, an electrical charge-based technique for
delivering molecules into cells, which has been used in advanced clinical studies. In parallel, we are considering other delivery methods for
ex vivo
introduction of biological material to cells, which may provide advantages in delivery
efficiency or cell viability.
We believe our focused approach to selecting our sentinel
in vivo
and
ex vivo
programs
positions us to build a pipeline across a range of indications and generate a wealth of data for opening up the potential therapeutic applications of the CRISPR/Cas9 technology across a broad range of diseases. Our collaboration and intellectual
property strategies focus on leveraging existing third-party expertise in therapeutic research, preclinical and clinical development, regulatory affairs, manufacturing and commercialization, while also enhancing our industry-leading access to
evolving genome editing technology, potential new therapeutic targets and delivery vehicles. Through our product research and development programs, we believe we can apply CRISPR/Cas9 technology to improve the lives of patients with significant
unmet medical needs.
Strategy
Our goal is to build
a fully integrated, product-driven biotechnology company, focused on developing and commercializing potentially curative CRISPR/Cas9-based therapeutics. Our approach to advancing the broad potential of genome editing includes plans to:
Focus on Sentinel Indications that Enable Us to Fully Develop the Potential of the CRISPR/Cas9 System.
To maximize our opportunity to
rapidly develop clinically successful products, we have applied a risk-mitigated approach to selecting sentinel indications with significant unmet medical needs based on four primary criteria:
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the type of edit: knockout, repair or insertion;
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the delivery modality for
in vivo
and
ex vivo
applications;
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the presence of established therapeutic endpoints; and
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the potential for the CRISPR/Cas9 system to provide therapeutic benefits when compared to existing therapeutic options.
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We believe these selection criteria position us to build a diversified pipeline, in which we are not reliant on any single delivery technology or editing
approach for success. In addition, we believe we can apply the learnings from these sentinel indications to inform our selection of additional indications and targets of interest. We are also exploring ways to identify potential new therapeutic
targets suitable for modulation with the CRISPR/Cas9 technology. We believe this approach serves to increase the probabilities of success in our sentinel indications, generate insights that will accelerate the development of additional therapeutic
products and broaden the opportunity for potential strategic alliances.
Aggressively Pursue
In Vivo
Liver
Indications to Develop Therapeutics Rapidly with Existing Delivery Technology.
For our sentinel
in vivo
indications, we selected well-validated targets in diseases with significant unmet medical needs where there are
predictive biomarkers, or measurable indicators of a biological condition or state, with strong disease correlation and where the CRISPR/Cas9 technology and delivery tools existing today could be applied towards developing a novel therapeutic. Our
initial
in vivo
pipeline opportunities target diseases of the liver, which we believe we can develop using our existing LNP delivery technology. The first
in vivo
indications we are evaluating are ATTR, HBV,
AATD and PH-1.
Continue to Develop and Expand our
Ex Vivo
Therapeutic Programs.
In collaboration with
Novartis, we are rapidly developing the CAR-T cell and HSC programs. We believe that our sentinel work in CAR-T cells and HSCs will guide us in building a portfolio of additional proprietary
ex vivo
opportunities through our
eXtellia division, including expanded immuno-oncology therapeutics beyond CAR-T cells, such as modified T cells, NK cells and TILs, and autoimmune applications of Tregs, in addition to potential applications for other cell types such as induced
pluripotent stem cells, mesenchymal stem cells and muscle satellite stem cells.
Continue to Leverage Strategic Partnerships to Accelerate Clinical
Development.
We view strategic partnerships as important drivers for accelerating the achievement of our goal of rapidly developing potentially curative therapies. The potential application of CRISPR/Cas9 is extremely broad, and we plan
to continue to identify partners who can contribute meaningful resources and insights to our programs and allow us to more rapidly expand our impact to broader patient populations. Our partnership focusing on CAR-T cells with Novartis, an industry
leader with one of the most advanced clinical CAR-T cell programs, and our partnership with Regeneron, a leader in genetics-driven drug discovery and development, exemplify this strategy.
Grow Our Leadership Position in the Field of Genome Editing.
We are committed to broadening our capabilities to remain at the cutting edge
of genome editing research. We will continue to invest internally in developing our platform capabilities, including innovative delivery modalities, technologies and tools to advance our therapeutic programs. We will also systematically explore
accessing external technologies or opportunities to enhance our leadership position in developing innovative therapeutics.
Our Platform
An integral part of developing our therapeutic product candidates and exploring additional potential applications of CRISPR/Cas9 to future indications
includes building and improving on various proprietary and in-licensed aspects of our technology platform. We continue to develop robust, high volume (high-throughput) capabilities centering around CRISPR/Cas9 components, editing strategies and
delivery methods that we believe will provide us with a competitive advantage in creating successful therapeutic product candidates.
Informatics
We have built a high-throughput, scalable data processing and analysis, or informatics, infrastructure to support various aspects of our platform,
including guide ribonucleic acid (RNA) selection and analysis of on- and off-
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target editing in cells. Depending on the desired editing strategy, we use our proprietary bioinformatics methods to design candidate guides and select those that we believe are more likely to be
highly specific and have high cutting efficiency. As we grow our experimental data set, we continue to incorporate guide performance into our algorithms to improve their predictive power.
Guide RNA Qualification
As part of the process to
identify guide RNAs for potential development candidates, we screen numerous guide RNAs for their ability to generate the required edit at the genomic site of interest, called on-target activity, as well as their propensity to generate unwanted
events at other sites in the genome, also known as off-target activity. To evaluate on-target activity, we use high-throughput sequencing methods to analyze the genomes of edited cells, allowing us to assess overall editing efficiency and to examine
the nature of the editing events, such as specific insertions or deletions.
For guide RNAs selected through our primary on-target screens, we perform a
variety of analyses to look for possible off-target editing events, including bioinformatic predictions and experimental methods. Part of our approach involves identifying candidate off-target sites based on experimental measurements of genome-wide
DNA breaks, as well as targeted sequencing of such candidate sites to evaluate actual off-target editing events in relevant cell types. We continue to optimize our guide RNA qualification capability over time by increasing our throughput, improving
our off-target activity detection accuracy and increasing our bioinformatics predictive accuracy.
Guide RNA format
CRISPR/Cas9 systems can function with guide RNAs having a variety of modifications, such as changes to the physical guide RNA structure or chemical
modifications of nucleotides. As part of our development of CRISPR/Cas9 therapeutics, we are engineering modified guide RNAs to, for example, improve editing efficiency and reduce the likelihood of an immune response. We believe our work in this
area will allow us to develop the most appropriate guides for therapeutic applications.
Nuclease
Our current preferred Cas9 protein is derived from a type of bacteria called
S. pyogenes
(
Spy
), which is the Cas9 used in the vast
majority of published CRISPR/Cas9 literature to date. As part of the therapeutic development process, we are adapting and engineering
Spy
Cas9 with the goal of improving its activity and manufacturability. In addition, we are
exploring other naturally-occurring Cas9 proteins and nucleases from other organisms, which may differ from
Spy
Cas9 in aspects such as specificity, size or mechanism of DNA cut. We are pursuing these alternative Cas9 forms and
other nucleases through ongoing internal work, by collaborating with our existing partners and scientific founders and by investigating in-licensing opportunities. We are also investigating targeted modifications of Cas9 that can modulate DNA
activity by mechanisms other than cleavage. We believe that different therapeutic applications may be best addressed using different forms of Cas9 or other nucleases, depending on the target cell or tissue of interest, the delivery method and the
desired type of edit.
Cas9 Edit type
While
knockout type edits can be made using only a Cas9 protein and guide RNA, repair and insertion type edits additionally require a template nucleic acid that contains the desired corrected or inserted sequence. The way in which the template is provided
depends on the delivery modality. For example, for
ex vivo
applications, the DNA template may be delivered by electroporation in combination with a Cas9-guide RNA complex. We are also investigating various
in
vivo
strategies for delivering repair and insertion templates, such as delivery by LNPs or by viral vectors. Further, we are developing methods to selectively promote template-based repair or insertion mechanisms in cells, as opposed to
non-template-based repair that otherwise may generate knockout type edits.
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In vivo
delivery
We are focusing our initial
in vivo
applications in the liver, with delivery of CRISPR/Cas9 components by LNPs.
LNPs encapsulate the therapeutic material, providing it with stability, targeted delivery capabilities, improved pharmacologic properties and controlled
circulation time, allowing for transient expression of Cas9. We see multiple advantages of using LNPs as our initial
in vivo
delivery vehicle, particularly as optimized by us for delivery of the CRISPR/Cas9 system. Certain LNPs have
demonstrated efficacy, safety and favorable tolerability and are currently used as a delivery system for therapeutic small interfering RNA (siRNA) as well as therapeutic messenger RNA (mRNA). mRNA is RNA that encodes proteins, while siRNA is RNA
that can interfere with the function of mRNA. There are currently several LNP/siRNA programs of other companies in the clinic, with the most advanced in Phase III development. LNP delivery of CRISPR/Cas9-based therapies, where potentially only one
or few treatment courses are needed, has the potential to show a more favorable safety profile when compared to therapeutic modalities like siRNAs where chronic dosing is needed. Additionally, LNPs are chemically well-defined and have a completely
synthetic route of manufacture, which permits greater scalability. We are currently advancing our programs using a set of biodegradable, well-tolerated lipids, which were developed by Novartis and in-licensed for use with CRISPR/Cas9 products. To
date, we have successfully demonstrated
in vivo
editing in mouse liver with a single dose of systemically delivered LNPs based on these lipids.
With our teams expertise in LNP delivery technology, we expect to be able to translate the LNPs that we are using for our preclinical evaluation to
clinical development in humans. In addition, we are exploring options for incorporating Cas9 into therapeutic products in multiple formats. For example, Cas9 can be delivered in its protein form or could be delivered as a nucleic acid, such as an
mRNA. For delivery of Cas9 mRNA, we are also investigating modifications that may improve expression and stability, as well as reduce the potential for an immune response. We plan to continue to further optimize LNP formats for a variety of
CRISPR/Cas9 therapeutic components, including templates for repair and insertion type edits. In parallel, we are exploring additional delivery vehicles, including synthetic particles and viral vectors, that we believe will allow us to target the
central nervous system, eye, muscle and other organs.
Ex vivo
delivery
Our
ex vivo
delivery approach is a clinically proven delivery method called electroporation, an electrical charge-based technique for
delivering molecules into cells. In parallel, we are exploring other delivery methods for
ex vivo
introduction of biological material to cells, which may provide advantages such as delivery efficiency. In human cells, we have been
able to achieve relatively high editing rates, including rates greater than 90%, of both copies of a single gene (bi-allelic editing), while preserving cell viability.
We have also simultaneously targeted multiple genes in an
ex vivo
setting and achieved high bi-allelic editing rates for both genes, demonstrating what
we believe to be therapeutically relevant editing of multiple genes simultaneously (multiplex editing). The ability to achieve multiplex editing may be critical in targeting certain diseases.
Our Pipeline
To accelerate the development and
commercialization of CRISPR/Cas9-based products in multiple therapeutic areas, we are targeting sentinel indications using
in vivo
and
ex vivo
approaches to demonstrate proof-of-concept of the various facets of our
technology, including the type of edit and CRISPR/Cas9 selectivity and efficiency. We believe that the learnings we gain from each indication will pave the way for rapid expansion of our pipeline by allowing us to target subsequent indications that
use the same or analogous delivery vehicles, guide structures and types of edits.
We believe that effective delivery methods will be important for the
clinical success of the CRISPR/Cas9 system. Our approach is to undertake a parallel effort on both
in vivo
and
ex vivo
delivery that leverages nearly two
10
decades of research and development in nucleic acid therapeutics and capitalizes on currently available, clinically and preclinically validated technologies, while developing next-generation
delivery methods optimized for the CRISPR/Cas9 system.
In Vivo
Pipeline
Our sentinel
in vivo
indications initially target chronic liver diseases, including ATTR, HBV, AATD and PH-1. Our initial efforts
on
in vivo
delivery focus on the use of LNPs for delivery of the CRISPR/Cas9 complex to the liver.
Transthyretin Amyloidosis Program
(Knockout Strategy)
Transthyretin (TTR) is a protein produced primarily in the liver, encoded by the
TTR
gene. This protein carries
retinol (vitamin A) and thyroxine (thyroid hormone) throughout the body. Certain mutations can cause the protein to aggregate and accumulate in tissues, resulting in a disorder called TTR-mediated amyloidosis (ATTR). Over 120 different genetic
mutations are currently known to cause ATTR. Protein accumulation in peripheral nerves or the heart can result in a severe loss of nerve or cardiac function. Mutations leading to nerve disease cause a syndrome called familial amyloidotic
polyneuropathy (FAP), whereas those leading to heart disease cause a syndrome called familial amyloidotic cardiomyopathy (FAC). Ongoing amyloid deposition in tissues due to disease progression results in the development of cardiomyopathy and other
cardiac symptoms observed in FAC patients. Typical onset of disease symptoms occurs during adulthood and can be fatal within two to 15 years. Estimates suggest that approximately 50,000 patients suffer from ATTR worldwide.
We believe that we can apply CRISPR/Cas9 technology to potentially cure ATTR by knocking out expression of the
TTR
gene in the liver. We expect
this approach to greatly reduce or eliminate the production of the TTR protein, which should slow or stop the accumulation of protein in the nerves and the heart. Current treatments and ongoing clinical trials in FAP have shown a significant
correlation between TTR reduction and clinical benefit. Additionally, these studies suggest that loss of
TTR
expression from the liver would be well-tolerated in adult humans. Accordingly, we believe targeting
TTR
genes
with CRISPR/Cas9 may improve patient outcomes by potentially eliminating defective TTR protein in a single or small number of treatments, as opposed to life-long therapy. We have begun to assess delivery of guide RNAs directed at
the
TTR
gene via LNPs and have achieved high levels of liver cell editing
in vitro
and
in vivo
as well as reduction of serum TTR protein in mice after a single intravenous administration, including
a 97% reduction in serum TTR protein driven by 70% gene editing efficiency in mouse liver, which have been maintained for at least four months in an ongoing study, as indicated in the figures below.
Mouse Liver Editing Rates and Serum TTR Protein Levels, Following a Single IV Administration
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Clinical Development Pathway
Our first in-human studies in ATTR are expected to take place in patients with ATTR who have started to exhibit symptoms related to amyloid deposition. The
key objective of these studies will be to show that the therapy can be delivered safely to the patient. A secondary objective will be to identify early indicators of efficacy, which may include reductions in serum levels of TTR protein. We expect
that the results of our preclinical studies, and discussions with the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) and other relevant regulatory agencies as well as patient advocacy groups will be important in informing
our trial design. Under our collaboration agreement, we expect to co-develop therapies targeting ATTR with Regeneron.
Hepatitis B Virus Program
(Knockout Strategy)
Hepatitis B is an infection of the liver caused by HBV that can progress from acute to chronic infection in approximately 5-10%
of infected adults. Chronic HBV can result in long-term health problems, including liver damage, liver failure, liver cancer or even death. Chronic HBV affects approximately 240 million people globally and contributes to an estimated 786,000
deaths each year. In the United States, an estimated 700,000 to 1.4 million persons have chronic HBV, with 2,000 to 4,000 HBV-related deaths per year.
We believe that treatment of HBV with a CRISPR/Cas9-based therapeutic has the potential to cure the disease as it could eradicate cccDNA reservoirs with one
or a few treatment courses. For this therapeutic program, we intend to use a knockout strategy to destroy or render inactive the copies of HBV cccDNA in infected human cells. We believe this therapy could offer a significant improvement over
existing treatment options that are life-long and do not cure the disease. We believe it is also possible that a common treatment solution can be developed for all genotypes of HBV through targeting portions of the cccDNA sequences that are the same
across genotypes. In addition, there is potential to reduce viral resistance as the virus itself is eradicated.
According to published research studies,
CRISPR/Cas9-mediated cuts can significantly reduce intracellular levels of cccDNA when tested
in vitro
. We believe we can use the CRISPR/Cas9 system to help eliminate the reservoirs of cccDNA in infected HBV patients. We intend to
evaluate different knockout approaches to eliminate cccDNA
in vivo
, including cleaving the cccDNA in various individual or a combination of locations.
We have completed a bioinformatic analysis of potential CRISPR/Cas9 target sites in the HBV genome to select a set of guide RNAs, including several which can
be effective across all HBV genotypes. We have identified potential CRISPR/Cas9 target sites by examining the known sequences of HBV isolated from patients and screening guide RNAs targeting the HBV genome. We use a variety of methods to screen
these guides for editing and cccDNA reduction activity. The lead guide RNAs from this screen will be assessed for their ability to prevent infection and propagation of HBV, and evaluated for off-target effects, in both cell and animal models of HBV.
Clinical Development Pathway
We expect our
clinical development path to indicate evidence of safety and antiviral activity in patients infected with HBV. The key study objective will be to show that the therapy can be delivered safely to the patient, with a secondary objective of identifying
early indicators of antiviral effect. We expect that the results of our preclinical studies and discussions with the FDA, EMA and other relevant regulatory agencies as well as with the HBV community, will be important for selecting the appropriate
patients and endpoints for our clinical trials.
Alpha-1 Antitrypsin Deficiency
Program (Knockout and Repair Strategies)
AATD is an inherited genetic disorder that may cause lung or liver disease. The lung disease may result in
chronic obstructive pulmonary disease (COPD), a progressive disease that causes substantial morbidity and mortality while the liver disease is characterized by inflammation and cirrhosis of the liver. In the United States, an estimated 60,000 to
100,000 people have AATD, which is the result of a mutation in the
SERPINA1
gene that
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normally produces secreted alpha-1 antitrypsin (AAT) protein. AAT is a protease inhibitor that blocks the activity of various enzymes such as neutrophil elastase, which is an enzyme that fights
infections, but when not adequately controlled by AAT, can attack normal tissues, such as lung tissue.
The most common form of AATD arises when a patient
has a mutation in both copies of the
SERPINA1
gene, which causes AAT to aggregate inside hepatocytes, a sub-population of liver cells, rather than being secreted from the liver. The inability to secrete AAT leaves the lung
unprotected from neutrophil elastase and can result in pulmonary disease. The pulmonary consequences of AATD can sometimes culminate in COPD. Estimates suggest that between 1% and 2% of all cases of COPD in the United States have AATD as the
underlying cause. In some patients, AAT accumulates in the liver, causing liver inflammation and cirrhosis, which leads to liver damage, scarring and in the most severe cases, liver failure or cancer. Liver disease associated with AATD is diagnosed
from infancy to adulthood, whereas lung disease is most common in adult patients.
We believe that we can apply the CRISPR/Cas9 technology to cure AATD by
addressing the defective
SERPINA1
gene. We intend to evaluate two editing approachesa knockout and a repair. Our knockout program for AATD will be best suited for patients with AATD-associated liver disease, as there is
currently no effective way to reduce the accumulation of mutated AAT in the liver. With this strategy, we intend to eliminate production of the aberrant form of AAT by knocking out the mutated
SERPINA1
gene with a Cas9-mediated cut.
We believe this knockout will halt the production and accumulation of AAT in the liver but will not by itself address the lack of AAT circulation that leads to lung disease. Therefore, in this approach, we expect that patients with AATD-associated
lung disease may have to be treated with other therapies, such as plasma protein supplementation to achieve levels of the normal form of AAT to be active against the lung disease.
We believe our repair approach for AATD will address the lung disease as well as the liver disease. With this strategy, we intend to correct the
mutated
SERPINA1
gene, which we believe will eliminate production of the aberrant form of AAT and also establish production of the normal protein in the liver. We believe this correction will reduce or eliminate liver inflammation
and increase levels of normal circulating AAT, which should protect the lung from neutrophil elastase, thereby reducing or eliminating the need for other therapies, such as plasma protein augmentation therapy. There is preclinical evidence that
hepatocytes with normal AAT may possess a growth advantage over those that express the mutated form, suggesting that repair of only a limited number of hepatocytes might be sufficient to address this disease. We expect the progress of this program
to follow our AATD knockout program. Depending on the results of our studies and potential development requirements and timelines, we may decide to pursue one or both of our knockout and repair programs in clinical development.
Clinical Development Pathway
For both our knockout and
repair strategies, our first in-human studies are expected to take place in patients with AATD. The key objective of these studies will be to show that the therapy can be delivered safely to the patient. A secondary objective will be to identify
early indicators of efficacy, which may include reductions in levels of mutated AAT protein, increases in production of normal circulating AAT protein and the required tests for determining liver and lung function. We will also seek to observe
whether we have achieved pre-determined levels of properly functioning AAT in the blood, which has been used historically as a biomarker for approval of augmentation therapy approaches. We expect that the results of our preclinical studies and
discussions with the FDA, EMA and other relevant regulatory agencies as well as the AATD community will be important for selecting the appropriate patients and endpoints for our clinical trials.
Inborn Errors of Metabolism (IEM) Program (Knockout, Repair and Insertion Strategies)
IEMs span a range of conditions, many severe or fatal, and frequently untreatable. Current treatment options for many IEMs are unsatisfactory and often
include bone marrow or liver transplants, which pose the challenge of serious side effects including high risk of mortality in some cases. Individual IEMs are rare disorders, many having an incidence of fewer than 1 in 100,000 births. These diseases
typically involve defects in single genes that code for enzymes that facilitate the metabolism of certain cellular components. Mutations in these enzymes can result in accumulation of metabolic intermediates, which are molecules that are precursor
compounds in the
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chemical pathway leading to final metabolic products, that are toxic or interfere with normal biology. We are evaluating a large set of candidate IEMs, including primary hyperoxaluria type 1
(PH-1), our lead IEM program; argininosuccinic lyase deficiency; ornithine transcarbamylase deficiency; phenylketonuria (PKU) and maple syrup urine disease. Our selection criteria for our initial IEM indications include identifying diseases that
originate in the liver, have well-defined mutations that can be addressed by a single knockout, repair or insertion approach, have readily measurable therapeutic endpoints with observable clinical responses, and for which there are no effective
treatments.
Ex Vivo
Pipeline
Our sentinel
ex vivo
programs are in CAR-T cell and HSC applications. Under our strategic collaboration with Novartis, our CAR-T cell program
is exclusive to Novartis. We retain the right to develop and commercialize certain of the HSC programs that we discover with Novartis while others will be proprietary to Novartis. Our
ex vivo
programs will help inform the broader
applicability of CRISPR/Cas9 in other relevant types of immune cells, such as T cells, NK cells and TILs, in addition to potential applications in other cell types such as induced pluripotent stem cells, mesenchymal stem cells and muscle satellite
stem cells.
For our
ex vivo
programs requiring delivery to extracted cells such as HSCs or T cells, we initially plan to deliver the
CRISPR/Cas9 complex by electroporation. In parallel with electroporation, we are exploring alternative technologies for delivery to cells
ex vivo
that may provide advantages in delivery efficiency or cell viability.
CAR-T Cell Program
CAR-T cell therapies are currently
being developed for blood cancers, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), multiple myeloma (MML) and chronic lymphocytic leukemia (CLL). In CAR-T cell therapy, naturally-occurring immune cells, specifically T
cells, are modified
ex vivo
by inserting a chimeric antigen receptor (CAR) into the T cells, thereby activating an immune response against cancer cells. CAR-T cell products, including Novartis CAR-T cell candidate, CTL019,
have shown clinical promise in addressing hematological malignancies such as ALL. While existing CAR-T cell products have shown great clinical promise, they can benefit from the application of CRISPR/Cas9 in multiple ways.
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CRISPR/Cas9 could be used to create a universal donor CAR-T cell by knocking out cell surface markers that cause a patients immune system to recognize another persons cells as foreign. Allowing multiple
patients to be treated using cells from a single donor could significantly streamline manufacturing and make CAR-T cell therapy more widely accessible.
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CRISPR/Cas9 could be used to modify the T cells to enhance their survival or activity against cancer cells.
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CRISPR/Cas9 could be used to introduce the CAR into a precise location with a specific integrated copy number, as opposed to the current method involving semi-random integration, thus potentially improving the safety
profile of the resulting cells.
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CRISPR/Cas9 could be used to knockout one or more of the proteins believed to be responsible for certain serious side effects that can result in dangerously high fevers or severe loss of blood pressure.
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We could potentially combine two or more of these approaches to further enhance CAR-T cell therapy.
HSC Program
HSCs are the stem cells from which all of
the various types of blood cells originate. HSCs can fully repopulate a patients blood system following transplantation of bone marrow, mobilized peripheral blood or cord blood, which contain HSCs. There are multiple potential opportunities
for treating patients using engineered HSCs, including to treat three common classes of blood-related disorders such as hemoglobin disorders, including sickle cell disease and beta thalassemia. There are limited treatment options available for these
types of blood disorders, and available options typically require chronic blood transfusions or bone marrow transplants. These
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procedures are associated with significant risk, including mortality. We believe the CRISPR/Cas9 system can be used to potentially provide curative benefits by correcting the underlying genetic
defect in blood cells of patients with these disorders. In additional applications, normal HSCs may be engineered
ex vivo
using CRISPR/Cas9 to express a therapeutic protein, which is then administered to patients in need of that
protein.
Challenges of developing stem cell products can include the relatively low quantity of available cells for treatment and a limited ability to
expand HSCs
ex vivo
. We expect to counter these challenges, if necessary, by employing a proprietary small molecule for HSC expansion to which Novartis has granted us rights. This small molecule could allow us to generate larger numbers
of HSCs for re-implantation in patients after editing. We expect that the application of this technology will improve the performance of the blood cell graft and improve patient outcomes and recovery times as more therapeutic cells can be
administered.
We are pursuing a number of potential gene targets and therapeutic indications in collaboration with Novartis. Under our collaboration with
Novartis, we and Novartis each have the right to designate a fixed number of HSC therapeutic targets during multiple selection windows, with Novartis having the right of first target selection. Our selection criteria for development programs
include, among others, disease severity, existing treatment options, delivery efficiency, the nature of the genetic edit required and the expected performance of cells modified by the procedure.
CAR-T Cell and HSC Development Collaboration with Novartis
Under this collaboration, we received an upfront technology access payment from Novartis of $10.0 million and are entitled to up to an additional
$40.0 million, in the aggregate, in additional technology access fees and research payments during the five-year collaboration term, subject to certain credits and adjustments in favor of Novartis. In addition, we are eligible to earn up to
$230.3 million in development, regulatory and sales-based milestone payments and mid-single-digit royalties, in each case, on a per-product basis for the products developed by Novartis, subject to certain target-based limitations. For more
information regarding our ongoing collaboration with Novartis, see the section below entitled CollaborationsNovartis Institutes for BioMedical Research, Inc.
Collaborations
To accelerate the development and
commercialization of CRISPR/Cas9-based products in multiple therapeutic areas, we have formed, and intend to seek other opportunities to form, strategic alliances with collaborators who can augment our leadership in CRISPR/Cas9 therapeutic
development.
Novartis Institutes for BioMedical Research, Inc.
In December 2014, we entered into a strategic collaboration agreement with Novartis, primarily focused on the
ex vivo
development of new
CRISPR/Cas9-based therapies using CAR-T cells and HSCs.
Under the terms of the collaboration, we and Novartis may research potential therapeutic,
prophylactic and palliative
ex vivo
applications of our CRISPR/Cas9 platform in HSCs and CAR-T cells. The collaboration is also governed by research plans for each of the HSC and CAR-T cell programs that outline the parties
responsibilities under, anticipated timelines of and budgets for the programs, and is overseen by a joint steering committee (JSC) formed by representatives from both companies. Among other activities, the JSC reviews the collaboration program and
forms subcommittees to evaluate and nominate the pool of potential research targets under and approve the research plans for the HSC and CAR-T cell programs.
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Within the HSC therapeutic space, Novartis may obtain exclusive rights to a limited number of HSC targets, to be
chosen by Novartis in multiple selection windows. We have the right to choose a limited number of HSC targets for our exclusive development and commercialization per the specified selection schedule. Following these selections by Novartis and us,
Novartis may obtain rights to research an additional limited number of HSC targets on a non-exclusive basis. Novartis is required to use commercially reasonable efforts to research, develop, and commercialize a specified number of HSC products
directed to each of their selected HSC targets.
We have also agreed to collaborate with Novartis on research activities for CAR-T cell targets pursuant
to the CAR-T cell program research plan approved by the CAR-T cell subcommittee of the JSC. After completion of the research activities contemplated by the CAR-T cell program research plan, Novartis will assume sole responsibility for developing any
products arising from that research plan and the costs and expenses of developing, manufacturing and commercializing selected research targets. Novartis is required to use commercially reasonable efforts to research, develop or commercialize at
least one CAR-T cell product directed to each of the selected CAR-T cell targets.
In the last two years of the five-year collaboration term, Novartis
will have the option to select a limited number of targets for research, development and commercialization of
in vivo
therapies using our CRISPR/Cas9 platform, on a non-exclusive basis. Following Novartis selection of
each
in vivo
target, Novartis may offer us the right to participate in the research and development of such targets, in which case an
in vivo
program research plan for such target will be entered into between us and
Novartis. Novartis is required to use commercially reasonable efforts to research, develop and commercialize at least one
in vivo
product directed to each of their selected
in vivo
targets. Novartis
in
vivo
target selections are subject to certain restrictions, including that the targets, or all targets within a limited number of organs: (i) have not already been reserved by us pursuant to our limited right to do so under the
agreement; (ii) are not the subject of an existing out-license of our CRISPR/Cas9 platform to a third party; and (iii) are not the subject of ongoing or planned research and development by us.
During the collaboration term, with respect to the HSC and CAR-T cell programs, and for as long as the applicable party continues to use commercially
reasonable efforts to research, develop and commercialize the HSC, CAR-T cell and
in vivo
products contemplated by the agreement, neither party may collaborate with a third party with regard to the activities contemplated by the
HSC, CAR-T cell or
in vivo
programs nor grant licenses to practice such partys intellectual property licensed under the agreement in the selected HSC or CAR-T cell or
in vivo
field to a third party.
Following the collaboration term, if Novartis fails to comply with its obligation to research, develop and commercialize at least one HSC or CAR-T cell product, we will have the right to terminate Novartis exclusive rights with respect to the
selected HSC or CAR-T cell target and terminate Novartis license to practice our intellectual property licensed under the agreement in such applicable target.
Under the agreement, we received an upfront technology access payment of $10.0 million and are entitled to additional technology access fees of $20.0
million and quarterly research payments of $1.0 million, or up to $20.0 million in the aggregate, during the five-year research term. In addition, for each product under the collaboration, subject to certain conditions, we may be eligible to receive
(i) up to $30.3 million in development milestones, including for the filing of an investigational new drug application and for the dosing of the first patient in each of Phase IIa, Phase IIb and Phase III clinical trials, (ii) up to $50.0
million in regulatory milestones for the products first indication, including regulatory approvals in the U.S. and the EU, (iii) up to $50.0 million in regulatory milestones for the products second indication, if any, including U.S.
and EU regulatory approvals, (iv) royalties on net sales in the mid-single digits, and (v) net sales milestone payments of up to $100.0 million. We may also be eligible to receive payments for: (i) each additional HSC target selected
by Novartis beyond its initial defined allocation, (ii) each
in vivo
target that Novartis selects and (iii) any exercise by Novartis of certain license options under the agreement. Additionally, at the inception of the
arrangement, Novartis invested $9.0 million to purchase our Class A-1 and Class A-2 Preferred Units. The difference between the cash proceeds received from Novartis for the units and the $11.6 million estimated fair value of those
units at the date of issuance was determined to be $2.6 million. Accordingly, $2.6 million of the upfront technology access payment was allocated to record the preferred units purchased by Novartis at fair value.
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We granted to Novartis a license to our CRISPR/Cas9 platform technology and Novartis granted us a non-exclusive
license to its small molecule for HSC expansion and to its LNP platform technology to research, develop and commercialize HSC and
in vivo
products, respectively. Our license grant to Novartis of our CRISPR/Cas9 platform technology, including
a sublicense to certain platform rights licensed from Caribou, is exclusive in the HSC, CAR-T cell and
in vivo
fields with respect to each target selected by Novartis pursuant to the agreement and the research plan as long as
Novartis continues to use commercially reasonable efforts to research, develop, and commercialize products directed to such targets. Upon the expiration of the collaboration term, Novartis shall have the option to access and obtain a non-exclusive
license to our CRISPR/Cas9 platform technology to research, develop and commercialize potential therapeutic, prophylactic and palliative products and services for a limited number of certain approved targets selected by Novartis, exercisable upon
written notice to us within a specified time after the expiration of the collaboration term. Such approved targets are subject to certain restrictions, including that the targets may not have been already reserved by us pursuant to our limited right
to do so under the agreement, may not be the subject of an existing out license of our CRISPR/Cas9 platform to a third party and may not be the subject of ongoing or planned research and development by us. This non-exclusive license will have a term
of five years commencing upon the completion of the technology transfer by us enabling Novartis to practice such licensed rights, and Novartis may not select more than a specified number of approved targets in each year of this license term.
Intellectual property developed out of the collaboration related to our CRISPR/Cas9 platform will be owned solely by us, while all other intellectual property
developed out of the collaboration, including intellectual property covering products arising from the collaboration, will be jointly owned by us and Novartis.
The collaboration term ends in December 2019. The term of the agreement expires on the later of (i) the expiration of Novartis payment obligations
under the agreement and (ii) the date of expiration of the last-to-expire of the patent rights licensed to us or Novartis under the agreement. Novartis royalty payment obligations expire on a country-by-country and product-by-product
basis upon the later of (i) the expiration of the last valid claim of the royalty-bearing patents covering such product in such country or (ii) 10 years after the first commercial sale of such product in such country. We may terminate the
agreement if Novartis or its affiliates institute a patent challenge against our intellectual property rights, and all improvements thereto, licensed to Novartis under the agreement. Novartis may terminate the agreement, without cause, upon
90 days written notice to us subject to certain conditions, including its payment of any accrued and future obligations as if the collaboration had continued through December 2019. Novartis may terminate the agreement if the owners or
licensees of U.S. patent 8,697,359 bring a suit against Novartis on or before December 31, 2017 claiming that the activities specifically contemplated by the collaboration research plans infringe an independent claim of such patent. Either
party may terminate the agreement in the event of the other partys uncured material breach or bankruptcyor insolvency-related events.
Regeneron Pharmaceuticals, Inc.
In April 2016,
we entered into a license and collaboration agreement with Regeneron. The agreement includes a product component to research, develop and commercialize CRISPR/Cas-based therapeutic products primarily focused on gene editing in the liver as well as a
technology collaboration component, pursuant to which we and Regeneron will engage in research and development activities aimed at discovering and developing novel technologies and improvements to CRISPR/Cas technology to enhance our gene editing
platform. Under this agreement, we also have the ability to access the Regeneron Genetics Center and proprietary mouse models to be provided by Regeneron for a limited number of our liver programs.
Under the terms of our collaboration, we and Regeneron have agreed to a target selection process, whereby Regeneron may obtain exclusive rights for up to ten
targets to be chosen by Regeneron during the collaboration term, subject to various adjustments and limitations set forth in the agreement. Of these ten total targets, Regeneron may select up to five non-liver targets, while the remaining targets
will be focused in the liver.
At the inception of the agreement, Regeneron selected the first of its ten targets, which will be subject to a
co-development and co-commercialization arrangement between us and Regeneron. We retain the exclusive right to
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solely develop products for certain indications. During the target selection process, we have the right to choose additional liver targets for our own development using commercially reasonable
efforts. Certain targets that either we or Regeneron select may be subject to further co-development and co-commercialization arrangements at our or Regenerons option, as applicable. In addition, subject to certain restrictions, Regeneron will
be able to replace a limited number of targets with substitute targets upon the payment of a specified replacement fee, in which case exclusive rights to the replaced target revert to us. Regenerons target selections are subject to certain
additional restrictions, including that non-liver targets are not the subject of ongoing or planned research and development by us or are not the subject of a collaboration or pending collaboration with a third party.
Research activities under the collaboration will be governed by evaluation and research and development plans that will outline the parties
responsibilities under, anticipated timelines of and budgets for, the various programs. We will assist Regeneron with the preliminary evaluation of liver targets, and Regeneron will be responsible for preclinical research and the conduct of clinical
development, manufacturing and commercialization of products directed to each of its exclusive targets under the oversight of the joint steering committee. We may assist, as requested by Regeneron, with the later discovery and research of product
candidates directed to any selected target. For each selected target, Regeneron is required to use commercially reasonable efforts to submit regulatory filings necessary to achieve initial investigational new drug (IND) acceptance for at least one
product directed to each applicable target, and following IND acceptance for at least one product, to develop and commercialize such product.
In
connection with this collaboration, Regeneron agreed to purchase $50.0 million of our common stock in a private placement, and we received a nonrefundable upfront payment of $75.0 million. In addition, we are eligible to earn, on a per-licensed
target basis, up to $25.0 million, $110.0 million and $185.0 million in development, regulatory and sales-based milestone payments, respectively. We are also eligible to earn royalties ranging from the high single digits to low teens, in each case,
on a per-product basis, which royalties are potentially subject to various reductions and offsets and are further subject to our existing low single-digit royalty obligations under our Caribou license agreement. In addition, Regeneron is obligated
to fund 50.0% of the agreed-upon research and development costs for the TTR program, the first target selected by Regeneron, which will be subject to a co-development and co-commercialization arrangement between us and Regeneron.
We have granted Regeneron exclusive rights to develop and commercialize products directed to its selected targets. The parties will jointly own intellectual
property created as part of the technology collaboration and target-specific research plans, subject to certain exceptions where Regeneron will solely own certain intellectual property specific to its products and we will solely own certain
CRISPR/Cas intellectual property arising during target evaluation activities. Each party has granted the other party specified intellectual property licenses to enable the other party to perform its obligations and exercise its rights under the
agreement, including license grants to enable each party to conduct research, development and commercialization activities pursuant to the terms of the agreement.
The collaboration term ends in April 2022, provided that Regeneron may make a one-time payment of $25.0 million to extend the term for an additional two-year
period. The agreement will continue until the date when no royalty or other payment obligations are due, unless earlier terminated in accordance with the terms of the agreement. Regenerons royalty payment obligations expire on a
country-by-country and product-by-product basis upon the later of (i) the expiration of the last valid claim of the royalty-bearing patents covering such product in such country, (ii) 12 years from the first commercial sale of such product
in such country, or (iii) the expiration of regulatory exclusivity for such product. We may terminate the agreement on a target-by-target basis if Regeneron or any of its affiliates institutes a patent challenge against our CRISPR/Cas or
certain other background patent rights. We may also terminate the agreement on a target-by-target basis if Regeneron does not proceed with the development of a product directed to a selected target within specified periods of time. Regeneron may
terminate the agreement, without cause, upon 180 days written notice to us, either in its entirety or on a target-by-target basis, in which event, certain rights in the terminated targets and associated intellectual property revert to us, as
described in the agreement. Following such termination, we will owe Regeneron
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royalties in the low to mid-single digits on any terminated targets that we subsequently commercialize on a product-by-product basis for a period of 12 years after the first commercial sale of
any such products. Either party may terminate the agreement either in its entirety or with respect to the technology collaboration or one or more of the targets selected by Regeneron, in the event of the other partys uncured material breach.
Potential Future Collaborations
We view
strategic partnerships as important drivers for helping accelerate our goal of rapidly treating patients. The potential application of CRISPR/Cas9 is extremely broad, and we plan to continue to identify partners who can contribute meaningful
resources and insights to our programs and allow us to more rapidly expand our impact to broader patient populations.
Intellectual Property
We believe we are well positioned in terms of our intellectual property because we:
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have built, and intend to expand, a broad worldwide portfolio of intellectual property, including patents and patent applications, in areas relevant to the development and commercialization of human therapeutic products
using CRISPR/Cas9 technology;
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protect our intellectual property by maintaining trade secrets relating to our proprietary technology innovations and know-how; and
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intend to take additional steps, where appropriate, to further protect our intellectual property rights, including, for example, through the use of copyright protection and regulatory protection available via orphan
drug designations, data exclusivity, market exclusivity, and patent term extensions.
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Our licensed patent portfolio encompasses foundational
filings on the use of CRISPR/Cas9 systems for gene editing, improvement modifications of these CRISPR systems, LNP technologies for delivering protein/nucleic acid complexes and RNA into cells, and cell expansion technology relevant to stem
cell-based therapies. We access these patent estates through licenses from Caribou Biosciences, Inc. (Caribou) and Novartis. We also actively apply for, maintain, and plan to defend and enforce, as needed, our internally developed and externally
licensed patent rights. Furthermore, we continue to search for and evaluate opportunities to in-license intellectual property relevant to our targeted therapeutic programs and platforms and to develop and acquire new intellectual property in
collaboration with third parties.
Our portfolio of patent rights includes the following:
Caribou Biosciences In-Licensed Intellectual Property
In July 2014, we entered into a license agreement with Caribou, as subsequently amended and supplemented, for an exclusive, worldwide license for human
therapeutic, prophylactic, and palliative uses, except for anti-fungal and anti-microbial uses, defined in the license agreement as our field of use, of any CRISPR/Cas9-related patents and applications owned, controlled or licensed by Caribou as
well as companion diagnostics to our product or product candidates. The license agreement also included exclusive rights in our field of use to any CRISPR/Cas9-related intellectual property developed by Caribou after July 16, 2014 and through a
future cut-off date to be determined when conditions defined in the agreement occur. The agreement further includes a non-exclusive research license to conduct research and development on product candidates and products. The Caribou licensed patent
portfolio includes several U.S. and foreign patents and patent applications owned by Caribou and U.S. and foreign patents and patent applications co-owned by The Regents of the University of California, the University of Vienna and
Dr. Emmanuelle Charpentier, as well as U.S. and foreign patents and patent applications owned or controlled by Pioneer Hi-Bred and its affiliates. We have the right to grant sublicenses to the Caribou licensed patent portfolio to third
parties in our field of use. Caribou retains the right to practice the licensed intellectual property in all other fields, including for its own specific therapeutics purposes, provided it does not pertain to the application of CRISPR/Cas9
technology to the development of products in our field of use.
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Pursuant to a services agreement entered into with Caribou in parallel with the license agreement, we also
received two years of research and development services from Caribou, which ended in November 2016. Any intellectual property developed under the services agreement is owned by Caribou and is included in, and subject to the terms of, our license
agreement with Caribou.
In relation to our founding, we issued Caribou 8,110,599 shares of our junior preferred stock. We paid Caribou $5.0 million over
the term of the two-year services agreement; and have agreed to pay 30.0% of Caribous patent prosecution, filing, and maintenance costs for the intellectual property included in the license agreement amounting to a total of $2.1 million
paid through December 31, 2016. We also granted Caribou an exclusive, royalty-free, worldwide license, with the right to sublicense, to any CRISPR/Cas9 patents, patent applications and know-how in Caribous retained fields of use owned or
developed by us between July 16, 2014 and a future cut-off date to be determined when conditions defined in the agreement occur. Caribou, which is obligated to pay a portion of our patent filing, prosecution and maintenance costs for any such
licensed intellectual property, also has an option to sublicense any CRISPR/Cas9 intellectual property in-licensed by us for uses and activities in its retained field of use.
The Caribou license agreement grants us sublicenses in our field of use to intellectual property in-licensed by Caribou from The Regents of the University of
California and the University of Vienna. Further, under the license agreement, we had an option to sublicense for our field of use any new intellectual property in-licensed by Caribou through a future cut-off date to be determined when conditions
defined in the agreement occur. In July 2015, we exercised our option to sublicense a portfolio in-licensed by Caribou from Pioneer Hi-Bred International, according to the terms described below.
The term of the Caribou license is until the expiration of the last-to-expire patent right that is licensed to either party. We must use commercially
reasonable and diligent efforts to research, develop, manufacture and commercialize at least one product. Either party may terminate the agreement in the event of the other partys uncured material breach, bankruptcy or insolvency-related
events, or breach of its obligations with respect to the included in-licenses. The license agreement with Caribou also gives us access, in our field of use, to Caribou internally developed IP. Since March 2013, Caribou has filed over 50 patent
applications in the United States and internationally, which relate to the CRISPR/Cas platform, including modified and improved CRISPR/Cas9 systems or components, and methods of use that are part of our license. We cannot ensure that these
applications will lead to issued claims that cover our products or activities. Any patents that grant from these applications will expire in or after 2034, assuming payment of necessary maintenance fees.
The Regents of the University of California and the University of Vienna IP
The Regents of the University of California and the University of Vienna (collectively, UC/Vienna) co-own a worldwide patent portfolio with
Dr. Emmanuelle Charpentier, which covers methods of use and compositions relating to engineered CRISPR/Cas9 systems for, among other things, cleaving or editing DNA and altering gene product expression in various organisms, including humans. We
refer to this co-owned worldwide patent portfolio as the UC/Vienna/Charpentier patent family. The earliest claimed priority date for this patent family is May 25, 2012. As of March 31, 2016, this family does not yet contain any issued
patents in the United States, but two patents have been granted by the United Kingdom Intellectual Property Office and corresponding applications are being prosecuted in the European Patent Office and other regional and national offices. Any patents
that ultimately issue from this family and are appropriately maintained will expire in or after [2033].
Caribou entered into an exclusive, worldwide
license in all fields, with the right to sublicense, for this patent family with UC/Vienna in April 2013 solely under UC/Vienna ownership rights. Caribous license remains in effect for the life of the last-to-expire patent or
last-to-be-abandoned patent application licensed, whichever is later. Through our license agreement with Caribou, we have an exclusive sublicense to UC/Viennas interest in this foundational CRISPR/Cas9 patent family for use in human
therapeutics, except for anti-fungal and anti-microbial uses as defined in the license agreement as our field of use. For products covered by this license and
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their companion diagnostics, we will owe low single-digit royalties on net sales. In addition, we may be subject to milestone payments of $0.1 million upon the first filing of an investigational
new drug application, a total of $0.5 million for Phase II and Phase III clinical trials, $0.5 million to $1.0 million for each of the first three approved new drug applications or biologics license applications in the United States, and $0.2
million for each of the first three approved indications in Europe. Caribou has the right to terminate its agreement with UC/Vienna at any time or the agreement may be terminated due to an uncured material breach. We cannot guarantee that Caribou
will maintain the UC/Vienna license for its full term. Should the license between Caribou and UC/Vienna be terminated for any reason, any compliant Caribou sublicenses as of the termination date will remain in effect and will be assigned to
UC/Vienna in place of Caribou. Specifically, if we are in compliance with our obligations under our sublicense and Caribou and UC/Vienna terminate their agreement, we would become UC/Viennas direct licensee instead of Caribou.
On April 13, 2015, UC/Vienna and Dr. Charpentier (collectively, UC/Vienna/Charpentier) jointly filed a request with the United States Patent and
Trademarks Office (USPTO) asking that an interference be declared between the UC/Vienna/Charpentier patent application and certain patents issued to the Broad Institute, Massachusetts Institute of Technology and the President and Fellows of Harvard
College (collectively, the Broad Institute patent family), which claim aspects of CRISPR/Cas9 systems and methods to edit genes in eukaryotic cells, including human cells. The Broad Institute patent family includes, for example, US 8,697,359, issued
on April 15, 2014. The earliest claimed priority date for the Broad Institute patent family is December 12, 2012. On January 11, 2016, the Patent Trial and Appeal Board (PTAB) of the USPTO declared an interference involving one
UC/Vienna/Charpentier application, 12 Broad issued patents and a Broad patent application. On February 15, 2017, the interference was dismissed by the PTAB after holding that UC/Vienna/Charpentiers claims in the interference, which are
broader in scope in that they are not restricted to use in eukaryotic cells, did not render obvious the claims from the Broad Institute patent family, which are all limited to use in eukaryotic cells. As a result of the PTABs decision, the
interference between the particular UC/Vienna/Charpentier patent application and the Broad patents and patent applications is terminated, subject to a timely appeal by UC/Vienna/Charpentier to the U.S. Court of Appeals for the Federal Circuit. If
UC/Vienna/Charpentier do not appeal, their patent application that was the subject of the interference may be prosecuted to potential issuance. In addition, UC/Vienna/Charpentier continue to prosecute other patent claims covering the CRISPR/Cas9
inventions, which could also result in allowable or issued patents in the United States. Certain of the claims being prosecuted by UC/Vienna/Charpentier, if found allowable by the USPTO, could lead to interference proceedings against patents or
patent applications owned by other parties, including the Broad Institute patent family with respect to certain claims relating to the use of CRISPR/Cas9 in eukaryotic cells. We cannot be certain which of these results, if any, will actually occur
or at what time, and the effects that any such results may have on us and our intellectual property position are currently unknown.
Pioneer Hi-Bred
International (DuPont Company) IP
Pioneer Hi-Bred and its affiliates, including the DuPont Company, have licensed to Caribou on a worldwide basis
various patent families relating to CRISPR/Cas systems, components and methods of use generally and CRISPR/Cas9 specifically in certain fields, which include Intellias field of use under our license agreement with Caribou. In July 2015, we
exercised our option under the license agreement with Caribou to sublicense these Pioneer patent families in our field of use. The license from Pioneer to Caribou will expire upon the expiration, abandonment or invalidation of the last patent or
patent application licensed from Pioneer to Caribou.
The licensed Pioneer portfolio includes a family of applications filed by Vilnius University that
discloses the components of a CRISPR/Cas9 system required for gene editing in non-bacterial organisms. In March 2017, the USPTO allowed claims covering the
in vitro
assembly and use of a recombinant CRISPR/Cas9 complex to modify DNA, which
could lead to the grant and issuance of a patent if Pioneer meets certain other procedural requirements. Patents obtained from this patent family will expire in or after 2033, assuming payment of necessary maintenance fees. We cannot ensure that
these applications will lead to issued claims that cover our products or activities.
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Invention Management Agreement
On December 15, 2016, we entered into a Consent to Assignments, Licensing and Common Ownership and Invention Management Agreement (the Invention
Management Agreement), with The Regents of the University of California, University of Vienna, Dr. Charpentier, Caribou, CRISPR Therapeutics AG, ERS Genomics Ltd. and TRACR Hematology Ltd. Under the Invention Management Agreement,
Dr. Charpentier retroactively consented to UC/Viennas CRISPR/Cas9 license to Caribou as well as Caribous sublicensing to Intellia certain of its rights to the UC/Vienna/Charpentier CRISPR/Cas9 intellectual property, subject to the
restrictions of our license from Caribou. Under the agreement, the parties commit to maintain and coordinate the prosecution, defense and enforcement of the CRISPR/Cas9 foundational patent portfolio worldwide, and each of the co-owners of the
intellectual property grants cross-consents to all existing and future licenses and sublicenses based on the rights of another co-owner. The Invention Management Agreement also includes retroactive approval by certain parties of certain prior
assignments of interests in patent rights to other parties, and provides for, among other things, (i) good faith cooperation among the parties regarding patent maintenance, defense and prosecution, (ii) cost-sharing arrangements, and
(iii) notice of and coordination in the event of third-party infringement of the subject patents. Unless earlier terminated by the parties, the Invention Management Agreement will continue in effect until the later of the last expiration date
of the UC/Vienna/Charpentier patents underlying the CRISPR/Cas9 technology, or the date on which the last underlying patent application is abandoned.
Novartis In-Licensed Intellectual Property
Our
December 2014 strategic collaboration and license agreement with Novartis grants us worldwide, non-exclusive, royalty-free rights to a portfolio of 14 Novartis patent families containing granted patents and pending applications in the United States
and internationally relating to LNP compositions, methods of use and modified nucleic acids. The license permits us to use the Novartis LNPs to develop therapeutic, prophylactic, and palliative CRISPR-based
in vivo
products. The
earliest claimed priority dates for the licensed patent families range from December 2009 through June 2013, and accordingly will expire by or after December 2030. The term of the license continues until the expiration of the last-to-expire patent
right that is licensed to either party. If we attempt to challenge any of the patents in the licensed families, Novartis may terminate the license on a patent-by-patent basis. We cannot guarantee that our products or delivery methods will be covered
by issued claims in these families.
In addition, Novartis has also granted us rights to use its proprietary small molecule for HSC expansion. Our rights
to this technology are subject to a single-digit royalty based on whether we develop and commercialize the relevant product solely or in collaboration with another third party.
Under our agreement with Novartis, any platform intellectual property developed as part of the collaboration is owned solely by us, while all other
intellectual property developed out of the collaboration, including product-based intellectual property, is jointly owned by us and Novartis. We cannot guarantee that intellectual property filed based on collaboration data will result in issued
claims covering our products or delivery methods. Under our agreement with Novartis, we have also granted Novartis a sublicense to the intellectual property we license under our agreement with Caribou for the Novartis-selected HSC and CAR-T cells
products, and
in vivo
products if applicable, with such sublicense being exclusive as long as Novartis uses commercially reasonable efforts to develop and commercialize those products.
Manufacturing
We currently have no commercial
manufacturing or cell processing capabilities. We are exploring qualified third-party organizations to produce or process bulk compounds, formulated compounds, viral vectors or engineered cells for IND-supporting activities and early stage clinical
trials. We expect that commercial quantities of any compound, vector, or engineered cells that we may seek to develop will be manufactured in facilities and by processes that comply with FDA and other regulations. At the appropriate time in the
product development process, we will determine whether to establish our own manufacturing facilities or continue to rely on third parties to manufacture commercial quantities of any products that we may successfully develop.
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Competition
The biotechnology industry is extremely competitive in the race to develop new products. While we believe we have significant competitive advantages with our
industry-leading expertise in gene editing, clinical development expertise and dominant intellectual property position, we currently face and will continue to face competition for our development programs from companies that use genome editing or
gene therapy development platforms and from companies focused on more traditional therapeutic modalities such as small molecules and antibodies. The competition is likely to come from multiple sources, including larger pharmaceutical companies,
biotechnology companies and academia. Many of these competitors may have access to greater capital and resources than us. For any products that we may ultimately commercialize, not only will we compete with any existing therapies and those therapies
currently in development, but we will also have to compete with new therapies that may become available in the future.
Competitors in our efforts to
provide genetic therapies to patients can be grouped into at least three sets based on their product discovery platforms:
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gene editing companies focused on CRISPR/Cas9 including: Casebia Therapeutics, CRISPR Therapeutics, Inc., Editas Medicine, Inc. and Tracr Hematology Limited;
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other gene editing companies including: bluebird bio, Inc., Cellectis S.A., Poseida, Inc., Precision BioSciences, Inc., and Sangamo BioSciences, and
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gene therapy companies developing
ex vivo
therapies including: bluebird bio, Inc., Cellectis S.A., Juno Therapeutics, Inc., and Kite Pharma, Inc.
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Our competitors will also include companies that are or will be developing other gene editing methods as well as small molecules, biologics and nucleic acid
based therapies for the same indications that we are targeting with our own CRISPR/Cas9-based therapeutics.
Government Regulation and Product Approval
We are subject to extensive regulation. We expect our future product candidates to be regulated as either drugs or biologics. Drug products are
subject to regulation primarily under the Federal Food, Drug, and Cosmetic Act (FD&C Act), and other federal, state, local and foreign statutes and regulations. Biological products are subject to regulation under the FD&C Act and the Public
Health Service Act (PHS Act), and other federal, state, local and foreign statutes and regulations. Both the FD&C Act and the PHS Act and their corresponding regulations govern, among other things, the testing, manufacturing, safety, efficacy,
labeling, packaging, storage, record keeping, distribution, reporting, advertising and other promotional practices involving drug and biological products. Before clinical testing of drug or biological products in the United States may begin, we must
submit an IND to the FDA, which reviews the clinical protocol, and the IND must become effective before clinical trials may begin. In some instances, we must also submit our protocols to the National Institutes of Health (NIH) through its
Recombinant DNA Advisory Committee (RAC) for review before initiating clinical testing.
Drug and biologic products must be approved by the FDA before
they may be legally marketed in the United States and by the appropriate foreign regulatory agencies before they may be legally marketed in foreign countries. The process of obtaining regulatory approvals and the subsequent compliance with
appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources and we may not be able to obtain the required regulatory approvals.
Within the FDA, the Center for Drug Evaluation and Research, or CDER, regulates drug products, including some biological products, while the Center for
Biologics Evaluation and Research (CBER) regulates many biological products not regulated by CDER. Depending on the nature of the particular product, our products may be evaluated by CBER, CDER or both. Proposed human clinical trials involving
nucleic acid transfer conducted at, or sponsored by, institutions receiving NIH funding for research with recombinant or synthetic nucleic acid molecules are also subject to review by the NIH RAC. Moreover, certain therapeutic protocols that raise
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important scientific, safety, medical, ethical, or social issues are discussed at the RACs quarterly public meetings. While the FDA has not provided specific guidance on gene editing in
humans, it has published guidance documents related to, among other things, gene therapy products in general, their preclinical assessment, observing subjects involved in gene therapy clinical trials for delayed adverse events, potency or other
quality testing, and chemistry, manufacturing and control information in gene therapy INDs.
Although the FDA has not yet approved any human gene therapy
product for sale, it has provided guidance for the development of gene therapy products which may be relevant to gene editing products as well. For example, the FDA has established the Office of Cellular, Tissue and Gene Therapies (OCTGT) within
CBER, to consolidate the review of gene therapy and related products, and the Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) to advise CBER on its reviews. In addition, the FDA has issued a growing body of clinical, chemistry,
manufacturing and control (CMC) guidance and other guidance, all of which are intended to facilitate industrys development of gene therapy products. In 2012, the European Medicines Agency approved a gene therapy product called Glybera, which
is the first gene therapy product approved by regulatory authorities anywhere in the Western world.
Ethical, social and legal concerns about gene-editing
technology, gene therapy, genetic testing and genetic research could result in additional regulations restricting or prohibiting the processes we may use. Federal and state agencies, congressional committees and foreign governments have expressed
interest in further regulating biotechnology. More restrictive regulations or claims that our products are unsafe or pose a hazard could prevent us from commercializing any product candidates. New government requirements may be established that
could delay or prevent regulatory approval of our product candidates under development. 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.
U.S. Drug and Biological Products Development Process
The FDA approves drugs through the New Drug Application (NDA) process and biologics through the Biologics License Application (BLA) process before they may be
legally marketed in the United States. This process generally involves the following:
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completion of extensive nonclinical, sometimes referred to as preclinical laboratory tests, and preclinical animal studies and applicable requirements for the humane use of laboratory animals and formulation studies in
accordance with applicable regulations, including good laboratory practice (GLP);
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submission to the FDA of an IND application, which must become effective before human clinical trials may begin;
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performance of adequate and well-controlled human clinical trials according to the FDAs regulations commonly referred to as good clinical practice (GCP) and any additional requirements for the protection of human
research subjects and their health information, to establish the safety and efficacy of the proposed product for its intended use;
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submission to the FDA of an NDA or BLA for marketing approval that includes substantial evidence of safety and efficacy or, for biological products, safety, purity, and potency, from nonclinical testing and clinical
trials;
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satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the product is produced to assess compliance with current good manufacturing practice (cGMP) to assure that the facilities,
methods and controls are adequate to preserve the products identity, strength, quality and purity and, if applicable, the FDAs current good tissue practice (cGTP) requirements for the use of human cellular and tissue products;
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positive results from potential FDA audit of the nonclinical study and clinical trial sites that generated the data in support of the NDA or BLA; and
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FDA review and approval of the NDA or licensure of the BLA.
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Before testing any drug or biological product candidate in humans, the product candidate enters the preclinical
testing stage. Preclinical tests, also referred to as nonclinical studies, include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies to assess the potential safety and activity of the product candidate.
The conduct of the preclinical tests must comply with federal regulations and requirements, including GLP.
Where a study involving the transfer of
nucleic acids into humans is conducted at, or sponsored by, institutions receiving NIH funding for recombinant DNA research or synthetic nucleic acid molecules, prior to the submission of an IND to the FDA, a protocol and related documentation is
submitted to and the study is registered with the NIH Office of Biotechnology Activities (OBA), pursuant to the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines). Compliance with the NIH Guidelines is mandatory for
investigators at institutions receiving NIH funds for research involving recombinant DNA; however, many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them. The NIH is responsible for convening the
RAC, a federal advisory committee that reviews research proposals involving human-gene transfer research and discusses, if needed, protocols that raise novel or particularly important scientific, safety or ethical considerations. The RAC decides
whether a protocol raises issues that warrant further discussion at its quarterly meetings, and the OBA will notify the FDA of the RACs decision regarding the necessity for full public review of a particular protocol. RAC proceedings and
reports are posted to the OBA web site and may be accessed by the public.
The clinical trial sponsor must submit the results of the preclinical tests,
together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND. Some preclinical testing may continue even after the IND is submitted. The IND
automatically becomes effective 30 days after receipt by the FDA, unless the FDA places the clinical trial on a clinical hold within that 30-day time period. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before
the clinical trial can begin. With gene therapy protocols, if the FDA allows the IND to proceed, but the RAC decides that full public review of the protocol is warranted, the FDA will request at the completion of its IND review that sponsors delay
initiation of the protocol until after completion of the RAC review process. The FDA may also impose clinical holds on a drug or biological product candidate at any time before or during clinical trials due to, among other reasons, safety concerns
or non-compliance with regulatory requirements. If the FDA imposes a clinical hold, trials may not recommence without FDA authorization and then only under terms authorized by the FDA. Accordingly, we cannot be sure that submission of an IND will
result in the FDA allowing clinical trials to begin, or that, once begun, issues will not arise that result in the suspension or termination of such trials.
Clinical trials involve the administration of the product candidate to healthy volunteers or patients under the supervision of qualified investigators,
generally physicians not employed by or under the study sponsors control. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion
criteria, and the parameters to be used to monitor subject safety, including stopping rules that assure a clinical trial will be stopped if certain adverse events should occur. Each protocol and any amendments to the protocol must be submitted to
the FDA as part of the IND. Clinical trials must be conducted and monitored in accordance with the FDAs regulations comprising the GCP requirements, including the requirement that all research subjects provide informed consent. Further, each
clinical trial must be reviewed and approved by an independent institutional review board (IRB) at or servicing each institution at which the clinical trial will be conducted. An IRB is charged with protecting the welfare and rights of study
participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the form and content of the informed consent
that must be signed by each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. Certain clinical trials also must be reviewed by an institutional biosafety committee (IBC), a local
institutional committee that reviews all forms of research conducted at that institution involving recombinant or synthetic nucleic acid molecules. The IBC assesses the safety of the research and identifies any potential risk to public health or the
environment and ensures that all research is conducted in compliance with NIH Guidelines.
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Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:
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Phase I. The product candidate is initially introduced into healthy human subjects and tested for safety. In the case of some products for severe or life-threatening diseases, especially when the product may be too
inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients.
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Phase II. The product candidate is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases
and to determine dosage tolerance, optimal dosage and dosing schedule.
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Phase III. Clinical trials are undertaken to further evaluate dosage, clinical efficacy, potency (for BLA products), and safety in an expanded patient population at geographically dispersed clinical trial sites. These
clinical trials are intended to establish the overall risk/benefit ratio of the product and provide an adequate basis for product approval and labeling.
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Post-approval clinical trials, sometimes referred to as Phase IV clinical trials, may be conducted after initial marketing approval. These clinical trials are
used to gain additional experience from the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow-up. The FDA recommends that sponsors observe subjects for potential gene therapy-related delayed
adverse events for a 15-year period, including a minimum of five years of annual examinations followed by ten years of annual queries, either in person or by questionnaire.
During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical data, and
clinical trial investigators. Annual progress reports detailing the status of the clinical trials must be submitted to the FDA. Written IND safety reports must be promptly submitted to the FDA, the NIH and the investigators for serious and
unexpected adverse events, any findings from other trials, tests in laboratory animals or
in vitro
testing that suggest a significant risk for human subjects, or any clinically important increase in the rate of a serious suspected
adverse reaction over that listed in the protocol or investigator brochure. The sponsor must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for reporting. The sponsor also must notify
the FDA of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsors initial receipt of the information. Phase I, Phase II and Phase III clinical trials may not be completed successfully
within any specified period, if at all. The FDA or the sponsor or its data safety monitoring board may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an
unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRBs requirements or if the product candidate has been
associated with unexpected serious harm to patients.
There are also requirements governing the reporting of ongoing clinical trials and completed
clinical trial results to public registries. Sponsors of certain clinical trials of FDA-regulated products, including drugs and biologics, are required to register and disclose certain clinical trial information to NIH. Information related to the
product, patient population, phase of investigation, study sites and investigators, and other aspects of the clinical trial is then made publicly available as part of the registration at www.clinicaltrials.gov. Sponsors are also obligated to
disclose the results of their clinical trials after completion. Disclosure of the results of these trials can be delayed until the new product or new indication being studied has been approved, up to a maximum of two years.
Human therapeutic products based on gene-editing technology are a new category of therapeutics. Because this is a relatively new and expanding area of novel
therapeutic interventions, there can be no assurance as to the length of the study period, the number of patients the FDA will require to be enrolled in the trials in order to establish the safety and efficacy for NDA products and the safety, purity
and potency for BLA products that are human gene editing therapeutics, or that the data generated in these trials will be acceptable to the FDA to support marketing approval. The NIH and the FDA have a publicly accessible database, the Genetic
Modification Clinical Research Information System, which includes information on gene transfer trials and serves as an electronic tool to facilitate the reporting and analysis of adverse events in these trials.
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Concurrent with clinical trials, companies usually complete additional animal trials and must also develop
additional information about the physical characteristics of the product candidate as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP, and in certain cases, cGTP, requirements. To help reduce
the risk of the introduction of adventitious agents with use of biological products, the PHS Act emphasizes the importance of manufacturing control for products whose attributes cannot be precisely defined. The manufacturing process must be capable
of consistently producing quality batches of the product candidate and, among other things, the sponsor must develop methods for testing the identity, strength, quality, potency and purity of the final product, if approval is sought under a BLA, and
testing methods to demonstrate that the drugs quality is adequate to preserve the drugs identity, strength, quality and purity, if approval is sought under an NDA. Additionally, appropriate packaging must be selected and tested and
stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.
U.S.
Review and Approval Processes
After the completion of clinical trials of a drug or biological product candidate, FDA approval of an NDA or BLA
must be obtained before commercial marketing of the drug or biological product. The NDA or BLA must include results of product development, laboratory and animal trials, human trials, information on the manufacture and composition of the product,
proposed labeling and other relevant information. In addition, under the Pediatric Research Equity Act (PREA), an NDA, BLA or supplement to an NDA or BLA for a product candidate with certain novel characteristics must contain data to assess the
safety and effectiveness of the product candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The Food
and Drug Administration Safety and Innovation Act (FDASIA) requires that a sponsor who is planning to submit a marketing application for a drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing
regimen or new route of administration submit an initial Pediatric Study Plan (PSP) within sixty days after an end-of-Phase 2 meeting or as may be agreed between the sponsor and FDA. The initial PSP must include, among other things, an outline of
the pediatric study or studies that the sponsor plans to conduct, including, to the extent practicable, study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed
information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information, along with any other information specified in FDA
regulations. The FDA and the sponsor must reach agreement on the PSP. A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from nonclinical studies,
early phase clinical trials, or other clinical development programs. The FDA may grant deferrals for submission of data or full or partial waivers. Unless otherwise required by regulation, PREA does not apply to any drug or biological product for an
indication for which orphan designation has been granted. The testing and approval processes require substantial time and effort and there can be no assurance that the FDA will accept the NDA or BLA for filing and, even if filed, that any approval
will be granted on a timely basis, if at all.
Under the Prescription Drug User Fee Act (PDUFA), as amended, each NDA or BLA must be accompanied by a user
fee. The FDA adjusts the PDUFA user fees on an annual basis. According to the FDAs fee schedule, effective through September 30, 2017, the user fee for an application requiring clinical data, such as an original NDA or BLA, is $2,038,810.
PDUFA also imposes an annual product fee for drugs and biologics ($97,750) and an annual establishment fee ($512,200) on facilities used to manufacture prescription drugs and biologics. Fee waivers or reductions are available in certain
circumstances, including a waiver of the application fee for the first application filed by a small business. Additionally, no user fees are assessed on NDAs or BLAs for products designated as orphan drugs, unless the product also includes a
non-orphan indication.
Within 60 days following submission of the application, the FDA reviews an NDA or BLA to determine if it is substantially complete
before the agency accepts it for filing. The FDA may refuse to file any NDA or BLA that it deems incomplete or not properly reviewable at the time of submission, including for failure to pay required fees, and may request additional information. In
this event, the application must be resubmitted with the
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additional information. The resubmitted application also is subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth
substantive review of the NDA or BLA. The FDA reviews the application to determine, among other things, whether the proposed product is safe and effective (or, in the case of biological products, safe, pure and potent), and whether the product is
being manufactured in accordance with cGMP, and in certain cases, cGTP, requirements to assure and preserve the products identity, safety, strength, quality, potency and purity. The FDA may refer applications for novel products or products
that present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under
what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions. During the FDA review and approval process, the FDA also will determine whether a Risk
Evaluation and Mitigation Strategy (REMS) is necessary to assure the safe use of the drug or biological product candidate. If the FDA concludes a REMS is needed, the sponsor of the NDA or BLA must submit a proposed REMS; the FDA will not approve the
application without a REMS, if required.
Before approving an NDA or BLA, the FDA will inspect the facilities at which the product is manufactured. The
FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP and, if applicable, cGTP requirements and adequate to assure consistent production of the product within required
specifications. Additionally, before approving an NDA or BLA, the FDA will typically inspect one or more clinical sites to assure that the clinical trials were conducted in compliance with IND study requirements and cGCP requirements. To assure
cGMP, cGTP and GCP compliance, an applicant must incur significant expenditure of time, money and effort in the areas of training, record keeping, production, and quality control.
Notwithstanding the submission of relevant data and information, the FDA may ultimately decide that the NDA or BLA does not satisfy its regulatory criteria
for approval and deny approval. Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data. If the agency decides not to approve the NDA or BLA in its present form, the FDA
will issue a complete response letter that usually describes all of the specific deficiencies in the application identified by the FDA. The deficiencies identified may be minor, for example, requiring clarifying labeling changes, or major, for
example, requiring product reformulation or additional clinical trials. Additionally, the complete response letter may include recommended actions that the applicant might take to place the application in a condition for approval. If a complete
response letter is issued, the applicant may either resubmit the application, addressing all of the deficiencies identified in the letter, challenge the determination set forth in the letter by requesting a hearing or withdraw the application.
If a product receives regulatory approval, the approval may be significantly limited to specific diseases, dosages or patient subgroups or the indications for
use may otherwise be limited, which could restrict the commercial value of the product. Further, the FDA may require that certain contraindications, warnings, precautions or adverse events be included in the product labeling. The FDA may impose
restrictions and conditions on product distribution, prescribing, or dispensing in the form of a REMS, or otherwise limit the scope of any approval. In addition, the FDA may require post marketing clinical trials, sometimes referred to as Phase IV
clinical trials, designed to further assess a products safety and effectiveness, and testing and surveillance programs to monitor the safety of approved products that have been commercialized.
One of the performance goals agreed to by the FDA under the PDUFA is to review 90% of NDAs for new molecular entities (NMEs) and original BLAs in 10 months
from the 60 day filing date and 90% of priority NME NDAs and original BLAs in six months from the 60 day filing date, whereupon a review decision is to be made. The goals for reviewing standard and priority non-NME NDAs are 10 months and six months,
respectively, measured from the date the FDA receives the application. The FDA does not always meet its PDUFA goal dates for standard and priority NME NDAs and BLAs and its review goals are subject to change from time to time. The review process and
the PDUFA goal date may be extended by three months if the FDA requests or the NDA or BLA sponsor otherwise provides additional information or clarification regarding information already provided in the submission within the last three months before
the PDUFA goal date.
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Orphan Drug Designation
The FDA may grant Orphan Drug Designation to drugs or biological products intended to treat a rare disease or condition that affects fewer than 200,000
individuals in the United States, or, if it affects more than 200,000 individuals in the United States, when there is no reasonable expectation that the cost of developing and marketing the drug or biological product for this type of disease or
condition will be recovered from sales in the United States. Orphan product designation must be requested before submission of an NDA or BLA. After the FDA grants orphan product designation, the identity of the therapeutic agent and its potential
orphan use are disclosed publicly by the FDA. Orphan product designation does not convey any advantage in or shorten the duration of the regulatory review and approval process
In the United States, Orphan Drug Designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs,
tax advantages and user-fee waivers. In addition, if a product receives the first FDA approval for the indication for which it has orphan designation, the product is entitled to orphan drug exclusivity, which means the FDA may not approve any other
application to market the same drug for the same orphan indication for a period of seven years, except in limited circumstances, such as a showing of clinical superiority over the product with orphan exclusivity or where the manufacturer with
orphan exclusivity is unable to assure sufficient quantities of the approved orphan designated product. Competitors, however, may receive approval of different products for the indication for which the orphan product has exclusivity or obtain
approval for the same product but for a different indication for which the orphan product has exclusivity, which may permit off-label use for the orphan indication. Orphan product exclusivity also could block the approval of one of our products for
seven years if a competitor obtains approval of the same drug or biological product as defined by the FDA for the same orphan indication or if our product candidate is determined to be contained within the competitors product for the same
indication or disease. If a drug or biological product designated as an orphan product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan product exclusivity.
Expedited Development and Review Programs
The
FDA has a Fast Track program that is intended to expedite or facilitate the process for reviewing new drug and biological products that meet certain criteria. Specifically, new drug and biological products are eligible for Fast Track designation if
they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. Fast Track designation applies to the combination of the product and the
specific indication for which it is being studied. The sponsor of a new drug or biologic may request that the FDA designate the product as a Fast Track product at any time during the clinical development of the product, but ideally not later than
the pre-NDA or pre-BLA meeting. The FDA may consider for review sections of the marketing application for a Fast Track product on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of
the sections of the application, the FDA agrees to accept sections of the application and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the application.
Any product submitted to the FDA for marketing, including under a Fast Track program, may be eligible for other types of FDA programs intended to expedite
development and review, such as priority review and accelerated approval. Any product is eligible for priority review if it treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness of the
treatment, prevention, or diagnosis of that condition. The FDA will attempt to direct additional resources to the evaluation of an application for a new drug or biological product designated for priority review in an effort to facilitate the review.
Additionally, a product may be eligible for accelerated approval. Drug and biological products studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing
treatments may be eligible for accelerated approval, which means that they may be approved on the basis of adequate and well-controlled clinical trials establishing that the product has an effect on a surrogate endpoint that is reasonably likely to
predict a clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or
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prevalence of the condition and the availability or lack of alternative treatments. As a condition of approval, the FDA may require that a sponsor of a product subject to accelerated approval
perform adequate and well-controlled post-marketing clinical trials. In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial
launch of the product.
In addition, under the provisions of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA), the FDA
established a Breakthrough Therapy Designation, which is intended to expedite the development and review of products that treat serious or life-threatening diseases or conditions. A breakthrough therapy is defined as a drug that is intended, alone
or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more
clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The designation includes all of the features of Fast Track designation, as well as more intensive FDA interaction and guidance. The
Breakthrough Therapy Designation is a distinct status from both accelerated approval and priority review, but these can also be granted to the same product candidate if the relevant criteria are met. The FDA must take certain actions, such as
holding timely meetings and providing advice, intended to expedite the development and review of an application for approval of a breakthrough therapy. All requests for breakthrough therapy designation will be reviewed within 60 days of receipt, and
FDA will either grant or deny the request.
Fast Track designation, priority review, accelerated approval and breakthrough therapy designation do not
change the standards for approval but may expedite the development or approval process. Where applicable, we plan to request Fast Track and Breakthrough Therapy Designation for our product candidates. Even if we receive one or both of these
designations for our product candidates, the FDA may later decide that our product candidates no longer meet the conditions for qualification. In addition, these designations may not provide us with a material commercial advantage.
Post-Approval Requirements
Maintaining
substantial compliance with applicable federal, state, and local statutes and regulations requires the expenditure of substantial time and financial resources. Rigorous and extensive FDA regulation of drug and biological products continues after
approval, particularly with respect to cGMP requirements. We will rely, and expect to continue to rely, on third parties for the production of clinical and commercial quantities of any products that we may commercialize. Manufacturers of our
products are required to comply with applicable requirements in the cGMP regulations, including quality control and quality assurance and maintenance of records and documentation. Other post-approval requirements applicable to drug and biological
products, include reporting of cGMP deviations that may affect the identity, potency, purity and overall safety of a distributed product, record-keeping requirements, reporting of adverse effects, reporting updated safety and efficacy information,
and complying with electronic record and signature requirements. After a BLA is approved, the product also may be subject to official lot release. As part of the manufacturing process, the manufacturer is required to perform certain tests on each
lot of the product before it is released for distribution. If the product is subject to official release by the FDA, the manufacturer submits samples of each lot of product to the FDA together with a release protocol showing a summary of the history
of manufacture of the lot and the results of all of the manufacturers tests performed on the lot. The FDA also may perform certain confirmatory tests on lots of some products, such as viral vaccines, before releasing the lots for distribution
by the manufacturer. In addition, the FDA conducts laboratory research related to the regulatory standards on the safety, purity, potency, and effectiveness of biological products.
We also would have to comply with the FDAs advertising and promotion requirements, such as those related to direct-to-consumer advertising, the
prohibition on promoting products for uses or in patient populations that are not described in the products approved labeling (known as off-label use), industry-sponsored scientific and educational activities, and promotional
activities involving the internet and social media platforms. Discovery of previously unknown problems or the failure to comply with the applicable regulatory requirements may result in
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restrictions on the labeling or marketing of a product, imposition of a REMS or post-market study requirement or withdrawal of the product from the market as well as possible civil or criminal
sanctions. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or after approval, may subject an applicant or manufacturer to administrative or judicial civil or criminal
sanctions and adverse publicity. FDA sanctions could include refusal to approve pending applications, withdrawal of an approval, clinical hold, warning or untitled letters, product recalls, product seizures, total or partial suspension of production
or distribution, injunctions, fines, refusals of government contracts, mandated corrective advertising or communications with doctors, debarment, restitution, disgorgement of profits, or civil or criminal penalties. Any agency or judicial
enforcement action could have a material adverse effect on us.
Drug and biological product manufacturers and other entities involved in the manufacture
and distribution of approved drugs and biological products are required to register their establishments with the FDA and certain other federal and state agencies, and are subject to periodic unannounced inspections by the FDA and certain other
federal and state agencies for compliance with cGMP, and in certain cases, cGTP, requirements and other laws. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP
compliance. Discovery of problems with a product after approval may result in restrictions on a product, manufacturer, or holder of an approved NDA or BLA, including withdrawal of the product from the market. In addition, changes to the
manufacturing process or facility generally require prior FDA approval before being implemented and other types of changes to the approved product, such as adding new indications and additional labeling claims, are also subject to further FDA review
and approval.
U.S. Patent Term Restoration and Marketing Exclusivity
Depending upon the timing, duration and specifics of the FDA approval of the use of our product candidates, some of our U.S. patents may be eligible for
limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments. The Hatch-Waxman Amendments permit a patent restoration term of up to five years as
compensation for patent term lost during product development and the FDA regulatory review process. However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the products approval date. The
patent term restoration period is generally one-half the time between the effective date of an IND and the submission date of an NDA or BLA plus the time between the submission date of an NDA or BLA and the approval of that application, except that
the review period is reduced by any time during which the applicant failed to exercise due diligence. Only one patent applicable to an approved product is eligible for the extension and the application for the extension must be submitted prior to
the expiration of the patent within a 60-day period from the date the product is first approved for commercial marketing. The USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration. In
the future, we may intend to apply for restoration of patent term for one of our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors
involved in the filing of the relevant NDA or BLA. However, there can be no assurance that any such extension will be granted to us.
Under Hatch-Waxman
Act, once an NDA is approved, potential competitors can rely upon the NDA upon expiration of certain patent and non-patent exclusivity periods, if any, to seek approval of competing products, including generic copies, via an abbreviated new drug
application, or ANDA, or 505(b)(2) application. Both the ANDA and 505(b)(2) application processes allow a competitor to obtain approval without conducting all of the preclinical and clinical testing necessary for approval of a full NDA, which could
result in a shorter and less expensive development and approval process.
The Hatch-Waxman Act provides for various periods of non-patent exclusivity to
protect new drugs approved via a full NDA from premature competition. First, federal law provides a period of up to five years exclusivity following approval of a drug containing a new chemical entity, or NCE, defined as an active moiety that has
not been approved previously. An active moiety, in turn, is defined as the molecule or ion responsible for the action of the drug substance. During this NCE exclusivity period, FDA cannot accept any ANDA or 505(b)(2) application referencing the NDA
of the protected listed drug; however, the five year exclusivity period is reduced
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to four years if the ANDA or 505(b)(2) application challenges to a listed patent for the protected drug product through submission of a paragraph IV certification (described below). Second, the
Hatch-Waxman Act also provides for a period of three years of exclusivity following approval of a listed drug that contains a previously approved active ingredient if the FDA determines that new clinical investigations, other than bioavailability
studies, that were conducted or sponsored by the applicant are essential to the approval of the application. Three-year exclusivity is typically awarded for changes to an approved drug product, such as new indications, dosage forms or dosing
regimens, and prohibits FDA from approving an ANDA or 505(b)(2) application with the protected innovation. As a general matter, three-year exclusivity does not prohibit the FDA from approving ANDAs or 505(b)(2) applications for competitive versions
of the original, unmodified drug product. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA; however, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of
the nonclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.
Additionally, in the event
that the sponsor of the listed drug has properly informed the FDA of patents covering its listed drug, applicants submitting an ANDA or 505(b)(2) application referencing the listed drug are required to make one of four patent certifications for each
listed patent, except for patents covering methods of use for which the ANDA or 505(b)(2) applicant is not seeking approval. If an applicant certifies its belief that one or more listed patents are invalid, unenforceable, or not infringed (and
thereby indicates it is seeking approval prior to patent expiration), which is known as a paragraph IV certification, it is required to provide notice of its filing to the NDA sponsor and the patent holder within certain time limits. If the patent
holder then initiates a suit for patent infringement against the ANDA or 505(b)(2) applicant within 45 days of receipt of the notice, the FDA cannot grant effective approval of the ANDA or 505(b)(2) application until either 30 months have passed or
there has been a court decision or settlement order holding or stating that the drug for which approval is being sought will not infringe the patents in question or that the patents are invalid or unenforceable. If the patent holder does not
initiate a suit for patent infringement within the 45 days, the ANDA or 505(b)(2) application may be approved immediately upon successful completion of FDA review, unless blocked by another listed patent or regulatory exclusivity period. If the ANDA
or 505(b)(2) applicant certifies that it does not intend to market its generic product before some or all listed patents on the listed drug expire (known as a Paragraph III certification), then the FDA cannot grant effective approval of the ANDA or
505(b)(2) application until those patents expire. The first of the ANDA applicants submitting substantially complete applications certifying that one or more listed patents for a particular product are invalid, unenforceable, or not infringed may
qualify for an exclusivity period of 180 days running from when the generic product is first marketed, during which subsequently submitted ANDAs containing similar certifications cannot be granted effective approval. The 180-day generic exclusivity
can be forfeited in various ways, including if the first applicant does not market its product within specified statutory timelines. If more than one applicant files a substantially complete ANDA on the same day, each such first applicant will be
entitled to share the 180-day exclusivity period, but there will only be one such period, beginning on the date of first marketing by any of the first applicants.
Biosimilars and Exclusivity
The Patient
Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010 (collectively, the Affordable Care Act), signed into law on March 23, 2010, includes a subtitle called the Biologics Price Competition
and Innovation Act of 2009 (BPCIA), which created an abbreviated approval pathway for biological products that are biosimilar to or interchangeable with an FDA-licensed reference biological product. To date, only four biosimilars have been licensed
under the BPCIA, although numerous biosimilars have been approved in Europe. The FDA has issued several draft and final guidance documents outlining an approach to review and approval of biosimilars and interchangeable biological products.
The BPCIA also contains various provisions regarding exclusivity for reference and interchangeable products and procedures for sharing and litigating patents
covering the reference product. The BPCIA, however, is complex and only beginning to be interpreted and implemented by the FDA. In addition, proposed legislation has sought to reduce the 12-year reference product exclusivity period. Other aspects of
the BPCIA, some of which may impact the BPCIA exclusivity provisions, have also been the subject of recent litigation. As a result, the ultimate impact, implementation, and meaning of the BPCIA is subject to significant uncertainty.
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Additional Regulation
In addition to the foregoing, state and federal laws regarding environmental protection and hazardous substances, including the Occupational Safety and Health
Act, the Resource Conservancy and Recovery Act and the Toxic Substances Control Act, all affect our business. These and other laws govern our use, handling and disposal of various biological, chemical and radioactive substances used in, and wastes
generated by, our operations. If our operations result in contamination of the environment or expose individuals to hazardous substances, we could be liable for damages and governmental fines. We believe that we are in material compliance with
applicable environmental laws and that continued compliance therewith will not have a material adverse effect on our business. We cannot predict, however, how changes in these laws may affect our future operations.
Other Healthcare Laws
In addition to FDA
restrictions on marketing of pharmaceutical and biological products, other U.S. federal and state healthcare regulatory laws restrict business practices in the pharmaceutical industry, which include, but are not limited to, state and federal
anti-kickback, false claims, data privacy and security, and physician payment transparency laws.
The federal Anti-Kickback Statute prohibits, among other
things, any person or entity from knowingly and willfully offering, paying, soliciting, receiving or providing any remuneration, directly or indirectly, overtly or covertly, to induce or in return for purchasing, leasing, ordering, or arranging for
or recommending the purchase, lease, or order of any item or service reimbursable, in whole or in part, under Medicare, Medicaid or other federal healthcare programs. The term remuneration has been broadly interpreted to include anything
of value. The Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and prescribers, purchasers, and formulary managers on the other. Although there are a number of statutory exceptions
and regulatory safe harbors protecting some common activities from prosecution, the exceptions and safe harbors are drawn narrowly. Practices that involve remuneration that may be alleged to be intended to induce prescribing, purchases, or
recommendations may be subject to scrutiny if they do not meet the requirements of a statutory or regulatory exception or safe harbor. Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor
does not make the conduct per se illegal under the Anti-Kickback Statute. Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all its facts and circumstances. Several courts have
interpreted the statutes intent requirement to mean that if any one purpose of an arrangement involving remuneration is to induce referrals of federal healthcare covered business, the statute has been violated. Penalties for violations of the
Anti-Kickback Statute include fines of up to $25,000 per violation and felony conviction punishable by imprisonment up to five years as well as possible exclusion from participation in federal healthcare programs, such as Medicare and Medicaid.
We may also be subject to data privacy and security regulation by both the federal government and the states and other jurisdictions outside the United States
in which we conduct our business. HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (HITECH) and their respective implementing regulations, including the Final HIPAA Omnibus Rule published on
January 25, 2013, impose specified requirements relating to the privacy, security and transmission of individually identifiable health information held by covered entities and their business associates. Among other things, HITECH makes
HIPAAs privacy and security standards directly applicable to business associates, defined as independent contractors or agents of covered entities that create, receive, maintain or transmit protected health information in
connection with providing a service for or on behalf of a covered entity. HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys
general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys fees and costs associated with pursuing federal civil actions. In addition, state laws govern the
privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same requirements, thus complicating compliance efforts.
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If our operations are found to be in violation of any of such laws or any other governmental regulations that
apply to us, we may be subject to penalties, including, without limitation, administrative, civil and criminal penalties, damages, fines, disgorgement, contractual damages, reputational harm, diminished profits and future earnings, the curtailment
or restructuring of our operations, exclusion from participation in federal and state healthcare programs and individual imprisonment, any of which could adversely affect our ability to operate our business and our financial results.
To the extent that any of our product candidates, once approved, are sold in a foreign country, we may be subject to similar foreign laws and regulations,
which may include, for instance, applicable post-marketing requirements, including safety surveillance, anti-fraud and abuse laws, and implementation of corporate compliance programs and reporting of payments or other transfers of value to
healthcare professionals.
U.S. Foreign Corrupt Practices Act
The U.S. Foreign Corrupt Practices Act, to which we are subject, prohibits corporations and individuals from engaging in certain activities to obtain or
retain business or to influence a person working in an official capacity. It is illegal to pay, offer to pay or authorize the payment of anything of value to any foreign government official, government staff member, political party or political
candidate in an attempt to obtain or retain business or to otherwise influence a person working in an official capacity.
Government Regulation
Outside of the United States
In addition to regulations in the United States, we will be subject to a variety of regulations in other
jurisdictions governing, among other things, clinical studies and any commercial sales and distribution of our products. Because biologically sourced raw materials are subject to unique contamination risks, their use may be restricted in some
countries.
Coverage and Reimbursement
Significant uncertainty exists as to the coverage and reimbursement status of any pharmaceutical or biological product for which we obtain regulatory
approval. In the United States and markets in other countries, patients who are prescribed treatments for their conditions and providers performing the prescribed services generally rely on third-party payors to reimburse all or part of the
associated healthcare costs. Patients are unlikely to use our products unless coverage is provided and reimbursement is adequate to cover a significant portion of the cost of our products. Sales of any products for which we receive regulatory
approval for commercial sale will therefore depend, in part, on the availability of coverage and adequate reimbursement from third-party payors. Third-party payors include government authorities, managed care providers, private health insurers and
other organizations.
The process for determining whether a third-party payor will provide coverage for a pharmaceutical or biological product typically
is separate from the process for setting the price of such product or for establishing the reimbursement rate that the payor will pay for the product once coverage is approved. Third-party payors may limit coverage to specific products on an
approved list, also known as a formulary, which might not include all of the FDA-approved products for a particular indication. A decision by a third-party payor not to cover our product candidates could reduce physician utilization of our products
once approved and have a material adverse effect on our sales, results of operations and financial condition. Moreover, a third-party payors decision to provide coverage for a pharmaceutical or biological product does not imply that an
adequate reimbursement rate will be approved. Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development. Additionally, coverage
and reimbursement for new products can differ significantly from payor to payor. One third-party payors decision to cover a particular medical product or service does not ensure that other payors will also provide coverage for the medical
product or service, or will provide coverage at an adequate reimbursement rate. As a result, the coverage determination process will require us to provide scientific and clinical support for the use of our products to each payor separately and will
be a time-consuming process.
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The containment of healthcare costs has become a priority of federal, state and foreign governments as well as
private third-party payors, and the prices of pharmaceutical or biological products have been a focus in this effort. Third-party payors are increasingly challenging the prices charged for medical products and services, examining the medical
necessity and reviewing the cost-effectiveness of pharmaceutical products, biological products, medical devices and medical services, in addition to questioning safety and efficacy. If these third-party payors do not consider our products to be
cost-effective compared to other available therapies, they may not cover our products after FDA approval or, if they do, the level of payment may not be sufficient to allow us to sell our products at a profit.
Employees
As of December 31, 2016, we had 104
full-time employees, 77 of whom were primarily engaged in research and development activities and 40 of whom have an M.D. or Ph.D. degree.
Our
Corporate Information
We were incorporated under the laws of the state of Delaware in May 2014 under the name AZRN, Inc. Our principal executive
offices are located at 40 Erie Street Suite 130, Cambridge, Massachusetts 02139. Our telephone number is (857) 285-6200, and our website is located at www.intelliatx.com. References to our website are inactive textual references only and the
content of our website should not be deemed incorporated by reference into this Annual Report on Form 10-K.
Available Information
Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to these reports filed or furnished pursuant
to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, are available free of charge on our website located at www.intelliatx.com as soon as reasonably practicable after they are filed with or furnished to the Securities and Exchange
Commission (the SEC). These reports are also available at the SECs Internet website at www.sec.gov. The public may also read and copy any materials filed with the SEC at the SECs Public Reference Room at 100 F Street, N.E.,
Washington D.C. 20549. Information on the operation of the Public Reference Room may be obtained by calling the SEC at 1-800-SEC-0330.
A copy of our
Corporate Governance Guidelines, Code of Conduct and Business Ethics and the charters of the Audit Committee, Compensation Committee and Nominating and Corporate Governance Committee are posted on our website, www.intelliatx.com, under
Investor Relations.
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Item 1A.
Risk Factors
Investing in our common stock involves a high degree of risk. Careful consideration should be given to the following risk factors, in addition to the other
information set forth in this Annual Report on Form 10-K and in other documents that we file with the SEC, in evaluating the Company and our business. If any of the following risks and uncertainties actually occurs, our business, prospects,
financial condition and results of operations could be materially and adversely affected. The risks described below are not intended to be exhaustive and are not the only risks facing the Company. New risk factors can emerge from time to time, and
it is not possible to predict the impact that any factor or combination of factors may have on our business, prospects, financial condition and results of operations.
Risks Related to Our Business, Technology and Industry
CRISPR/Cas9 genome editing technology is a novel technology that is not yet clinically validated for human therapeutic use. The approaches we are taking
to discover and develop novel therapeutics using CRISPR/Cas9 systems are unproven and may never lead to marketable products. If we are unable to develop viable product candidates, achieve regulatory approval for any such product candidate or market
and sell any product candidates, we may never achieve profitability.
We are focused on developing potentially curative medicines utilizing the
CRISPR/Cas9 genome editing technology. Although there have been significant advances in the field of gene therapy, which typically involves introducing a copy of a gene into a patients cell, and genome editing in recent years, CRISPR-based
genome editing technologies are new and largely unproven. The CRISPR/Cas9 technologies that we have licensed and that we intend to develop have not yet been clinically tested by us, nor are we aware of any clinical trials for safety or efficacy
having been completed by third parties involving these technologies. The scientific evidence to support the feasibility of developing products based on these technologies is both preliminary and limited. Successful development of products by us will
require solving a number of issues, including safely delivering a therapeutic into target cells within the human body or in an
ex vivo
setting, optimizing the efficiency and specificity of such products, and ensuring the therapeutic
selectivity and efficacy of such products. There can be no assurance we will be successful in solving any or all of these issues.
We have concentrated
our research efforts to date on bringing CRISPR/Cas9 therapeutics to the clinic for our initial indications, which we call our sentinel indications, and our future success is highly dependent on the successful development of CRISPR-based genome
editing technologies, cellular delivery methods and therapeutic applications. Our sentinel indications are the focus of our initial development efforts, and we may decide to alter or abandon these programs as new data become available and we gain
experience in developing CRISPR/Cas9-based therapeutics. We cannot be sure that our CRISPR/Cas9 technologies will yield satisfactory products that are safe and effective, scalable or profitable in our sentinel indications or any other indication we
pursue.
Public perception and related media coverage of potential therapy-related safety issues, including adoption of new therapeutics or novel
approaches to treatment, as well as ethical concerns related specifically to genome editing and CRISPR/Cas9, may adversely influence the willingness of subjects to participate in clinical trials, or if any therapeutic is approved, of physicians and
patients to subscribe to the novel treatment mechanics. Physicians, health care providers and third-party payors often are slow to adopt new products, technologies and treatment practices that require additional upfront costs and training.
Physicians may not be willing to undergo training to adopt this novel and personalized therapy, may decide the therapy is too complex to adopt without appropriate training and may choose not to administer the therapy. In addition, responses by the
U.S., state or foreign governments to negative public perception or ethical concerns may result in new legislation or regulations that could limit our ability to develop or commercialize any product candidates, obtain or maintain regulatory approval
or otherwise achieve profitability. Based on these and other factors, health care providers and payors may decide that the benefits of this new therapy do not or will not outweigh its costs.
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Intellectual property owned by third parties relating to CRISPR/Cas9 or other related technologies necessary to
develop, manufacture and commercialize CRISPR/Cas9 therapeutics, such as delivery technologies, chemical modifications and manufacturing methods, could adversely impact our ability to ultimately market and sell products. Currently, the respective
owners of the UC/Vienna/Charpentier patent application and the Broad Institute patent family allege owning intellectual property claiming aspects of CRISPR/Cas9 systems and methods to edit genes in eukaryotic cells, including human cells, which may
impact our ability to market and sell CRISPR/Cas9-based human therapeutics. In January 2016, the PTAB initiated an interference proceeding to determine which set of intellectual property was invented first and, thus, entitled to the patents covering
these inventions. On February 15, 2017, the PTAB dismissed the proceeding finding that the respective patent claims involved in the interference were distinct such that they did not meet the legal requirement to proceed with the interference.
As a result of this proceedings dismissal, the PTAB did not make a decision regarding which party actually first invented the use of CRISPR/Cas9 systems and methods to edit genes in eukaryotic cells. For additional information regarding the
risks that may apply to our and our licensors intellectual property rights, see the section entitled Risks Related to Our Intellectual Property appearing elsewhere in this report for more information.
Our ability to generate product revenue is dependent on the success of our application of CRISPR/Cas9 technology for human therapeutic use, which is at
an early stage of development and will require significant additional discovery efforts, preclinical testing and clinical studies, as well as applicable regulatory guidance for preclinical testing and clinical studies from the FDA and other
regulatory authorities, before we can seek regulatory approval and begin commercial sales of any potential product candidates.
Our ability to
generate product revenue is highly dependent on our ability to obtain regulatory approval of and successfully commercialize one or more of our product candidates. Any product candidates we discover will require preclinical, clinical and regulatory
review and approval in each jurisdiction in which we intend to market the products, substantial investment, access to sufficient commercial manufacturing capacity and significant marketing efforts before we can generate any revenue from product
sales. Before obtaining marketing approval from regulatory authorities for the sale of a product candidate, we must conduct extensive clinical trials to demonstrate the safety, purity and potency, as well as the effectiveness of the product
candidates in humans. We cannot be certain that any of our product candidates will be successful in clinical trials and even if successful, they may not receive regulatory approval.
Our approach to developing therapies for genetic-based diseases centers on using the CRISPR/Cas9 technology to introduce or remove genetic information to
treat various disorders. Because this is a new therapeutic approach, discovering, developing and commercializing our product candidates subject us to a number of challenges, including:
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obtaining regulatory approval from the FDA and other regulatory authorities that have very limited or no experience with the clinical development of CRISPR/Cas9 therapeutics;
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seeking and obtaining regulatory approval from the FDA and other regulatory authorities in light of no guidance regarding potential regulatory pathways for this category of therapeutics, including preclinical and
clinical requirements for approval of an IND;
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educating medical personnel regarding the potential benefits and side effect profile of each of our product candidates;
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developing processes for the safe administration of these products, including long-term follow-up for all patients who receive treatment with any of our product candidates;
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sourcing clinical and, if approved, commercial supplies for the materials used to manufacture and process our product candidates;
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developing a manufacturing process and distribution network with a cost of goods that allows for an attractive return on investment; and
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establishing sales and marketing capabilities after obtaining any regulatory approval to gain market acceptance.
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Additionally, because our technology involves gene editing across multiple cell and tissue types, we are subject
to many of the challenges and risks that gene therapies face, including:
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regulatory requirements governing gene and cell therapy products have changed frequently and may continue to change in the future. To date, no products that involve the genetic modification of patient cells have been
approved in the United States and only two have been approved in the EU;
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improper insertion of a gene sequence into a patients chromosome could lead to lymphoma, leukemia or other cancers, other aberrantly functioning cells or other diseases, including death;
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the FDA recommends a follow-up observation period of 15 years or longer for all patients who receive treatment using gene therapies, and we may need to adopt such an observation period for our product candidates; and
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clinical trials using genetically modified cells conducted at institutions that receive funding for recombinant DNA research from the NIH, are subject to review by the RAC. Although the FDA decides whether individual
protocols may proceed, the RAC review process can impede the initiation of a clinical trial, even if the FDA has reviewed the study and it has become effective under an IND.
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To date, although human clinical trials for other genome editing-based therapeutics have been authorized by the FDA, neither we nor any other company has
received regulatory approval in the U.S. or EU to commence human clinical trials utilizing CRISPR/Cas9 or to market therapeutics utilizing any genome editing technology, including CRISPR/Cas9. There is no certainty that the FDA or EMA will apply to
CRISPR/Cas9 product candidates the same regulatory pathway and requirements it is applying to other genome editing therapeutics; and the FDA and other regulatory authorities have not yet provided written guidance regarding preclinical or clinical
studies or regulatory approval pathways for gene editing therapeutics.
In addition, if any product candidates encounter safety or efficacy problems,
developmental delays, regulatory issues or other problems, our development plans and business could be significantly harmed. Further, competitors that are developing products with similar technology may experience problems with their product
candidates or programs that could in turn cause us to identify problems with our product candidates and programs that would potentially harm our business.
Further, significant uncertainty exists regarding the future scope and effect of the FDAs regulatory framework, in particular relating to the review and
approval of human therapeutic products because the new U.S. presidential administration and federal legislators have publicly declared their intention to significantly modify the current regulatory framework. These changes to the FDA requirements
could impact our ability to obtain approval for our products or sell them profitably. In addition, in the EU, the decision of the United Kingdom to withdraw from the European Union may require the EMA to relocate to another country and recruit and
retain new personnel to review and approve our submissions for regulatory approval in Europe. EMAs relocation could result in delays and other changes that may impact the timing and our ability to obtain approval for our products. Also, the
United Kingdom may enact legislation related to the approval and oversight of human therapeutics in that nation. Until any such legislation is enacted, we will be uncertain as to its effects on our business, including our ability to seek and obtain
approval for our products in the United Kingdom.
Even if we obtain regulatory approval of any product candidates, such candidates may not gain
market acceptance among physicians, patients, hospitals, third-party payors and others in the medical community.
The use of the CRISPR/Cas9
system as a framework for developing gene editing therapies is a recent development and may not become broadly accepted by physicians, patients, hospitals, third-party payors and others in the medical community. A variety of factors will influence
whether our product candidates are accepted in the market, including, for example:
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the clinical indications for which our product candidates are approved;
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the potential and perceived advantages of our product candidates over alternative treatments;
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the prevalence and severity of any side effects;
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product labeling or product insert requirements of the FDA or other regulatory authorities;
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limitations or warnings contained in the labeling approved by the FDA or other regulatory authorities;
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the timing of market introduction of our product candidates as well as competitive products;
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the cost of treatment in relation to alternative treatments;
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the amount of upfront costs or training required for health care providers to administer our product candidates;
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the availability of adequate coverage, reimbursement and pricing by third-party payors and government authorities;
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patients ability to access physicians and medical centers capable of delivering any therapies that we develop;
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the willingness of patients to pay out of pocket in the absence of coverage and reimbursement by third-party payors and government authorities;
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the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies;
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relative convenience and ease of administration, including as compared to alternative treatments and competitive therapies;
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any restrictions on the use of our product candidates together with other medications;
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interactions of our product candidates with other medicines patients are taking;
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potential adverse events for any products developed, or negative interactions with regulatory agencies, by us or others in the gene therapy and gene editing fields; and
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the effectiveness of our sales and marketing efforts and distribution support.
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Even if our products achieve
market acceptance, we may not be able to maintain that market acceptance over time if new products or technologies are introduced that are more favorably received than our products, are more cost effective or render our products obsolete. In
addition, adverse publicity due to the ethical and social controversies surrounding the therapeutic use of CRISPR/Cas9 or other therapeutics mediums, such as viral vectors that we anticipate using in our clinical trials may limit market acceptance
of our product candidates. If our product candidates are approved but fail to achieve market acceptance among physicians, patients, hospitals, third-party payors or others in the medical community, we will not be able to generate significant
revenue.
Negative public opinion and increased regulatory scrutiny of CRISPR/Cas9, gene editing or gene therapy generally may damage public
perception of the safety of any product candidates that we develop and adversely affect our ability to conduct our business or obtain regulatory approvals for such product candidates.
Gene therapy in general, and gene editing in particular, remain novel technologies, with no gene therapy product approved to date in the United States and
only two gene therapy products approved to date in the EU. Public perception may be influenced by claims that gene therapy or gene editing, including through the use of CRISPR/Cas9, is unsafe or unethical, and gene therapy or gene editing may not
gain the acceptance of the public or the medical community. In particular, our success will depend upon physicians who specialize in the treatment of diseases targeted by our product candidates prescribing treatments that involve the use of our
product candidates in lieu of, or in addition to, existing treatments with which they are more familiar and for which greater clinical data may be available. In addition, responses by the U.S., state or foreign governments to negative public
perception or ethical concerns may result in new legislation or regulations that could limit our ability to develop or commercialize any product candidates, obtain or maintain regulatory approval or otherwise achieve profitability. More restrictive
statutory regimes, government regulations or negative public opinion would have
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an adverse effect on our business, financial condition, results of operations and prospects and may delay or impair the development and commercialization of our product candidates or demand for
any products we may develop. For example, earlier gene therapy trials led to several well-publicized adverse events, including cases of leukemia and death, and the FDA recently initiated a clinical hold on a CAR-T cell therapy clinical trial due to
patient deaths, and the company developing the therapy ultimately decided to stop the program. Serious adverse events in our clinical trials, or other clinical trials involving gene therapy or gene editing products or our competitors products,
even if not ultimately attributable to the relevant product candidates, and the resulting publicity could result in increased government regulation, unfavorable public perception, potential regulatory delays in the testing or approval of our product
candidates, stricter labeling requirements for those product candidates that are approved and a decrease in demand for any such product candidate.
Coverage and reimbursement may be limited or unavailable in certain market segments for our product candidates, if approved, which could make it
difficult for us to sell any product candidates or therapies profitably.
The success of our product candidates, if approved, depends on the
availability of adequate coverage and reimbursement from third-party payors, including government agencies. In addition, because our product candidates represent new approaches to the treatment of genetic-based diseases, we cannot be sure that
coverage and reimbursement will be available for, or accurately estimate the potential revenue from, our product candidates or assure that coverage and reimbursement will be available for any product that we may develop.
Patients who are provided medical treatment for their conditions generally rely on third-party payors to reimburse all or part of the costs associated with
their treatment. Adequate coverage and reimbursement from governmental healthcare programs, such as Medicare and Medicaid, and commercial payors are critical to new product acceptance.
Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which drugs and treatments they
will cover and the amount of reimbursement. Coverage and reimbursement by a third-party payor may depend upon a number of factors, including the third-party payors determination that use of a product is:
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a covered benefit under its health plan;
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safe, effective and medically necessary;
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appropriate for the specific patient;
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neither experimental nor investigational.
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In the United States, no uniform policy of coverage and
reimbursement for products exists among third-party payors. As a result, obtaining coverage and reimbursement approval of a product from a government or other third-party payor is a time-consuming and costly process that could require us to provide
to each payor supporting scientific, clinical and cost-effectiveness data for the use of our products on a payor-by-payor basis, with no assurance that coverage and adequate reimbursement will be obtained. Even if we obtain coverage for a given
product, the resulting reimbursement payment rates might not be adequate for us to achieve or sustain profitability or may require co-payments that patients find unacceptably high. Additionally, third-party payors may not cover, or provide adequate
reimbursement for, long-term follow-up evaluations required following the use of our gene-modifying products. Patients are unlikely to use our product candidates unless coverage is provided and reimbursement is adequate to cover a significant
portion of the cost of our product candidates. Because our product candidates may have a higher cost of goods than conventional therapies, and may require long-term follow up evaluations, the risk that coverage and reimbursement rates may be
inadequate for us to achieve profitability may be greater. There is significant uncertainty related to insurance coverage and reimbursement of newly approved products. It is difficult to predict at this time what third-party payors will decide with
respect to the coverage and reimbursement for our product candidates.
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Moreover, increasing efforts by governmental and third-party payors in the United States and abroad to cap or
reduce healthcare costs may cause such organizations to limit both coverage and the level of reimbursement for newly approved products and, as a result, they may not cover or provide adequate payment for our product candidates. We expect to
experience pricing pressures in connection with the sale of any of our product candidates due to the trend toward managed healthcare, the increasing influence of health maintenance organizations, cost containment initiatives and additional
legislative changes.
We intend to seek approval to market our product candidates in both the United States and in selected foreign jurisdictions. If we
obtain approval in one or more foreign jurisdictions for our product candidates, we will be subject to rules and regulations in those jurisdictions. In some foreign countries, particularly those in the EU, the pricing of pharmaceutical products,
including biologics is subject to governmental control and other market regulations which could put pressure on the pricing and usage of our product candidates. In these countries, pricing negotiations with governmental authorities can take
considerable time after obtaining marketing approval of a product candidate. In addition, market acceptance and sales of our product candidates will depend significantly on the availability of adequate coverage and reimbursement from third-party
payors for our product candidates and may be affected by existing and future health care reform measures.
Research and development of
biopharmaceutical products is inherently risky. We may not be successful in our efforts to use and enhance our gene editing technology to create a pipeline of product candidates, obtain regulatory approval and develop commercially successful
products, or we may expend our limited resources on programs that do not yield a successful product candidate and fail to capitalize on potential product candidates or diseases that may be more profitable or for which there is a greater likelihood
of success. If we fail to develop product candidates, our commercial opportunity, if any, will be limited.
We do not currently have any product
candidates. We are at an early stage of development and our technology and approach has not yet led, and may never lead, to any product candidate or any approved or commercially successful products. Even if we are successful in building our pipeline
of product candidates, completing clinical development, obtaining regulatory approvals and commercializing product candidates will require substantial additional funding are prone to the risks of failure inherent in therapeutic product development.
Investment in biopharmaceutical product development involves significant risk that any potential product candidate will fail to demonstrate adequate efficacy or an acceptable safety profile, gain regulatory approval, or become commercially viable.
We cannot provide any assurance that we will be able to successfully advance any product candidates that we discover through the research process. Our
research programs may initially show promise, yet fail to yield product candidates for clinical development or commercialization for many reasons, including the following:
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our technology and approach may not be successful in identifying product candidates;
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we may not be able or willing to assemble sufficient resources to acquire or discover product candidates;
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our product candidates may not succeed in preclinical or clinical testing;
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our planned risk mitigation strategy for selecting our sentinel indications may fail or we may not be able to efficiently apply learnings from our initial development programs to future development programs;
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we may be unable to optimize the therapeutic efficiency, specificity, or selectivity of our future products candidates;
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our therapeutic delivery systems may fail so that even a product candidate with therapeutic activity does not demonstrate a clinically meaningful therapeutic effect;
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a product candidate may not demonstrate in patients the biological, chemical and pharmacological properties identified in laboratory and non-clinical studies, or they may interact with human biological systems in
unforeseen, ineffective or even harmful ways;
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a product candidate may on further study be shown to have harmful side effects or other characteristics that indicate it is unlikely to be effective or otherwise does not meet applicable regulatory criteria;
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the therapeutic effect of a product candidate may not be permanent and may diminish over time;
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a single treatment course may not be sufficient for a cure or therapeutic benefit; it may take several treatment courses for the product to be effective;
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a well-defined and achievable pathway to regulatory approval may never materialize for a specific product candidate;
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competitors may develop alternatives that render our product candidates obsolete or less attractive;
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product candidates we develop may be covered by third-party or other exclusive rights or may not receive desired regulatory exclusivity, and we may be unable to maintain, expand or protect our intellectual property
rights;
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the market for a product candidate may change during our program so that the continued development of that product candidate is no longer reasonable;
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a product candidate may not be capable of being produced in commercial quantities at an acceptable cost, or at all;
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we may be unable to successfully maintain existing collaborations or licensing arrangements or enter into new ones throughout the development process as appropriate; and
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a product candidate may not be accepted as safe and effective by physicians, patients, hospitals, third-party payors and others in the medical community.
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If any of these events occur, we may be forced to abandon our development efforts for a program or programs, or we may not be able to identify, discover,
develop or commercialize product candidates, which would have a material adverse effect on our business and could potentially cause us to cease operations.
Because we have limited financial and managerial resources, we focus on research programs that we identify as our sentinel indications. 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 that may later prove to have greater commercial potential,
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 retain sole development and commercialization rights. For additional
information regarding the factors that will affect our ability to achieve revenue from product sales, see the risk factor entitled -We have never generated any revenue from product sales and our ability to generate revenue from product sales
and become profitable depends significantly on our success in a number of factors.
If we do not successfully develop and commercialize product
candidates based upon our approach, we will not be able to obtain product revenue in future periods, which likely would result in significant harm to our financial position and adversely affect our stock price. Further, our current focus on
CRISPR/Cas9 technology for developing products as opposed to multiple, more proven technologies for product development increases the risk associated with our business. If we are not successful in developing a product candidate using CRISPR/Cas9
technology, we may not be able to successfully implement an alternative product development strategy.
Clinical development involves a lengthy and
expensive process, with an uncertain outcome. We may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of any product candidates.
All of our lead programs are still in the discovery stage, and their risk of failure is high. It is impossible to predict when or if any of our programs will
prove effective and safe in humans or will receive regulatory approval. Before obtaining marketing approval from regulatory authorities for the sale of any product candidate, we must complete preclinical development and then conduct extensive
clinical trials to demonstrate the safety and
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efficacy of any of our future product candidates in humans. Preclinical and clinical testing is expensive, difficult to design and implement, can take many years to complete and is uncertain as
to outcome. We may be unable to establish clinical endpoints that applicable regulatory authorities would consider clinically meaningful, and a clinical trial can fail at any stage of testing. The outcome of preclinical testing and early clinical
trials may not be predictive of the success of later clinical trials, and interim results of a clinical trial do not necessarily predict final results. Moreover, preclinical and clinical data are often susceptible to varying interpretations and
analyses, and many companies that have believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval of their products.
Successful completion of clinical trials is a prerequisite to submitting an NDA or BLA to the FDA, a Marketing Authorization Application (MAA) to the EMA and
similar approval filings to comparable foreign regulatory authorities, for each product candidate and, consequently, the ultimate approval and commercial marketing of any product candidates. We do not know whether any of our clinical trials will
begin or be completed on schedule, if at all.
We may experience delays in completing our preclinical studies and initiating or completing clinical
trials. We also may experience numerous unforeseen events during, or as a result of, any future clinical trials that we could conduct, which could delay or prevent our ability to receive marketing approval or commercialize our product candidates,
including:
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regulators or institutional review boards (IRBs) or ethics committees may not authorize us or our investigators to commence a clinical trial or conduct a clinical trial at a prospective trial site;
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we may experience delays in reaching, or fail to reach, agreement on acceptable terms with prospective trial sites and prospective contract research organizations (CROs), the terms of which can be subject to extensive
negotiation and may vary significantly among different CROs and trial sites;
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clinical trials of any product candidates may fail to show safety or efficacy, produce negative or inconclusive results and we may decide, or regulators may require us, to conduct additional preclinical studies or
clinical trials or we may decide to abandon product development programs;
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the number of patients required for clinical trials of any product candidates may be larger than we anticipate, enrollment in these clinical trials may be slower than we anticipate or participants may drop out of these
clinical trials or fail to return for post-treatment follow-up at a higher rate than we anticipate;
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our third-party contractors may fail to comply with regulatory requirements or meet their contractual obligations to us in a timely manner, or at all, or may deviate from the clinical trial protocol or drop out of the
trial, which may require that we add new clinical trial sites or investigators;
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we may elect to, or regulators, IRBs or ethics committees may require that we or our investigators, suspend or terminate clinical research or trials for various reasons, including noncompliance with regulatory
requirements or a finding that the participants are being exposed to unacceptable health risks;
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the cost of preclinical studies and clinical trials of any product candidates may be greater than we anticipate;
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the supply or quality of our product candidates or other materials necessary to conduct clinical trials of our product candidates may be insufficient or inadequate;
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our product candidates may have undesirable side effects or other unexpected characteristics, causing us or our investigators, regulators, IRBs or ethics committees to suspend or terminate the trials, or reports may
arise from preclinical or clinical testing of other gene therapies or gene editing based therapies that raise safety or efficacy concerns about our product candidates; and
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the FDA or other regulatory authorities may require us to submit additional data, such as long-term toxicology studies, or impose other requirements before permitting us to initiate a clinical trial.
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We could also encounter delays if a clinical trial is suspended or terminated by us, the IRBs of the institutions
in which such trials are being conducted, the Data Safety Monitoring Board (DSMB) for such trial or FDA or other regulatory authorities. Such authorities may impose such a suspension or termination 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 FDA 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 or treatment, failure to establish or achieve clinically meaningful trial endpoints, changes in governmental regulations or administrative
actions or lack of adequate funding to continue the clinical trial. Many of the factors that cause, or lead to, a delay in the commencement or completion of clinical trials may also ultimately lead to the denial of regulatory approval of our product
candidates. Further, the FDA or other regulatory authorities may disagree with our clinical trial design and our interpretation of data from clinical trials, or may change the requirements for approval even after they have reviewed and commented on
the design for our clinical trials.
Our product development costs will increase if we experience delays in clinical testing or marketing approvals. We do
not know whether any of our preclinical studies or clinical trials will begin as planned, will need to be restructured or will be completed on schedule, or at all. Significant preclinical or clinical trial delays also could shorten any periods
during which we may have the exclusive right to commercialize our product candidates and may allow our competitors to bring products to market before we do, potentially impairing our ability to successfully commercialize our product candidates and
harming our business and results of operations. Any delays in our preclinical or future clinical development programs may harm our business, financial condition and prospects significantly.
Inconclusive results, lack of efficacy, adverse events or additional safety concerns in clinical trials that we or others conduct may impede the
regulatory approval process or overall market acceptance of our future product candidates.
Therapeutic applications of gene editing technologies,
and CRISPR/Cas9 in particular, are unproven and must undergo rigorous clinical trials and regulatory review before receiving marketing authorization. If the results of our clinical studies or those of any other third parties, including with respect
to gene editing technology, are inconclusive, fail to show efficacy or if such clinical trials give rise to safety concerns or adverse events, we may:
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be delayed in obtaining marketing approval for our future product candidates, if at all;
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obtain approval for indications or patient populations that are not as broad as intended or desired;
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obtain approval with labeling that includes significant use or distribution restrictions or safety warnings;
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be subject to the addition of labeling statements, such as warnings or contraindications, or other types of regulatory restrictions or scrutiny;
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be subject to changes in the way the product is administered;
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be required to perform additional clinical studies to support approval or be subject to additional post-marketing testing requirements;
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have regulatory authorities modify or withdraw their written guidance, if any, regarding the applicable regulatory approval pathway or any approval of the product in question, or impose restrictions on its distribution
in the form of a modified REMS;
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experience damage to our reputation.
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Additionally, our future product candidates could potentially cause other
adverse events that have not yet been predicted and the potentially permanent nature of gene editing effects, including CRISPR/Cas9s effects, on genes may make these adverse events irreversible. The inclusion of critically ill patients in our
clinical studies or
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those of our competitors may result in deaths or other adverse medical events, including those due to other therapies or medications that such patients may be using. Any of these events could
prevent us from achieving or maintaining regulatory approval or market acceptance of our future product candidates and impair our ability to achieve profitability.
We have never generated any revenue from product sales and our ability to generate revenue from product sales and become profitable depends
significantly on our success in a number of factors.
We have no products approved for commercial sale, have not generated any revenue from
product sales, and do not anticipate generating any revenue from product sales until sometime after we have received regulatory approval for the commercial sale of a product candidate that we discover. Our ability to generate revenue and achieve and
retain profitability depends significantly on our success in many factors, including:
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selecting commercially viable product candidates and effective delivery methods;
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completing research and nonclinical and clinical development of product candidates;
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obtaining regulatory approvals and marketing authorizations for product candidates for which we complete clinical trials;
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developing a sustainable and scalable manufacturing process for product candidates, including establishing and maintaining commercially viable supply relationships with third parties and potentially establishing our own
manufacturing capabilities and infrastructure;
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launching and commercializing product candidates for which we obtain regulatory approvals and marketing authorizations, either directly or with a collaborator or distributor;
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accurately assessing the size and addressability of potential patient populations;
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obtaining market acceptance of our product candidates as viable treatment options;
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addressing any competing technological and market developments;
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negotiating favorable terms in any collaboration, licensing or other arrangements into which we may enter or which may be necessary for us to develop, manufacture or commercialize our product candidates;
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maintaining good relationships with our collaborators and licensors;
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maintaining, protecting and expanding our portfolio of intellectual property rights, including patents, trade secrets and know-how;
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avoiding infringement of or obtaining licenses to any valid intellectual property owned or controlled by third parties; and
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attracting, hiring and retaining qualified personnel.
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Even if one or more product candidates that we discover
and develop are approved for commercial sale, we anticipate incurring significant costs associated with commercializing any approved product candidate and the timing of such costs may be out of our control. Our expenses could increase beyond
expectations if we are required by the FDA or other regulatory agencies, domestic or foreign, to change our manufacturing processes or assays, or to perform clinical, nonclinical or other types of additional studies. If we are successful in
obtaining regulatory approvals to market one or more product candidates, our revenue will be dependent, in part, upon the size of the markets in the territories for which we gain regulatory approval, the accepted price for the product, the ability
to get reimbursement at any price and whether we own the commercial rights for that territory. If the number of our addressable disease patients is not as significant as we estimate, the indication approved by regulatory authorities is narrower than
we expect or the reasonably accepted population for treatment is narrowed by competition, physician choice or treatment guidelines, we may not generate significant revenue from sales of such products, even if approved. If we are not able to generate
revenue from the sale of any approved products, we may never become profitable.
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We face significant competition in an environment of rapid technological change. The possibility that our
competitors may achieve regulatory approval before we do or develop therapies that are more advanced or effective than ours may harm our business and financial condition or our ability to successfully market or commercialize our product candidates.
The biotechnology and pharmaceutical industries, including the gene editing field, are characterized by rapidly changing technologies,
significant competition and a strong emphasis on intellectual property. We face substantial competition from many different sources, including large and specialty pharmaceutical and biotechnology companies, academic research institutions, government
agencies and public and private research institutions.
Competitors in our efforts to provide genetic therapies to patients can be grouped into at least
three sets based on their product discovery platforms:
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gene editing companies focused on CRISPR/Cas9 including: Casebia Therapeutics, CRISPR Therapeutics, Inc., Editas Medicine, Inc. and Tracr Hematology Limited;
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other gene editing companies including: bluebird bio, Inc., Cellectis S.A., Poseida, Inc., Precision BioSciences, Inc. and Sangamo BioSciences; and
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gene therapy companies developing ex vivo therapies including: bluebird bio, Inc., Cellectis S.A., Juno Therapeutics, Inc. and Kite Pharma, Inc.
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Our competitors will also include companies that are or will be developing other gene editing methods as well as small molecules, biologics and nucleic
acid-based therapies for the same indications that we are targeting with our CRISPR/Cas9-based therapeutics.
Any advances in gene therapy or gene editing
technology made by a competitor may be used to develop therapies that could compete against any of our product candidates. Many of these competitors have substantially greater research and development capabilities and financial, scientific,
technical, intellectual property, manufacturing, marketing, distribution and other resources than we do, and we may not be able to successfully compete with them.
To become and remain profitable, we must discover, develop and eventually commercialize product candidates with significant market potential, which will
require us to be successful in a range of challenging activities. These activities can include completing preclinical studies and clinical trials of product candidates, obtaining marketing approval for product candidates, manufacturing, marketing
and selling products that are approved and satisfying any post-marketing requirements. Even if we are successful in selecting and developing any product candidates, in order to compete successfully we may need to be first-to-market or demonstrate
that our CRISPR/Cas9-based products are superior to therapies based on the same or different treatment methods. If we are not first-to-market or are unable to demonstrate such superiority, any products for which we are able to obtain approval may
not be successful. Furthermore, in certain jurisdictions, if a competitor has orphan drug status for a product and if our product candidate is determined to be contained within the scope of a competitors orphan drug exclusivity, then approval
of our product for that indication or disease could potentially be blocked, for example, for up to seven years in the United States and 10 years in the EU.
We may never succeed in any or all of these activities and, even if we do, we may never generate revenues that are significant or large enough to achieve
profitability. If we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis. Our failure to become and remain profitable would decrease the value of our company and could impair our ability
to raise capital, maintain our research and development efforts, expand our business or continue our operations.
We have a very limited operating
history, which may make it difficult to evaluate our current business and predict our future performance.
We are very early in our development
efforts and all of our lead programs are still in the discovery stage. We were formed in May 2014, have no products approved for commercial sale and have not generated any revenue
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from product sales. Our ability to generate product revenue or profits, which we do not expect will occur for many years, if ever, will depend heavily on the successful development and eventual
commercialization of our product candidates, which may never occur. We may never be able to develop or commercialize a marketable product.
Each of our
programs will require additional discovery research and then preclinical and clinical development, regulatory approval in multiple jurisdictions, obtaining manufacturing supply, capacity and expertise, building of a commercial organization,
substantial investment and significant marketing efforts before we generate any revenue from product sales. In addition, our product candidates must be approved for marketing by the FDA or certain other foreign regulatory agencies, including the
EMA, before we may commercialize any product.
Our limited operating history, particularly in light of the rapidly evolving gene editing field, may make
it difficult to evaluate our current business and predict our future performance. Our very short history as an operating company makes any assessment of our future success or viability subject to significant uncertainty. We will encounter risks and
difficulties frequently experienced by very early stage companies in rapidly evolving fields. If we do not address these risks successfully, our business will suffer.
We have incurred net losses in each period since our inception, anticipate that we will continue to incur net losses in the future and may never achieve
profitability.
We are not profitable and have incurred losses in each period since our inception. Our net loss was $31.6 million for the year
ended December 31, 2016. As of December 31, 2016, we had an accumulated deficit of $53.6 million. We expect these losses to increase as we continue to incur significant research and development and other expenses related to our ongoing
operations, seek regulatory approvals for our future product candidates, scale-up manufacturing capabilities, maintain, expand and protect our intellectual property portfolio and hire additional personnel to support the development of our product
candidates and to enhance our operational, financial and information management systems.
A critical aspect of our strategy is to invest significantly in
our technology to improve the efficacy and safety of potential product candidates that we discover. Even if we succeed in discovering, developing and ultimately commercializing one or more of these product candidates, we will continue to incur
losses for the foreseeable future relating to our substantial research and development expenditures to develop our technologies. We may encounter unforeseen expenses, difficulties, complications, delays and other unknown factors that may adversely
affect our business. The size of our future net losses will depend, in part, on the rate of future growth of our expenses and our ability to generate revenue. Our prior losses and expected future losses have had and will continue to have an adverse
effect on our stockholders equity and working capital. Further, the net losses we incur may fluctuate significantly from quarter to quarter and year to year, such that a period to period comparison of our results of operations may not be a
good indication of our future performance.
We will need to raise substantial additional funding. If we fail to obtain additional financing, we may
be unable to complete the development and commercialization of any product candidates.
Our operations have required substantial amounts of cash
since inception, and we expect to spend substantial amounts of our financial resources on our discovery programs going forward. If we are able to identity product candidates that are eventually approved, we will require significant additional
amounts in order to launch and commercialize our product candidates. For the foreseeable future, we expect to continue to rely on additional financing to achieve our business objectives.
We will require additional capital for the further development and commercialization of any product candidates and may need to raise additional funds sooner
if we choose to expand more rapidly than we presently anticipate or due to other unanticipated factors.
We cannot be certain that additional funding will
be available on acceptable terms, or at all. We have no committed source of additional capital and if we are unable to raise additional capital in sufficient amounts or on
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terms acceptable to us, we may have to significantly delay, scale back or discontinue the development or commercialization of our product candidates or other research and development initiatives.
Our collaboration and license agreements may also be terminated if we are unable to meet the payment or other obligations under the agreements. We could be required to seek collaborators for product candidates at an earlier stage than otherwise
would be desirable or on terms that are less favorable than might otherwise be available or relinquish or license on unfavorable terms our rights to product candidates in markets where we otherwise would seek to pursue development or
commercialization ourselves.
Any of the above events could significantly harm our business, prospects, financial condition and results of operations and
cause the price of our common stock to decline.
Raising additional capital may cause dilution to our stockholders and restrict our operations.
We will need additional capital in the future to continue our planned operations. To the extent that we raise additional capital through the sale
of equity or convertible debt securities, the ownership interest of our existing stockholders may be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect the rights of our common stockholders.
Debt financing and preferred equity financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring
dividends.
If we experience delays or difficulties in the enrollment of patients in clinical trials, our ability to complete clinical trials or our
receipt of necessary regulatory approvals could be delayed or prevented.
We may not be able to initiate or continue clinical trials for any
future 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 similar regulatory authorities outside the United States. If patients are unwilling to
participate in our clinical studies because of concerns about, or negative publicity from, adverse events in the gene editing field, the novel nature of the CRISPR/Cas9 gene editing technology, the irreversibility of the effects of CRISPR/Cas9 or
for other reasons, including competitive clinical studies for similar patient populations, then the timeline for recruiting patients, conducting studies and obtaining regulatory approval of potential products may be delayed. These delays could
result in increased costs, delays in advancing our product development, delays in testing the effectiveness of our technology or termination of the clinical studies altogether. In addition, any patients who would otherwise be eligible for clinical
trials that we may hold may instead enroll in clinical trials of product candidates of our competitors.
Patient enrollment is affected by other factors
including:
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the size, location and nature of the patient population;
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the severity of the disease under investigation;
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the patient eligibility criteria for the study in question;
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the perceived risks and benefits of the product candidate under study;
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the design of the clinical trial;
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our payments for conducting clinical trials;
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the patient referral practices of physicians;
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the ability to monitor patients adequately during and after treatment; and
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the proximity and availability of clinical trial sites for prospective patients.
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Our inability to enroll a
sufficient number of patients for clinical trials would result in significant delays and could require us to abandon one or more clinical trials altogether. Enrollment delays in clinical trials may result in increased development costs for any of
our potential future product candidates, which would cause the value
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of our company to decline and limit our ability to obtain additional financing. Furthermore, we expect to rely on CROs and clinical trial sites to ensure the proper and timely conduct of our
clinical trials, and, while we expect to enter into agreements governing their committed activities, we will have limited influence over their actual performance.
We expect to expand our research, development and regulatory capabilities, and, as a result, we may encounter difficulties in hiring capable personnel
and otherwise managing our growth, which could disrupt our operations.
We expect to experience significant growth in the number of our employees
and the scope of our operations, particularly in the areas of technology research, product development, regulatory affairs and, if any product candidates are submitted for or receive marketing approval, sales, marketing and distribution. To manage
our anticipated future growth, we must continue to implement and improve our managerial, operational and financial systems, expand our facilities and continue to recruit and train additional qualified personnel. Due to our limited financial
resources and the limited experience of our management team in managing a company with such anticipated growth, we may not be able to recruit and train additional qualified personnel or to otherwise effectively manage the expansion of our
operations. The expansion of our operations may lead to significant costs and may divert our management and business development resources. Any inability to manage growth could delay the execution of our business and development plans or disrupt our
operations.
Our future success depends on our ability to retain key executives and to attract, retain and motivate qualified personnel.
We are highly dependent on the research and development, clinical, legal and business development expertise of Nessan Bermingham, Ph.D., our
President and Chief Executive Officer, John M. Leonard, M.D., our Executive Vice President, Research & Development, Graeme Bell, our Executive Vice President, Chief Financial Officer, and José E. Rivera, our Executive Vice President,
General Counsel as well as the other principal members of our management, scientific and clinical teams. Although we have entered into employment arrangements with our executive officers, each of them may terminate their employment with us at any
time. We do not maintain key person insurance for any of our executives or other employees.
Recruiting and retaining qualified scientific,
clinical, manufacturing and sales and marketing personnel will also be important for our success. The loss of the services of our executive officers or other key employees could impede the achievement of our research, development and
commercialization objectives and seriously harm our ability to successfully implement our business strategy. Furthermore, replacing executive officers and key employees may be difficult and may take an extended period of time because of the limited
number of individuals in our industry with the breadth of skills and experience required to successfully develop, gain regulatory approval of and commercialize products using our technology. Competition to hire from this limited pool is intense, and
we may be unable to hire, train, retain or motivate these key personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies, universities and research institutions for similar personnel. The market for
qualified personnel in the biotechnology space generally, and gene editing and gene therapy fields in particular, in and around the Cambridge, Massachusetts area is especially competitive. In addition, we rely on consultants and advisors, including
scientific and clinical advisors, to assist us in formulating our research and development and commercialization strategies. 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. Further, some of the qualified personnel that we hire and recruit are not United States citizens, and there is uncertainty with regard to their future employment status
due to the new U.S. presidential administrations announced intention of modifying the legal framework for non-U.S. citizens to be employed in the United States. If we are unable to continue to attract and retain high quality personnel, our
ability to pursue our growth strategy will be limited.
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If, in the future, we are unable to establish sales, marketing and distribution capabilities or enter into
agreements with third parties to sell, market and distribute products based on our technologies, we may not be successful in commercializing our products if and when any products candidates or therapies are approved and we may not be able to
generate any revenue.
We do not currently have a sales, marketing or distribution infrastructure and, as a company, have no experience in the
sale, marketing or distribution of therapeutic products. To achieve commercial success for any approved product candidate for which we retain sales and marketing responsibilities, we must build our sales, marketing, managerial and other
non-technical capabilities or make arrangements with third parties to perform these services. In the future, we may choose to build a focused sales and marketing infrastructure to sell, or participate in sales activities with our collaborators for,
some of our product candidates if they are approved.
There are risks involved with both establishing our own sales and marketing capabilities and
entering into arrangements with third parties to perform these services. For example, recruiting and training a sales force is expensive and time consuming and could delay any product launch. If the commercial launch of a product candidate for which
we recruit a sales force and establish marketing capabilities is delayed or does not occur for any reason, we would have prematurely or unnecessarily incurred these commercialization expenses. This may be costly and our investment would be lost if
we cannot retain or reposition our sales and marketing personnel.
Factors that may inhibit our efforts to commercialize our product candidates on our own
include:
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our inability to recruit, train and retain adequate numbers of effective sales and marketing personnel;
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the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe any future product candidates that we may develop;
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the lack of complementary treatments to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines;
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the location of patients in need of our product candidates and the treating physicians who may prescribe the products; and
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unforeseen costs and expenses, as well as legal and regulatory requirements, associated with creating and operating a sales and marketing organization.
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If we enter into arrangements with third parties to perform sales, marketing and distribution services, our product revenue or the profitability to us from
these revenue streams is likely to be lower than if we were to market and sell any product candidates that we develop ourselves. In addition, we may not be successful in entering into arrangements with third parties to sell and market our product
candidates or may be unable to do so on terms that are favorable to us. We likely will have little control over such third parties and any of them may fail to devote the necessary resources and attention to sell and market our product candidates
effectively. If we do not establish sales and marketing capabilities successfully, either on our own or in collaboration with third parties, we may not be successful in commercializing our product candidates. Further, our business, results of
operations, financial condition and prospects will be materially adversely affected.
Our technological advancements and any potential for revenue
may be derived in part from our collaborations with Novartis and Regeneron, and if either of these collaboration agreements were to be terminated, our business, financial condition, results of operations and prospects would be harmed.
In December 2014, we entered into a collaboration agreement with Novartis regarding the discovery of new CRISPR/Cas9-based therapies principally using CAR-T
cells and HSCs. Under the Novartis collaboration agreement, we received a commitment to advance multiple programs. Pursuant to the Novartis agreement, we granted Novartis exclusive rights to further develop any products arising out of the CAR-T cell
program during the research term. Regarding HSCs, we plan to jointly advance multiple programs with Novartis and have agreed to a process for assigning development and ownership rights, which will enable us to develop our own proprietary HSC
pipeline.
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In April 2016, we entered into a collaboration agreement with Regeneron that includes a product component to
research, develop and commercialize CRISPR/Cas-based therapeutic products primarily focused on gene editing in the liver as well as a technology collaboration component, pursuant to which we and Regeneron will engage in research and development
activities aimed at discovering and developing novel technologies and improvements to CRISPR/Cas technology to enhance our gene editing platform. Pursuant to the Regeneron collaboration agreement, we granted Regeneron exclusive rights to select up
to ten targets, subject to certain restrictions, while we retain the rights to solely develop our sentinel indications, other than ATTR, which is subject to a co-development and co-commercialization arrangement with Regeneron and have the right to
choose additional liver targets for our own development during the collaboration term. Certain other of the development targets under the Regeneron agreement may also be subject to a co-development/co-commercialization arrangement with the other
party at the other partys option.
Either Novartis or Regeneron may change its strategic focus or pursue alternative technologies in a manner that
results in reduced, delayed or no revenue to us. Each of Novartis and Regeneron has a variety of marketed products and product candidates under collaboration with other companies, including some of our competitors, and Novartiss or
Regenerons respective corporate objectives may not be consistent with our best interests. If either of our collaboration partners fails to develop, obtain regulatory approval for or ultimately commercialize any product candidate from the
development programs governed by the respective collaboration agreement in the applicable territories, or if either of our collaboration partners terminates our collaboration with it, our business, financial condition, results of operations and
prospects could be harmed. In addition, any dispute or litigation proceedings we may have with either Novartis or Regeneron in the future could delay development programs, create uncertainty as to ownership of or access to intellectual property
rights, distract management from other business activities and generate substantial expense.
Our existing and future collaborations will be
important to our business. If we are unable to maintain any of these collaborations, or if these collaborations are not successful, our business could be adversely affected.
We have limited capabilities for product development and do not yet have any capability for sales, marketing or distribution. Accordingly, we have entered,
and plan to enter, into collaborations with other companies, including our therapeutic-focused collaboration agreements with Novartis and Regeneron, that we believe can provide such capabilities. These collaborations provide us with important
technologies and funding for our programs and technology, and we expect to receive additional technologies and funding under these and other collaborations in the future. Our existing therapeutic collaborations, and any future collaborations we
enter into, may pose a number of risks, including the following:
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collaborators have significant discretion in determining the efforts and resources that they will apply;
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collaborators may not perform their obligations as expected;
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collaborators may not pursue development and commercialization of any product candidates that achieve regulatory approval or may elect not to continue or renew development or commercialization programs or license
arrangements based on clinical trial results, changes in the collaborators strategic focus or available funding, or external factors, such as a strategic transaction that may divert resources or create competing priorities;
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collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new
formulation of a product candidate for clinical testing;
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collaborators could develop independently or with third parties products that compete directly or indirectly with our products and product candidates if the collaborators believe that the competitive products are more
likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours;
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product candidates discovered in collaboration with us may be viewed by our collaborators as competitive with their own product candidates or products, which may cause collaborators to cease to devote resources to the
development or commercialization of our product candidates;
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collaborators may fail to comply with applicable legal and regulatory requirements regarding the development, manufacture, sale, distribution or marketing of a product candidate or product;
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collaborators with sale, marketing and distribution rights to one or more of our product candidates that achieve regulatory approval may not commit sufficient resources to the sale, marketing and distribution of such
product or products;
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disagreements with collaborators, including disagreements over proprietary rights, contract interpretation or the preferred course of development, sales or marketing, might cause delays or terminations of the research,
development or commercialization of product candidates, might lead to additional and burdensome responsibilities for us with respect to product candidates, or might result in litigation or arbitration, any of which would be time-consuming and
expensive;
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collaborators may not properly maintain or defend their or our relevant intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our
intellectual property or proprietary information or expose us to potential litigation and liability;
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collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability;
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if a collaborator of ours is involved in a business combination or cessation, the collaborator might deemphasize or terminate the development or commercialization of any product candidate licensed to it by us; and
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collaborations may be terminated by the collaborator, and, if terminated, we could be required to raise additional capital to pursue further development or commercialization of the applicable product candidates.
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If our therapeutic collaborations do not result in the successful discovery, development and commercialization of products or if one of our
collaborators terminates its agreement with us, we may not receive any future research funding or milestone or royalty payments under the collaboration. If we do not receive the funding we expect under these agreements, our development and
commercialization of our technology and product candidates could be delayed and we may need additional resources to develop product candidates and our technology. All of the risks relating to product development, regulatory approval and
commercialization described in this report also apply to the activities of our therapeutic collaborators.
Additionally, if one of our collaborators
terminates its agreement with us, we may find it more difficult to attract new collaborators and our perception in the business and financial communities could be adversely affected.
For some of our programs, we may in the future determine to collaborate with pharmaceutical and biotechnology companies for development and potential
commercialization of therapeutic products. We face significant competition in seeking appropriate collaborators. Our ability to reach a definitive agreement for a collaboration will depend, among other things, upon our assessment of the
collaborators resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborators evaluation of a number of factors. If we are unable to reach agreements with suitable collaborators on a timely
basis, on acceptable terms, or at all, we may have to curtail the development of a product candidate, reduce or delay its development program or one or more of our other development programs, delay its potential commercialization or reduce the scope
of any sales or marketing activities, or increase our expenditures and undertake development or commercialization activities at our own expense. If we elect to fund and undertake development or commercialization activities on our own, we may need to
obtain additional expertise and additional capital, which may not be available to us on acceptable terms or at all. If we fail to enter into collaborations and do not have sufficient funds or expertise to undertake the
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necessary development and commercialization activities, we may not be able to further develop our product candidates, bring them to market or continue to develop our technology and our business
may be materially and adversely affected.
Gene editing products are novel and may be complex and difficult to manufacture. We could experience
manufacturing problems that result in delays in the development or commercialization of our product candidates or otherwise harm our business.
The manufacturing process used to produce CRISPR/Cas9-based product candidates may be complex, as they are novel and have not been validated for clinical and
commercial production. Several factors could cause production interruptions, including equipment malfunctions; facility unavailability or contamination; raw material cost, shortages or contamination; natural disasters; disruption in utility
services; human error; insufficient personnel; inability to meet legal or regulatory requirements; or disruptions in the operations of our suppliers.
Our
product candidates will require processing steps that are more complex than those required for most small molecule drugs. Moreover, unlike small molecules, the physical and chemical properties of a complex product such as ours generally cannot be
fully characterized. As a result, assays of the finished product or relevant components may not be sufficient to ensure that the product will perform in the intended manner. Accordingly, we will employ multiple steps to control the manufacturing
process to assure that the process works and the product candidate is made strictly and consistently in compliance with the process. 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 and litigation, insufficient inventory or production interruption. We may encounter problems achieving adequate quantities and quality of
clinical grade materials that meet FDA, EMA or other applicable standards or specifications with consistent and acceptable production yields and costs.
In addition, the FDA, the EMA and other foreign 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. Under some circumstances, the FDA, the EMA or other foreign regulatory authorities may require that we not distribute a lot until the relevant agency authorizes its release. Slight
deviations in the manufacturing process, including those affecting quality attributes and stability, may result in unacceptable changes in the product that could result in lot failures, product recalls or production interruption. Lot failures,
product recalls or production interruption could cause us to delay product launches or clinical trials, which could be costly to us and otherwise harm our business, financial condition, results of operations and prospects. Problems in our
manufacturing process could restrict our ability to meet market demand for our products.
We also may encounter problems hiring and retaining the
experienced scientific, quality-control and manufacturing personnel needed to operate our manufacturing processes, which could result in delays in production or difficulties in maintaining compliance with applicable regulatory requirements.
Any problems in our manufacturing process or facilities 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.
We expect to rely on
third parties to manufacture our clinical product supplies, and we intend to rely on third parties for at least a portion of the manufacturing process of our product candidates, if approved. Our business could be harmed if the third parties fail to
provide us with sufficient quantities of product inputs or fail to do so at acceptable quality levels or prices or fail to meet legal and regulatory requirements.
We do not currently own any facility that may be used as our clinical-scale manufacturing and processing facility and must eventually rely on outside vendors
to manufacture supplies and process our product candidates. We have not yet caused any product candidates to be manufactured or processed on a commercial scale and may not be able to do so for any of our product candidates. We will make changes as
we work to optimize the
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manufacturing process, and we cannot be sure that even minor changes in the process will result in therapies that are safe, potent or effective.
The facilities used by our contract manufacturers to manufacture our product candidates must be approved by the FDA or other foreign regulatory agencies
pursuant to inspections that will be conducted after we submit an application to the FDA or other foreign regulatory agencies. We do not control the manufacturing process of, and will be completely dependent on, our contract manufacturing partners
for compliance with legal and regulatory requirements for manufacture, including cGMP, and in certain cases, cGTP, requirements of our product candidates. If our contract manufacturers cannot successfully manufacture material that conforms to our
specifications and the strict regulatory requirements of the FDA or other regulatory authorities, they will not be able to secure and/or maintain regulatory approval for their manufacturing facilities. In addition, we have no control over the
ability of our contract manufacturers to maintain adequate quality control, quality assurance and qualified personnel. If the FDA or a comparable foreign regulatory authority does not approve these facilities for the manufacture of our product
candidates or if it withdraws any such approval in the future, we may need to find alternative manufacturing facilities, which would significantly impact our ability to develop, obtain regulatory approval for or market our product candidates, if
approved.
We will rely on third parties to conduct our clinical trials. If these third parties do not successfully carry out their contractual
duties or meet expected deadlines or comply with legal and regulatory requirements, we may not be able to obtain regulatory approval of or commercialize any potential product candidates.
We will depend upon third parties, including independent investigators, to conduct our clinical trials under agreements with universities, medical
institutions, CROs, strategic partners and others. We expect to have to negotiate budgets and contracts with CROs and trial sites, which may result in delays to our development timelines and increased costs.
We will rely heavily on third parties over the course of our clinical trials, and, as a result, will have limited control over the clinical investigators and
limited visibility into their day-to-day activities, including with respect to their compliance with the approved clinical protocol and other legal, regulatory and scientific standards. Nevertheless, we are responsible for ensuring that each of our
studies is conducted in accordance with the applicable protocol and legal, regulatory and scientific standards, and our reliance on third parties does not relieve us of our legal responsibilities. We and these third parties are required to comply
with good clinical practice, or GCP, requirements, which are regulations and guidelines enforced by the FDA and comparable foreign regulatory authorities for product candidates in clinical development. Regulatory authorities enforce these GCP
requirements through periodic inspections of trial sponsors, clinical investigators and trial sites. If we or any of these third parties fail to comply with applicable GCP requirements, the clinical data generated in our clinical trials may be
deemed unreliable and the FDA or comparable foreign regulatory authorities may require us to suspend or terminate these trials or perform additional preclinical studies or clinical trials before approving our marketing applications. We cannot be
certain that, upon inspection, such regulatory authorities will determine that any of our clinical trials comply with the GCP requirements. In addition, our clinical trials must be conducted with product produced under cGMP, and in certain cases,
cGTP, requirements and may require a large number of test patients.
Our failure or any failure by these third parties to comply with these requirements
or to recruit a sufficient number of patients may require us to repeat clinical trials, which would delay the regulatory approval process. Moreover, our business may be implicated if any of these third parties violates applicable federal, state or
local, as well as foreign, laws and regulations, such as the fraud and abuse or false claims laws and regulations or privacy and security laws.
Any third
parties conducting our future clinical trials will not be our employees and, except for remedies that may be available to us under our agreements with such third parties, we cannot control whether or not they devote sufficient time and resources to
our ongoing preclinical, clinical, and nonclinical programs. These third parties may also have relationships with other commercial entities, including our competitors, for whom they
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may also be conducting clinical trials or other product development activities, which could affect their performance on our behalf. If these third parties do not successfully carry out their
contractual duties or obligations or meet expected deadlines, if they need to be replaced or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical protocols or regulatory requirements
or for other reasons, our clinical trials may be extended, delayed or terminated and we may not be able to complete development of, obtain regulatory approval of or successfully commercialize our product candidates. As a result, our financial
results and the commercial prospects for our product candidates would be harmed, our costs could increase and our ability to generate revenue could be delayed.
If any of our relationships with these third-party CROs or others terminate, we may not be able to enter into arrangements with alternative CROs or other
third parties or to do so on commercially reasonable terms. Switching or adding additional CROs involves additional cost and requires management time and focus. In addition, the transition to a new CRO may result in delays, which can materially
impact our ability to meet our desired clinical development timelines. Though we carefully manage our relationships with our CROs, there can be no assurance that we will not encounter similar challenges or delays in the future or that these delays
or challenges will not have a material adverse impact on our business, financial condition and prospects.
Unfavorable global economic conditions or
political developments could adversely affect our business, financial condition or results of operations.
Our results of operations could be
adversely affected by general conditions in the global economy and in the global financial markets. For example, recent political unrest and global financial crises caused extreme volatility and disruptions in the capital and credit markets. A
severe or prolonged economic downturn, political unrest or additional global financial crises, could result in a variety of risks to our business, including weakened demand for our products, if approved, or our ability to raise additional capital
when needed on acceptable terms, if at all. A weak or declining economy could also strain our suppliers, possibly resulting in supply disruption. Any of the foregoing could harm our business and we cannot anticipate all of the ways in which the
current economic climate, further political developments and financial market conditions could adversely impact our business.
Our internal computer
systems, or those of our collaborators or other contractors or consultants, may fail or suffer security breaches, which could result in a material disruption of our product development programs.
Our internal computer systems and those of our current and any future collaborators and other contractors or consultants are vulnerable to damage from
computer viruses, unauthorized access, natural disasters, terrorism, war and telecommunication and electrical failures. While we have not experienced any such material system failure, accident or security breach to date, if such an event were to
occur and cause interruptions in our operations, it could result in a disruption of our development programs and our business operations, whether due to a loss of our trade secrets or other proprietary information or other similar disruptions. For
example, the loss of clinical trial data from completed or future clinical trials could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. To the extent that any disruption or
security breach were to result in a loss of, or damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability, our competitive position could be harmed and the further
development and commercialization of our product candidates could be delayed.
Risks Related to Government Regulation
The regulatory approval process for our potential product candidates in the United States, EU and other jurisdictions is currently uncertain and will be
lengthy, time-consuming and inherently unpredictable and we may experience significant delays in the clinical development and regulatory approval, if any, of our product candidates.
The research, testing, manufacturing, labeling, approval, selling, import, export, marketing and distribution of drug products, including biologics, are
subject to extensive regulation by the FDA in the United States and other
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regulatory authorities. We are not permitted to market any drug or biological product in the United States until we receive regulatory approval from the FDA. We have not previously submitted an
NDA or BLA to the FDA, or similar approval filings to comparable foreign authorities. An NDA or BLA must include extensive preclinical and clinical data and supporting information to establish that the product candidate is safe and effective or, for
biological products, safe, pure and potent for each desired indication. The application must also include significant information regarding the chemistry, manufacturing and controls for the product, and the manufacturing facilities must complete a
successful pre-approval inspection by the FDA, or applicable foreign authority, prior to the approval or licensure of the product. We expect the novel nature of our product candidates to create further challenges in obtaining regulatory approval.
For example, the FDA currently has no experience evaluating CRISPR/Cas9-based therapies for human therapeutic use. The FDA may also require a panel of experts, referred to as an Advisory Committee, to deliberate on the adequacy of the safety and
efficacy data to support approval. The opinion of the Advisory Committee, although not binding, may have a significant impact on our ability to obtain approval of any product candidates that we develop based on the completed clinical trials.
Moreover, while we are not aware of any specific genetic or biomarker diagnostic tests for which regulatory approval would be necessary in order to advance any of our product candidates to clinical trials or potential commercialization, in the
future regulatory agencies may require the development and approval of such tests. Accordingly, the regulatory approval pathway for such product candidates may be uncertain, complex, expensive and lengthy, and approval may not be obtained.
In addition, clinical trials can be delayed or terminated for a variety of reasons, including delays or failures related to:
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obtaining and maintaining regulatory authorization to conduct a trial, if applicable;
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the availability of financial resources to begin and complete the planned trials;
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reaching agreement on acceptable terms with prospective CROs and clinical trial sites, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and trial sites;
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obtaining approval at each clinical trial site by an independent IRB;
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recruiting suitable patients to participate in a trial in a timely manner;
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having patients complete a trial or return for post-treatment follow-up;
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clinical trial sites deviating from trial protocol, not complying with GCP requirements or dropping out of a trial;
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addressing any patient safety concerns that arise during the course of a trial;
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addressing any conflicts with new or existing laws or regulations;
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adding new clinical trial sites; or
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manufacturing qualified materials under cGMP regulations for use in clinical trials.
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Patient enrollment is a
significant factor in the timing of clinical trials and is affected by many factors. Further, a clinical trial may be suspended or terminated by us, the IRBs for the institutions in which such trials are being conducted, the DSMB for such trial or
the FDA or other regulatory authorities 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 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. If we experience termination of, or delays in the completion of, any clinical trial of product candidates, the commercial prospects for our product candidates will be
harmed, and our ability to generate product revenue will be impaired. In addition, any delays in completing any clinical trials will increase our costs, slow down our product development and approval process and jeopardize our ability to commence
product sales and generate revenue.
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Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean
that we will be successful in obtaining regulatory approval of product candidates in other jurisdictions.
Obtaining and maintaining regulatory
approval of our product candidates in one jurisdiction does not guarantee that we will be able to obtain or maintain regulatory approval in any other jurisdiction, but a failure or delay in obtaining regulatory approval in one jurisdiction may have
a negative effect on the regulatory approval process in others. For example, even if the FDA grants marketing approval of a product candidate, comparable regulatory authorities in foreign jurisdictions must also approve the manufacturing, marketing
and sale of the product candidate in those countries. Approval procedures vary among jurisdictions and can involve requirements and administrative review periods different from those in the United States, including additional preclinical studies or
clinical trials as clinical studies conducted in one jurisdiction may not be accepted by regulatory authorities in other jurisdictions. In many jurisdictions outside the United States, a product candidate must be approved for reimbursement before it
can be approved for sale in that jurisdiction. In some cases, the price that we are allowed to charge for our products is also subject to approval.
Obtaining foreign regulatory approvals and compliance with foreign regulatory requirements could result in significant delays, difficulties and costs for us
and could delay or prevent the introduction of our products in certain countries. If we fail to comply with the regulatory requirements in international markets or to receive applicable marketing approvals, our target market will be reduced and our
ability to realize the full market potential of our product candidates will be harmed.
Even if we receive regulatory approval of any product
candidates or therapies, we will be subject to ongoing regulatory obligations and continued regulatory review, which may result in significant additional expense and we may be subject to penalties if we fail to comply with regulatory requirements or
experience unanticipated problems with our product candidates.
If any of our product candidates are approved, they will be subject to ongoing
regulatory requirements for manufacturing, labeling, packaging, distribution, storage, advertising, promotion, sampling, record-keeping, conduct of post-marketing studies and submission of safety, efficacy and other post-market information,
including both federal and state requirements in the United States and requirements of comparable foreign regulatory authorities. In addition, we will be subject to continued compliance with cGMP and GCP, and in certain cases, cGTP, requirements for
any clinical trials that we conduct post-approval.
Manufacturers and manufacturers facilities are required to comply with extensive FDA, and
comparable foreign regulatory authority requirements, including ensuring that quality control and manufacturing procedures conform to cGMP, and in certain cases, cGTP, requirements. As such, we and our contract manufacturers will be subject to
continual review and inspections to assess compliance with cGMP and adherence to commitments made in any NDA or BLA, other marketing application, and previous responses to inspection observations. Accordingly, we and others with whom we work must
continue to expend time, money, and effort in all areas of regulatory compliance, including manufacturing, production and quality control.
Any regulatory
approvals that we receive for our product candidates may be subject to limitations on the approved indicated uses for which the product may be marketed or to the conditions of approval, or contain requirements for potentially costly post-marketing
testing, including Phase IV clinical trials and surveillance to monitor the safety and efficacy of the product candidate. The FDA may also require a REMS program as a condition of approval of our product candidates, which could entail requirements
for long-term patient follow-up, a medication guide, physician communication plans or additional elements to ensure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. In addition, if the FDA or a
comparable foreign regulatory authority approves our product candidates, we will have to comply with legal or regulatory requirements including submissions of safety and other post-marketing information and reports and registration.
The FDA may seek to impose consent decrees or withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems
occur after the product reaches the market. Later discovery of
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previously unknown problems with our product candidates, including adverse events of unanticipated severity or frequency, or with our third-party manufacturers or manufacturing processes, or
failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical studies to assess new safety risks; or imposition of distribution
restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:
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restrictions on the marketing or manufacturing of our products, withdrawal of the product from the market or voluntary or mandatory product recalls;
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fines, warning letters or holds on clinical trials;
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refusal by the FDA to approve pending applications or supplements to approved applications filed by us or suspension or revocation of license approvals;
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product seizure or detention or refusal to permit the import or export of our product candidates; and
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injunctions or the imposition of civil or criminal penalties.
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The FDA strictly regulates marketing, labeling,
advertising, and promotion of products that are placed on the U.S. market. Products may be promoted only for the approved indications and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws
and regulations prohibiting the promotion of off-label uses and a company that is found to have improperly promoted off-label uses may be subject to significant liability. The policies of the FDA and of other regulatory authorities may change and
additional government regulations may be enacted that could prevent, limit or delay regulatory approval of our product candidates. We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or
administrative action, either in the United States or abroad. If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory and legal compliance,
we may lose any marketing approval that we may have obtained and we may not achieve or sustain profitability.
Healthcare cost control initiatives,
including healthcare legislative reform measures, may have a material adverse effect on our business and results of operations.
Third-party
payors, whether domestic or foreign, or governmental or commercial, are developing increasingly sophisticated methods of controlling healthcare costs. In both the United States and certain foreign jurisdictions, there have been, and are expected to
continue to be, a number of legislative and regulatory changes to the health care system that could impact our ability to sell our products profitably. In the United States, however, significant uncertainty exists regarding the provision and
financing of health care because the new presidential administration and federal legislators have publicly declared their intention to significantly modify the current legal and regulatory framework for the health care system but details have not
been agreed upon or disclosed.
Current legislation at the United States federal and state levels seeks to reduce healthcare costs and improve the quality
of healthcare. In March 2010, the Affordable Care Act was enacted, which substantially changed the way health care is financed by both governmental and private insurers, and significantly impacted the U.S. pharmaceutical and biotechnology industry.
The Affordable Care Act, among other things, subjects biologic products to potential competition by lower-cost biosimilars, addresses a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for
drugs that are inhaled, infused, instilled, implanted or injected, increases the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program, extends the Medicaid Drug Rebate program to utilization of prescriptions of
individuals enrolled in Medicaid managed care organizations, subjects manufacturers to new annual fees and taxes for certain branded prescription drugs and biologic agents and provides incentives to programs that increase the federal
governments comparative effectiveness research. At this time, the full effect that the Affordable Care Act would have on our business remains unclear. Further, significant uncertainty exists regarding the future scope and effect of the
Affordable Care Act because the new presidential administration and
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federal legislators have publicly declared their intention to significantly modify or repeal the legislation. These changes to the Affordable Care Act could impact our ability to sell our
products profitably.
Other legislative changes relevant to the health care system have been adopted in the United States since the Affordable Care Act
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 legislations automatic reduction to several government programs. This includes aggregate reductions of Medicare payments to
providers of 2% per fiscal year, which went into effect in April 2013, and will remain in effect through 2024 unless additional Congressional action is taken. In January 2013, the American Taxpayer Relief Act of 2012, was signed into
law, which, among other things, further reduced Medicare payments to several providers, including hospitals and other treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from
three to five years. These laws may result in additional reductions in Medicare, Medicaid and other healthcare funding, which could have a material adverse effect on our customers and, accordingly, our financial operations.
There have been, and likely will continue to be, legislative and regulatory proposals at the foreign, federal and state levels directed at broadening the
availability of healthcare and containing or lowering the cost of healthcare. As indicated previously, significant uncertainty exists regarding the future scope and effect of current health care legislation and regulations because the new
presidential administration and federal legislators have publicly declared their intention to significantly modify or repeal the current legislative framework. We cannot predict the initiatives that may be adopted in the future, any of which could
limit or modify the amounts that foreign, federal and state governments as well as private payors, including patients, will pay for healthcare products and services, which could result in reduced demand for our product candidates or additional
pricing pressures.
The continuing efforts of governments, insurance companies, managed care organizations and other payors of healthcare services to
contain or reduce costs of healthcare and/or impose price controls could harm our business, financial conditions and prospects and may adversely affect:
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the demand for or utilization of our product candidates, if we obtain regulatory approval;
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our ability to set a price that we believe is fair for our products;
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our ability to generate revenue and achieve or maintain profitability;
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the level of taxes, fees and rebates that we are required to pay; and
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the availability of capital.
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Any denial in coverage or reduction in reimbursement from Medicare or other
government programs, including state and foreign programs, may result in a similar denial or reduction in payments from private payors, which may adversely affect our future profitability.
Our employees, independent contractors, clinical investigators, CROs, consultants, commercial partners and vendors may engage in misconduct or other
improper activities, including noncompliance with regulatory standards and requirements, which could have a material adverse effect on our business.
We are exposed to the risk of non-compliance, fraud, misconduct or other illegal activity by our employees, independent contractors, clinical investigators,
CROs, consultants, commercial partners and vendors. Misconduct by these parties could include intentional, reckless and/or negligent conduct that fails to: comply with federal and state laws and those of other applicable jurisdictions; provide true,
complete and accurate information to the FDA and other similar foreign regulatory bodies; comply with manufacturing standards; comply with federal and state data privacy, security, fraud and abuse and other healthcare laws and regulations in the
United States and similar foreign privacy or fraudulent misconduct laws; or report financial information or data accurately; or disclose unauthorized activities to us. If we obtain FDA approval of any of our product candidates and begin
commercializing those products in the United States, our potential exposure under such laws will increase
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significantly, and our costs associated with compliance with such laws are also likely to increase. These laws may impact, among other things, our current activities with clinical investigators
and research patients, as well as proposed and future sales, marketing and education programs. In particular, the promotion, sales and marketing of healthcare products and services, as well as certain 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. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing
and promotion, including promotion and marketing of off-label uses of our products, structuring and commission(s), certain customer incentive programs and other business arrangements generally. Activities subject to these laws also involve the
improper use of information obtained in the course of clinical trials or creating fraudulent data in our preclinical studies or clinical trials, which could result in regulatory sanctions and cause serious harm to our reputation. It is not always
possible to identify and deter misconduct by employees and other third parties, 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
governmental investigations or other actions or lawsuits stemming from a failure to comply with these laws or regulations. Additionally, we are subject to the risk that a person or government could allege such fraud or other misconduct, even if none
occurred. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of significant fines or other
sanctions.
We may be subject, directly or indirectly, to federal and state healthcare fraud and abuse laws, false claims laws, physician payment
transparency laws and health information privacy and security laws. If we are unable to comply, or have not fully complied, with such laws or their relevant foreign counterparts, we could face substantial penalties.
If we obtain FDA approval for any of our product candidates and begin commercializing those products in the United States, our operations may be directly, or
indirectly through our customers and third-party payors, subject to various federal and state fraud and abuse laws, including, without limitation, the federal Anti-Kickback Statute, the federal False Claims Act, and physician sunshine laws and
regulations. These laws or their relevant foreign counterparts may impact, among other things, our proposed sales, marketing, and education programs and our relationships with healthcare providers, physicians and other parties through which we
market, sell and distribute our products for which we obtain marketing approval. In addition, we may be subject to patient privacy regulation by the federal government and the states in the United States as well as other jurisdictions. The laws that
may affect our ability to operate include:
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the federal Anti-Kickback Statute, which prohibits, among other things, knowingly and willfully soliciting, receiving, offering or paying any remuneration (including any kickback, bribe, or rebate), directly or
indirectly, overtly or covertly, in cash or in kind, to induce, or in return for, either the referral of an individual, or the purchase, lease, order or recommendation of any good, facility, item or service, for which payment may be made, in whole
or in part, under a federal healthcare program, such as the Medicare and Medicaid programs. A person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation;
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federal civil and criminal false claims laws and civil monetary penalties laws, including the civil False Claims Act, which impose criminal and civil penalties on individuals or entities for, among other things,
knowingly presenting, or causing to be presented to the U.S. federal government, claims for payment or approval that are false or fraudulent or knowingly making a false statement to avoid, decrease or conceal an obligation to pay money to the
federal government. In addition, the government may assert that a claim including items and services resulting from a violation of the U.S. federal Anti-Kickback Statute constitutes a false of fraudulent claim for purposes of the False Claims Act;
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the federal Health Insurance Portability and Accountability Act of 1996 (HIPAA), which imposes criminal and civil
liability for knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by,
or under the custody or control of,
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any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or
making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services. Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute
or specific intent to violate it in order to have committed a violation;
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HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, and their respective implementing regulations, which impose requirements on certain covered healthcare providers,
health plans, and healthcare clearinghouses as well as their respective business associates that perform services for them that involve the use, or disclosure of, individually identifiable health information, relating to the privacy, security and
transmission of individually identifiable health information without appropriate authorization;
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the U.S. federal physician payment transparency requirements, sometimes referred to as the Physician Payments Sunshine Act, created under the Affordable Care Act, and their implementing regulations, which
require manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Childrens Health Insurance Program to report annually to the Centers for Medicare and Medicaid Services,
information related to payments or other transfers of value made to physicians, other healthcare providers, and teaching hospitals, as well as ownership and investment interests held by physicians, other healthcare providers, and their immediate
family members; and
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the Federal Food, Drug and Cosmetic Act, which prohibits, among other things, the commercialization of adulterated or misbranded of drugs and medical devices.
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Additionally, we are subject to state and foreign equivalents of each of the healthcare laws described above, among others, some of which may be broader in
scope and may apply regardless of the payor.
Because of the breadth of these laws and the limited 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. In addition, recent health care reform legislation has strengthened these laws. For example, the Affordable Care Act, among other things,
amends the intent requirement of the federal Anti-Kickback Statute and criminal healthcare fraud statutes. As a result of such amendment, a person or entity no longer needs to have actual knowledge of these statutes or specific intent to violate
them in order to have committed a violation. Moreover, the Affordable Care Act provides that the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or
fraudulent claim for purposes of the False Claims Act.
Efforts to ensure that our business arrangements with third parties will comply with applicable
healthcare laws and regulations as well as other legal requirements will involve substantial costs. It is possible that governmental and enforcement authorities will conclude that our business practices may not comply with current or future
statutes, regulations or case law interpreting applicable fraud and abuse or other healthcare laws and regulations. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those
actions could have a significant impact on our business, including the imposition of civil, criminal and administrative penalties, damages, disgorgement, monetary fines, possible exclusion from participation in Medicare, Medicaid and other U.S.
federal healthcare programs, contractual damages, reputational harm, diminished profits and future earnings, and curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results
of operations. In addition, the approval and commercialization of any of our product candidates outside the United States will also likely subject us to foreign equivalents of the healthcare laws mentioned above, among other foreign laws.
If we fail to comply with environmental, health and safety, and laboratory animal welfare laws and regulations, we could become subject to fines or
penalties or incur costs that could harm our business.
We are subject to numerous federal, state and local environmental, health and safety, and
laboratory animal welfare laws and regulations. These legal requirements include those governing laboratory procedures and the
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handling, use, storage, treatment and disposal of hazardous materials and wastes as well as those which regulate the care and use of animals in research. Our operations will involve research
using research animals and the use of hazardous and flammable materials, including chemicals and biological materials. Our operations also may produce hazardous waste products. We generally anticipate contracting with third parties for the disposal
of these materials and wastes. We will not be able to eliminate the risk of contamination or injury from these materials. In the event of contamination or injury resulting from any use by us of hazardous materials, we could be held liable for any
resulting damages, and any liability could exceed our resources. We also could incur significant costs associated with civil or criminal fines and penalties for failure to comply with such laws and regulations.
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. We do not maintain insurance for environmental liability or toxic tort claims that may be asserted against us in connection with our storage
or disposal of biological, hazardous or radioactive materials.
In addition, we may incur substantial costs in order to comply with current or future
environmental, health and safety, and laboratory animal welfare laws and regulations. These current or future laws and regulations may impair our research, development or production efforts. Our failure to comply with these laws and regulations also
may result in substantial fines, penalties or other sanctions.
Risks Related to Our Intellectual Property
Third-party claims of intellectual property infringement against us, our licensors or our collaborators may prevent or delay our product discovery and
development efforts.
Our commercial success depends in part on our avoiding infringement of the valid patents and proprietary rights of third
parties.
Numerous U.S. and foreign issued patents and pending patent applications owned by third parties exist in the fields in which we are developing
our product candidates. As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that our product candidates may give rise to claims of infringement of the patent rights of others. We cannot guarantee
that our technology, future product candidates or the use of such product candidates do not infringe third-party patents. It is also possible that we have failed to identify relevant third-party patents or applications.
Third parties may assert that we infringe their patents or that we are otherwise employing their proprietary technology without authorization, and may sue us.
There may be third-party patents of which we are currently unaware with claims to compositions, formulations, methods of manufacture or methods of use or treatment that cover product candidates we discover and develop. Because patent applications
can take many years to issue, there may be currently pending patent applications that may later result in issued patents that our product candidates may infringe. In addition, third parties may obtain patents in the future and claim that use of our
technologies or the manufacture, use or sale of our product candidates infringes upon these patents. If any such third-party patents were held by a court of competent jurisdiction to cover our technologies or product candidates, the holders of any
such patents may be able to block our ability to commercialize the applicable product candidate unless we obtain a license under the applicable patents, or until such patents expire or are finally determined to be held invalid or unenforceable. Such
a license may not be available on commercially reasonable terms or at all. If we are unable to obtain a necessary license to a third-party patent on commercially reasonable terms, our ability to commercialize our product candidates may be impaired
or delayed, which could in turn significantly harm our business.
Third parties asserting their patent rights against us may seek and obtain injunctive or
other equitable relief, which could effectively block our ability to further develop and commercialize our product candidates. For example, the Broad Institute patent family includes issued patents in the U.S. and Europe that purport to cover
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certain aspects of the CRISPR/Cas9 gene editing platform for use on eukaryotic cells, including human cells. In January 2016, an interference proceeding was declared in the USPTO between certain
U.S. patents and one application of the Broad Institute patent family and the claims from one UC/Vienna/Charpentier patent application we license through Caribou to determine which set of inventors invented first and, thus, is entitled to patents on
the invention. In February 2017, the PTAB dismissed the interference proceeding without making any decision regarding inventorship or priority between the patents and applications at issue. It is now possible that the Broad Institute could seek to
assert its patent family against us based on our CRISPR/Cas9-based activities, including commercialization. Defense of these or similar claims, regardless of their merit, would involve substantial litigation expense, would be a substantial diversion
of management and other employee resources from our business and may impact our reputation. In the event of a successful claim of infringement against us, we may have to pay substantial damages, including treble damages and attorneys fees for
any adjudicated willful infringement, obtain one or more licenses from third parties, pay royalties or redesign our infringing products, which may be impossible or require substantial time and monetary expenditure. In that event, we may be unable to
further develop and commercialize our product candidates, which could harm our business significantly.
If we are found to infringe a third partys
valid intellectual property rights, we could be required to obtain a license from such third party to continue developing and marketing our products and technology. However, we may not be able to obtain any required license on commercially
reasonable terms or at all. Even if we were able to obtain a license, it could be non-exclusive, thereby giving our competitors access to the same technologies licensed to us. We could be forced, including by court order, to cease commercializing,
manufacturing or importing the infringing technology or product. In addition, we could be found liable for monetary damages, including treble damages and attorneys fees if we are found to have willfully infringed a patent. A finding of
infringement could prevent us from commercializing our product candidates, force us to redesign our infringing products or force us to cease some or all of our business operations, any of which could materially harm our business and could prevent us
from further developing and commercializing our proposed future product candidates thereby causing us significant harm. Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar negative
impact on our business.
Under our license agreement with Caribou, we sublicense a patent family from The Regents of the University of California
and the University of Vienna that is co-owned by Dr. Emmanuel Charpentier. The outcome of recent proceedings related to this patent family may affect our ability to utilize the intellectual property sublicensed under our license agreement with
Caribou.
The Broad Institute patent family includes issued patents in the U.S. and Europe that purport to cover certain aspects of the
CRISPR/Cas9 gene editing platform for use on eukaryotic cells, including human cells. On January 11, 2016, the PTAB declared an interference proceeding between certain patents and a patent application of the Broad Institute patent family and
one UC/Vienna/Charpentier patent application to determine, based on priority of invention, whether the contested inventions belong either to UC/Vienna/Charpentier or to the Broad Institute. This interference proceeding was discontinued by the PTAB
in February 2017 without any finding regarding inventorship or priority. In discontinuing the interference proceeding, the PTAB found that the claim sets presented by the two parties were patentably distinct from each other and, thus,
did not meet the statutory requirements for continuing the proceeding. As a result of the PTABs decision, the interference between the particular UC/Vienna/Charpentier patent application and the Broad patents and patent applications is
terminated, subject to a timely appeal by UC/Vienna/Charpentier to the U.S. Court of Appeals for the Federal Circuit. If UC/Vienna/Charpentier do not appeal, their patent application that was the subject of the interference may be prosecuted to
potential issuance. In addition, UC/Vienna/Charpentier continue to prosecute other patent claims covering the CRISPR/Cas9 inventions, which could also result in allowable or issued patents in the United States. Certain of the claims being prosecuted
by UC/Vienna/Charpentier, if found allowable by the USPTO, could lead to interference proceedings against patents or patent applications owned by other parties, including the Broad Institute patent family, with respect to certain claims relating to
the use of CRISPR/Cas9 in eukaryotic cells. We cannot be certain which of these results, if any, will actually occur. Further, the effects that any such results may have on us and our intellectual property position, including whether
UC/Vienna/Charpentier will
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ultimately be successful in prosecuting to issuance a patent covering the CRISPR/Cas9 system that we are able to use under our license agreement with Caribou, are currently unknown. The Broad
could seek to assert its issued patents against us based on our CRISPR/Cas9-based activities, including commercialization. Defense of these claims, regardless of their merit, would involve substantial litigation expense, would be a substantial
diversion of management and other employee resources from our business and may impact our reputation. In the event of a successful claim of infringement against us, we may have to pay substantial damages, including treble damages and attorneys
fees for willful infringement, obtain one or more licenses from third parties, pay royalties or redesign our infringing products, which may be impossible or require substantial time and monetary expenditure. In that event, we could be unable to
further develop and commercialize our product candidates, which could harm our business significantly.
We may be subject to claims challenging the
inventorship of our patents and other intellectual property.
We may in the future be subject to claims that former employees, collaborators or
other third parties have an interest in our patents or other intellectual property as an inventor or co-inventor or other claims challenging the inventorship of our patents or ownership of our intellectual property (including patents and
intellectual property that we in-license). For example, the UC/Vienna/Charpentier patent family that is covered by our license agreement with Caribou is co-owned by UC/Vienna and Dr. Charpentier, and our sublicense rights are derived from the
first two co-owners and not from Dr. Charpentier. Therefore, our rights to these patents are not exclusive and third parties, including competitors, may have access to intellectual property that is important to our business. In addition, we may
have inventorship disputes arise from conflicting obligations of collaborators, consultants or others who are involved in developing our technology and product candidates. Litigation or other legal proceedings may be necessary to defend against
these and other claims challenging inventorship. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, valuable
intellectual property. Such an outcome could have a material adverse effect on our business. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and other
employees.
We depend on intellectual property licensed from third parties and termination of any of these licenses could result in the loss of
significant rights, which would harm our business.
We are dependent on patents, know-how and proprietary technology, both our own and licensed
from others, including Caribou and Novartis. Any termination of these licenses, or a finding that such intellectual property lacks legal effect, could result in the loss of significant rights and could harm our ability to commercialize any product
candidates.
Disputes may also arise between us and our licensors, our licensors and their licensors, or us and third parties that co-own intellectual
property with our licensors or their licensors, regarding intellectual property subject to a license agreement, including those relating to:
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the scope of rights, if any, granted under the license agreement and other interpretation-related issues;
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whether and the extent to which our technology and processes infringe on intellectual property of the licensor that is not subject to the license agreement;
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whether our licensor or its licensor had the right to grant the license agreement;
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whether third parties are entitled to compensation or equitable relief, such as an injunction, for our use of the intellectual property without their authorization;
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our right to sublicense patent and other rights to third parties under collaborative development relationships;
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whether we are complying with our obligations with respect to the use of the licensed technology in relation to our development and commercialization of product candidates;
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our involvement in the prosecution, defense and enforcement of the licensed patents and our licensors overall patent strategy;
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the allocation of ownership of inventions and know-how resulting from the joint creation or use of intellectual property by our licensors and by us and our partners; and
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the amounts of royalties, milestones or other payments due under the license agreement.
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If disputes over
intellectual property that we have licensed prevent or impair our ability to maintain our current licensing arrangements on acceptable terms, or are insufficient to provide us the necessary rights to use the intellectual property, we may be unable
to successfully develop and commercialize the affected product candidates. If we or any such licensors fail to adequately protect this intellectual property, our ability to commercialize our products could suffer.
We depend, in part, on our licensors to file, prosecute, maintain, defend and enforce patents and patent applications that are material to our business.
Patents relating to our product candidates are controlled by certain of our licensors. Each of our licensors or their licensors generally has
rights to file, prosecute, maintain and defend the patents we have licensed from such licensor. If these licensors or any future licensees and in some cases, co-owners from which we do not yet have licenses, having rights to file, prosecute,
maintain, and defend our patent rights fail to adequately conduct these activities for patents or patent applications covering any of our product candidates, our ability to develop and commercialize those product candidates may be adversely affected
and we may not be able to prevent competitors from making, using or selling competing products. We cannot be certain that such activities by our licensors have been or will be conducted in compliance with applicable laws and regulations or in our
best interests, or will result in valid and enforceable patents or other intellectual property rights. Pursuant to the terms of the license agreements with our licensors, the licensors may have the right to control enforcement of our licensed
patents or defense of any claims asserting the invalidity of these patents and, even if we are permitted to pursue such enforcement or defense, we cannot ensure the cooperation of our licensors or, in some cases, other necessary parties, such as the
co-owners of the intellectual property from which we have not yet obtained a license. We cannot be certain that our licensors, and in some cases, their co-owners, will allocate sufficient resources or prioritize their or our enforcement of such
patents or defense of such claims to protect our interests in the licensed patents. For example, with respect to our sublicensed rights from Caribou to UC/Vienna/Charpentier intellectual property, UC retained the right to control the prosecution,
enforcement and defense of this intellectual property in its license agreement with Caribou and, pursuant to the Invention Management Agreement, shares these responsibilities with CRISPR Therapeutics and, under certain circumstances, ERS, as the
designated managers of the intellectual property.
Even if we are not a party to legal actions involving our licensed intellectual property, an adverse
outcome could harm our business because it might prevent us from continuing to license intellectual property that we may need to operate our business. In addition, even when we have the right to control patent prosecution of licensed patents and
patent applications, enforcement of licensed patents, or defense of claims asserting the invalidity of those patents, we may still be adversely affected or prejudiced by actions or inactions of our licensors and their counsel that took place prior
to or after our assuming control.
We may not be successful in obtaining or maintaining necessary rights to product components and processes or
other technology for our product development pipeline.
The growth of our business will likely depend in part on our ability to acquire or
in-license additional proprietary rights. For example, our programs may involve additional product candidates, delivery systems or technologies that may require the use of additional proprietary rights held by third parties. Our ultimate product
candidates may also require specific modifications or formulations to work effectively and efficiently. These modifications or formulations may be covered by intellectual property rights held by others. We may be unable to acquire or in-license any
relevant third-party intellectual property rights that we identify as necessary or important to our business operations.
Additionally, we sometimes
collaborate with academic institutions to accelerate our preclinical research or development under written agreements with these institutions. Typically, these institutions provide us with an option to negotiate a license to any of the
institutions rights in technology resulting from the collaboration. Regardless of such option, we may be unable to negotiate a license within the specified timeframe or under terms that are acceptable to us. If we are unable to do so, the
institution may offer the intellectual property rights to other parties, potentially blocking our ability to pursue our program.
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The licensing and acquisition of third-party intellectual property rights is a competitive practice and companies
that may be more established, or have greater resources than we do, may also be pursuing strategies to license or acquire third-party intellectual property rights that we may consider necessary or attractive in order to commercialize our product
candidates. More established companies may have a competitive advantage over us due to their larger size and cash resources or greater clinical development and commercialization capabilities. There can be no assurance that we will be able to
successfully complete such negotiations and ultimately acquire the rights to the intellectual property surrounding the additional product candidates that we may seek to acquire.
If we are unable to successfully obtain rights to valid third-party intellectual property or to maintain the existing intellectual property rights we have, we
may have to abandon development of such program and our business and financial condition could suffer.
We could be unsuccessful in obtaining or
maintaining adequate patent protection for one or more of our products or product candidates, or asserting and defending our intellectual property rights that protect our products and technologies.
We anticipate that we will file additional patent applications both in the United States and in other countries, as appropriate. However, we cannot predict:
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if and when any patents will issue;
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the degree and range of protection any issued patents will afford us against competitors, including whether third parties will find ways to invalidate or otherwise circumvent our patents;
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whether others will apply for or obtain patents claiming aspects similar to those covered by our patents and patent applications; or
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whether we will need to initiate litigation or administrative proceedings to assert or defend our patent rights, which may be costly whether we win or lose.
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Composition of matter patents for biological and pharmaceutical products are generally considered to be the strongest form of intellectual property protection
for those types of products, as such patents provide protection without regard to any method of use. We cannot be certain, however, that any claims in our pending or future patent applications covering the composition of matter of our product
candidates will be considered patentable by the USPTO or by patent offices in foreign countries, or that the claims in any of our ultimately issued patents will be considered valid and enforceable by courts in the United States or foreign countries.
Method of use patents protect the use of a product for the specified method. This type of patent does not prevent a competitor from making and marketing a product that is identical to our product for an indication that is outside the scope of the
patented method. Moreover, even if competitors do not actively promote their product for our targeted indications, physicians may prescribe these products off-label for those uses that are covered by our method of use patents. Although
off-label prescriptions may infringe or contribute to the infringement of method of use patents, the practice is common and such infringement is difficult to prevent or prosecute.
The strength of patents in the biotechnology and pharmaceutical field can be uncertain, and evaluating the scope of such patents involves complex legal and
scientific analyses. The patent applications that we own or in-license may fail to result in issued patents with claims that cover any product candidates or uses thereof in the United States or in other foreign countries.
Further, the patent prosecution process is expensive and time-consuming, and we may not be able to file and prosecute all necessary or desirable patent
applications at a reasonable cost, in a timely manner, or in all jurisdictions. It is also possible that we will fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection. Moreover,
in some circumstances, we do not have the right to control the preparation, filing and prosecution of patent applications, or to maintain the patents, covering technology that we license from third parties. We may also require the cooperation of our
licensors or other necessary parties, such as the co-owners of the intellectual property from which we have not yet obtained a
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license, in order to enforce the licensed patent rights, and such cooperation may not be provided. Therefore, these patents and applications may not be prosecuted and enforced in a manner
consistent with the best interests of our business.
The laws of foreign countries may not protect our rights to the same extent as the laws of the United
States and we may fail to seek or obtain patent protection in all major markets. For example, European patent law restricts the patentability of methods of treatment of the human body more than United States law does. Publications of discoveries in
the scientific literature often lag behind the actual discoveries, and patent applications in the United States and other jurisdictions are typically not published until 18 months after filing, or in some cases not at all. Therefore, we will be
unable to know with certainty whether we were the first to make any inventions claimed in any patents or patent applications, or that we were the first to file for patent protection of such inventions, nor can we know whether those from whom we
license patents were the first to make the inventions claimed or were the first to file.
The issuance of a patent is not conclusive as to its
inventorship, scope, validity or enforceability, and our owned and licensed patents may be challenged in the courts or patent offices in the United States and abroad. There is a substantial amount of litigation as well as administrative proceedings
for challenging patents, including interference, derivation, and reexamination proceedings before the USPTO and oppositions and other comparable proceedings in foreign jurisdictions, involving patents and other intellectual property rights in the
biotechnology and pharmaceutical industries, and we expect this to be true for the CRISPR/Cas9 space as well. In addition, since the passage of the America Invents Act in 2013, U.S. law also provides for other procedures to challenge patents,
including
inter partes
reviews and post-grant reviews, that add uncertainty to the possibility of challenge to our developed or licensed patents and patent applications in the future. Furthermore, for U.S. applications in which all claims are
entitled to a priority date before March 16, 2013, an interference proceeding can be provoked by a third party or instituted by the USPTO to determine who was the first to invent any of the subject matter covered by the patent claims of our
applications.
Such challenges may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated or held
unenforceable, in whole or in part, which could limit our ability to stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our technology and products. Given the
amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized. As a result, our owned and licensed
patent portfolio may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours.
Furthermore,
even if they are unchallenged, our patents and patent applications may not adequately protect our intellectual property or prevent others from designing their products to avoid being covered by our claims. If the breadth or strength of protection
provided by the patent applications we hold is threatened, this could dissuade companies from collaborating with us to develop, and could threaten our ability to commercialize, product candidates. Further, if we encounter delays in our clinical
trials, the period of time during which we could market product candidates under patent protection would be reduced. Because patent applications in the United States and most other countries are confidential for a period of time after filing, we
cannot be certain that we were the first to file any patent application related to our product candidates.
Our pending and future patent applications or
the patent applications that we obtain rights to through in-licensing arrangements may not result in patents being issued which protect our technology or future product candidates, in whole or in part, or which effectively prevent others from
commercializing competitive technologies and products. Changes in either the patent laws or interpretation of the patent laws in the United States and other countries may diminish the value of our patents or narrow the scope of our patent
protection.
Litigation or other administrative proceedings challenging our intellectual property, including interferences, derivation, reexamination,
inter partes
reviews and post-grant reviews, may result in a decision adverse to our interests and, even if we are successful, may result in substantial costs and distract our management and other employees. Furthermore, there could be public
announcement of the results of hearings, motions or other interim
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proceedings or developments in any proceeding challenging the issuance, scope, validity and enforceability of our developed or licensed intellectual property. If securities analysts or investors
perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock.
Any of these potential negative
developments could impact the scope, validity, enforceability or commercial value of our patent rights and, as a result, have material adverse effect on our business, financial condition, results of operations or prospects.
Confidentiality agreements with employees and third parties may not prevent unauthorized disclosure of trade secrets and other proprietary information.
In addition to the protection afforded by patents, we seek to rely on trade secret protection and confidentiality agreements to protect
proprietary know-how that is not patentable or that we elect not to patent. We also utilize proprietary processes for which patents are difficult to enforce. In addition, other elements of our product discovery and development processes involve
proprietary know-how, information, or technology that is not covered by patents. Trade secrets, however, may be difficult to protect. We seek to protect our proprietary processes, in part, by entering into confidentiality agreements with our
employees, consultants, outside scientific advisors, contractors, and collaborators. Although we use reasonable efforts to protect our trade secrets, our employees, consultants, outside scientific advisors, contractors, and collaborators might
intentionally or inadvertently disclose our trade secret information to competitors. In addition, competitors may otherwise gain access to our trade secrets or independently develop substantially equivalent information and techniques. Furthermore,
the laws of some foreign countries do not protect proprietary rights to the same extent or in the same manner as the laws of the United States. As a result, we may encounter significant problems in protecting and defending our intellectual property
both in the United States and abroad. If we are unable to prevent unauthorized material disclosure of our intellectual property to third parties, or misappropriation of our intellectual property by third parties, we may not be able to establish or
maintain a competitive advantage in our market, which could materially adversely affect our business, operating results, and financial condition.
We have limited foreign intellectual property rights and may not be able to protect our intellectual property rights throughout the world.
We have limited intellectual property rights outside the United States. Filing, prosecuting, maintaining and defending patents on product candidates in all
countries throughout the world would be prohibitively expensive, and our intellectual property rights in some countries outside the United States can have a different scope and strength than do those in the United States. In addition, the laws of
some foreign countries, such as China, Brazil, Russia, India, and South Africa, do not protect intellectual property rights to the same extent as federal and state laws in the United States. Consequently, we may not be able to prevent third parties
from practicing our inventions in all countries outside the United States, or from selling or importing products made using our inventions in and into the United States or other jurisdictions. Competitors may use our technologies in jurisdictions
where we have not obtained patent protection to develop their own products and further, may export otherwise infringing products to territories where we have patent protection, but enforcement rights are not as strong as those in the United States.
These products may compete with our products and our patents or other intellectual property rights may not be effective or adequate to prevent them from competing. Further, in jurisdictions outside the United States, a license may not be enforceable
unless all the owners of the intellectual property agree or consent to the license.
Many companies have encountered significant problems in protecting
and defending intellectual property rights in foreign jurisdictions. The legal systems of certain countries, such as China, Brazil, Russia, India, and South Africa, do not favor the enforcement of patents, trade secrets and other intellectual
property, particularly those relating to biopharmaceutical products, which could make it difficult in those jurisdictions for us to stop the infringement or misappropriation of our patents or other intellectual property rights, or the marketing of
competing products in violation of our proprietary rights. Proceedings to enforce our patent and other intellectual property rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from
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other aspects of our business. Furthermore, such proceedings could put our patents at risk of being invalidated, held unenforceable, or interpreted narrowly, could put our patent applications at
risk of not issuing, and could provoke third parties to assert claims of infringement or misappropriation against us. We may not prevail in any lawsuits that we initiate and the damages or other remedies awarded, if any, may not be commercially
meaningful. Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or license.
We may be involved in lawsuits to protect or enforce our patents or the patents of our licensors, which could be expensive, time-consuming, and
unsuccessful.
Competitors may infringe our patents or the patents of our licensors. To cease such infringement or unauthorized use, we may be
required to file patent infringement claims, which can be expensive and time-consuming. In addition, in an infringement proceeding or a declaratory judgment action against us, a court may decide that one or more of our patents is not valid or is
unenforceable, or may refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question. An adverse result in any litigation or defense proceeding could put one or more of our
patents at risk of being invalidated, held unenforceable or interpreted narrowly and could put our patent applications at risk of not issuing. Defense of these claims, regardless of their merit, would involve substantial litigation expense and would
be a substantial diversion of employee resources from our business.
Interference or derivation proceedings provoked by third parties or brought by the
USPTO may be necessary to determine the priority of inventions with respect to, or the correct inventorship of, our patents or patent applications or those of our licensors. An unfavorable outcome could result in a loss of our current patent rights
and could require us to cease using the related technology or to attempt to license rights to it from the prevailing party. Our business could be harmed if the prevailing party does not offer us a license on commercially reasonable terms.
Litigation, interference or derivation proceedings may result in a decision adverse to our interests and, even if we are successful, may result in substantial costs and distract our management and other employees.
Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our
confidential information could be compromised by disclosure during this type of litigation or proceeding. In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments. If
securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock.
Issued patents covering our product candidates could be found invalid or unenforceable if challenged in court or before the USPTO or comparable foreign
authority.
If we or one of our licensing partners initiate legal proceedings against a third party to enforce a patent covering one of our
product candidates, the defendant could counterclaim that the patent covering our product candidate is invalid or unenforceable. In patent litigation in the United States, defendant counterclaims alleging invalidity or unenforceability are
commonplace, and there are numerous grounds upon which a third party can assert invalidity or unenforceability of a patent. Third parties may also raise similar claims before administrative bodies in the United States or other jurisdictions, even
outside the context of litigation. Such mechanisms include re-examination,
inter partes
review, post-grant review and equivalent proceedings in foreign jurisdictions, such as opposition or derivation proceedings. Such proceedings
could result in revocation or amendment to our patents in such a way that they no longer cover and protect our product candidates. The outcome following legal assertions of invalidity and unenforceability is unpredictable. With respect to the
validity of our patents, for example, we cannot be certain that there is no invalidating prior art of which we, our patent counsel, and the patent examiner were unaware during prosecution. If a defendant were to prevail on a legal assertion of
invalidity, unpatentability and/or unenforceability, we would lose at least part, and perhaps all, of the patent protection on our product candidates. Such a loss of patent protection could have a material adverse impact on our business.
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We may be subject to claims that our employees, consultants, or independent contractors have wrongfully
used or disclosed confidential information of third parties.
We have received confidential and proprietary information from third parties. In
addition, we employ individuals who were previously employed at other biotechnology or pharmaceutical companies as well as academic research institutions. We may be subject to claims that we or our employees, consultants, or independent contractors
have inadvertently or otherwise used or disclosed confidential information of these third parties or our employees former employers. Litigation may be necessary to defend against these claims. Even if we are successful in defending against
these claims, litigation could result in substantial cost and be a distraction to our management and employees.
Obtaining and maintaining our
patent protection depends on compliance with various procedural, document submission, fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these
requirements.
Periodic maintenance fees on any issued patent are due to be paid to the USPTO and foreign patent agencies in several stages over
the lifetime of the patent. The USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent application process. Although an
inadvertent lapse can in many cases be cured by payment of a late fee or by other means in accordance with the applicable rules, there are situations in which noncompliance can result in abandonment or lapse of the patent or patent application,
resulting in partial or complete loss of patent rights in the relevant jurisdiction. Noncompliance events that could result in abandonment or lapse of a patent or patent application include failure to respond to official actions within prescribed
time limits, non-payment of fees, and failure to properly legalize and submit formal documents. In any such event, our competitors might be able to enter the market, which would have a material adverse effect on our business.
We may be required to pay certain milestones and royalties under our license agreements with third-party licensors.
Under our current and future license agreements, we may be required to pay milestones and royalties based on our revenues from sales of our products utilizing
the technologies licensed or sublicensed from third parties, including Caribou and Novartis, and these royalty payments could adversely affect the overall profitability for us of any products that we may seek to commercialize. In order to maintain
our license rights under these license agreements, we will need to meet certain specified milestones, subject to certain cure provisions, in the development of our product candidates and in the raising of funding. In addition,
these agreements contain diligence milestones and we may not be successful in meeting all of the milestones in the future on a timely basis or at all. We will need to outsource and rely on third parties for many aspects of the clinical
development, sales and marketing of our products covered under our license agreements. Delay or failure by these third parties could adversely affect the continuation of our license agreements with their third-party
licensors.
If our trademarks and trade names are not adequately protected, then we may not be able to build name recognition in our markets of
interest and our business may be adversely affected.
If our trademarks and trade names are not adequately protected, then we may not be able to
build name recognition in our markets of interest and our business may be adversely affected. Our unregistered trademarks or trade names may be challenged, infringed, circumvented or declared generic or determined to be infringing on other marks. We
may not be able to protect our rights to these trademarks and trade names, which we need to build name recognition among potential partners or customers in our markets of interest. At times, competitors may adopt trade names or trademarks similar to
ours, thereby impeding our ability to build brand identity and possibly leading to market confusion. In addition, there could be potential trade name or trademark infringement claims brought by owners of other registered trademarks or trademarks
that incorporate variations of our unregistered trademarks or trade names. Over the long term, if we are unable to successfully register our trademarks and trade names and establish name recognition based on our trademarks and trade names, then we
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may not be able to compete effectively and our business may be adversely affected. Our efforts to enforce or protect our proprietary rights related to trademarks, trade secrets, domain names,
copyrights or other intellectual property may be ineffective and could result in substantial costs and diversion of resources and could adversely impact our financial condition or results of operations.
Risks Related to Our Common Stock
An active
trading market for our common stock may not be sustained.
In May 2016, we closed our initial public offering. Prior to this offering, there was
no public market for our common stock. Although we have completed our initial public offering and shares of our common stock are listed and trading on The NASDAQ Global Market, an active trading market for our shares may not be sustained. If an
active market for our common stock does not continue, it may be difficult for our stockholders to sell their shares without depressing the market price for the shares or sell their shares at or above the prices at which they acquired their shares or
sell their shares at the time they would like to sell. Any 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 price of our common stock may be volatile and fluctuate substantially.
Our stock price is likely to be volatile. The stock market in general and the market for smaller biopharmaceutical companies in particular have
experienced extreme volatility that has often been unrelated to the operating performance of particular companies. The market price for our common stock may be influenced by many factors, including:
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the success of competing products or technologies;
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results of clinical trials of our product candidates or those of our competitors;
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developments or disputes concerning patent applications, issued patents or other proprietary rights;
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regulatory or legal developments in the United States and other countries;
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the recruitment or departure of key personnel;
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the level of expenses related to any of our product candidates or clinical development programs;
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the results of our efforts to discover, develop, acquire or in-license additional product candidates or products;
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actual or anticipated changes in estimates as to financial results, development timelines or recommendations by securities analysts;
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variations in our financial results or the financial results of companies that are perceived to be similar to us;
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sales of a substantial number of shares of our common stock in the public market, or the perception in the market that the holders of a large number of shares intend to sell shares;
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changes in the structure of healthcare payment systems;
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market conditions in the pharmaceutical and biotechnology sectors;
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general economic, industry and market conditions; and
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the other factors described in this
Risk Factors
section.
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Our principal stockholders and
management own a significant percentage of our stock and, if they choose to act together, will be able to control or exercise significant influence over matters subject to stockholder approval.
Our executive officers, directors and principal stockholders, together with their respective affiliates, beneficially owned approximately 71.2% of our capital
stock following the closing of our initial public offering and
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concurrent private placements. Accordingly, our executive officers, directors and principal stockholders, if they choose to act together, will be able to determine the composition of the board of
directors, retain the voting power to approve all matters requiring stockholder approval, including mergers and other business combinations, and continue to have significant influence over our operations. This concentration of ownership could have
the effect of delaying or preventing a change in our control or otherwise discouraging a potential acquirer from attempting to obtain control of us that may be in the best interests of our stockholders. This in turn could have a material adverse
effect on our stock price and may prevent attempts by our stockholders to replace or remove the board of directors or management.
We have broad
discretion over the use of our cash and cash equivalents and may not use them effectively.
Our management has broad discretion to use our cash
and cash equivalents to fund our operations and could spend these funds in ways that do not improve our results of operations or enhance the value of our common stock. The failure by our management to apply these funds effectively could result in
financial losses that could have a material adverse effect on our business, cause the price of our common stock to decline and delay the development of our product candidates. Pending our use to fund operations, we may invest our cash and cash
equivalents in a manner that does not produce income or that loses value.
Anti-takeover provisions in our charter documents and under Delaware law
could make an acquisition of us difficult, limit attempts by our stockholders to replace or remove our current management and adversely affect our stock price.
Provisions of our certificate of incorporation and by-laws may delay or discourage transactions involving an actual or potential change in our control or
change in our management, including transactions in which stockholders might otherwise receive a premium for their shares, or transactions that our stockholders might otherwise deem to be in their best interests. Therefore, these provisions could
adversely affect the price of our stock. Among other things, the certificate of incorporation and by-laws will:
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permit the board of directors to issue up to 5,000,000 shares of preferred stock, with any rights, preferences and privileges as they may designate;
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provide that the authorized number of directors may be changed only by resolution of the board of directors;
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provide that all vacancies, including newly created directorships, may, except as otherwise required by law, be filled by the affirmative vote of a majority of directors then in office, even if less than a quorum;
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divide the board of directors into three classes;
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provide that a director may only be removed from the board of directors by the stockholders for cause;
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require that any action to be taken by our stockholders must be effected at a duly called annual or special meeting of stockholders, and may not be taken by written consent;
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provide that stockholders seeking to present proposals before a meeting of stockholders or to nominate candidates for election as directors at a meeting of stockholders must provide notice in writing in a timely manner,
and meet specific requirements as to the form and content of a stockholders notice;
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prevent cumulative voting rights (therefore allowing the holders of a plurality of the shares of common stock entitled to vote in any election of directors to elect all of the directors standing for election, if they
should so choose);
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require that, to the fullest extent permitted by law, a stockholder reimburse us for all fees, costs and expenses incurred by us in connection with a proceeding initiated by such stockholder in which such stockholder
does not obtain a judgment on the merits that substantially achieves the full remedy sought;
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provide that special meetings of our stockholders may be called only by the chairman of the board, our chief executive officer (or president, in the absence of a chief executive officer) or by the board of directors;
and
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provide that stockholders will be permitted to amend the bylaws only upon receiving at least two-thirds of the total votes entitled to be cast by holders of all outstanding shares then entitled to vote generally in the
election of directors, voting together as a single class.
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In addition, because we are incorporated in Delaware, we are governed by the
provisions of Section 203 of the Delaware General Corporation Law, which generally prohibits a Delaware corporation from engaging in any of a broad range of business combinations with any interested stockholder for a period of three
years following the date on which the stockholder became an interested stockholder.
Our certificate of incorporation provides that the
Court of Chancery of the State of Delaware will be the exclusive forum for substantially all disputes between us and our stockholders, which could limit our stockholders ability to obtain a favorable judicial forum for disputes with us or our
directors, officers or employees.
Our certificate of incorporation provides that the Court of Chancery of the State of Delaware is the exclusive
forum for any derivative action or proceeding brought on our behalf, any action asserting a breach of fiduciary duty, any action asserting a claim against us arising pursuant to the Delaware General Corporation Law, our certificate of incorporation
or our by-laws, any action to interpret, apply, enforce, or determine the validity of our certificate of incorporation or bylaws, or any action asserting a claim against us that is governed by the internal affairs doctrine. The choice of forum
provision may limit a stockholders ability to bring a claim in a judicial forum that it finds favorable for disputes with us or our directors, officers or other employees, which may discourage such lawsuits against us and our directors,
officers and other employees. Alternatively, if a court were to find the choice of forum provision contained in our certificate of incorporation to be inapplicable or unenforceable in an action, we may incur additional costs associated with
resolving such action in other jurisdictions, which could adversely affect our business and financial condition.
We incur significant costs as a
result of operating as a public company, and our management is required to devote substantial time to new compliance initiatives and corporate governance practices.
As a public company, and particularly after we are no longer an emerging growth company under applicable SEC regulations, we incur significant
legal, accounting and other expenses. The Sarbanes-Oxley Act of 2002, the Dodd-Frank Wall Street Reform and Consumer Protection Act, the listing requirements of The NASDAQ Global Market and other applicable securities rules and regulations impose
various requirements on public companies, including establishment and maintenance of effective disclosure and financial controls and corporate governance practices. Our management and other personnel devote a substantial amount of time to these
compliance initiatives.
Pursuant to Section 404 of the Sarbanes-Oxley Act of 2002 (Section 404), we are required to furnish a report by our
management on our internal control over financial reporting. However, while we remain an emerging growth company, we are not required to include an attestation report on internal control over financial reporting issued by our independent registered
public accounting firm. To achieve compliance with Section 404 within the prescribed period, we are engaged in a process to document and evaluate our internal control over financial reporting, which is both costly and challenging. In this
regard, we will need to continue to dedicate internal resources, potentially engage outside consultants and adopt a detailed work plan to assess and document the adequacy of internal control over financial reporting, continue steps to improve
control processes as appropriate, validate through testing that controls are functioning as documented and implement a continuous reporting and improvement process for internal control over financial reporting. If we identify one or more material
weaknesses, it could result in an adverse reaction in the financial markets due to a loss of confidence in the reliability of our financial statements.
If securities or industry analysts do not continue to publish research reports about our business, or if they issue an adverse opinion about our
business, our stock price and trading volume could decline.
The trading market for our common stock may be influenced, in part, by the research
and reports that industry or securities analysts publish about us or our business. If one or more of the analysts who cover us issues an adverse
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opinion about our company, our stock price would likely decline. If one or more of these analysts ceases research coverage of us or fails to regularly publish reports on us, we could lose
visibility in the financial markets, which in turn could cause our stock price or trading volume to decline.