T£ Ifll
`
`July 2, 2014
`
`VIA HAND DELIVERY
`
`Dockets Management Branch, HFA-305
`
`Food and Drug Administration
`
`Department of Health and Human Services
`
`5630 Fishers Lane, Room 1061
`
`Rockville, MD 20852
`
`Re:
`
`Citizen Petition Requesting That FDA Refrain From Approving Any
`Abbreviated New Drug Application Referencing Copaxone® (glatiramer
`acetate injection) Until Certain Conditions Are Met
`
`Dear Sir or Madam:
`
`On behalf of Teva Pharmaceutical Industries Ltd., Teva Neuroscience, Inc. (“'I'eva”)1
`hereby submits this Citizen Petition pursuant to 21 C.F.R. § 10.30 and sections 505(j) and 505(q)
`of the Federal Food, Drug, and Cosmetic Act (“FFDCA”), 21 U.S.C. §§ 3550) and 35S(q). For
`the reasons that follow, Teva respectfully requests that the Commissioner of Food and Drugs
`consider the scientific information submitted in this Petition and refrain from approving any
`abbreviated new drug application (“ANDA") that references Copaxone® (glatiramer acetate
`injection) unless and until the conditions specified in this Petition are satisfied to assure that
`follow—on products are safe and effective. Teva manufactures and distributes Copaxone®, a
`treatment for the reduction of frequency of relapses in relapsing-remitting multiple sclerosis
`(“RRMS”).
`
`This Petition is submitted following guidance from the Food and Drug Administration
`(“FDA” or “the Agency”) in the letter dated June 9, 2014 (attached hereto as Exhibit 1). In the
`letter, the Agency asks that Teva make public through the citizen petition process information
`submitted on May 23, 2014 as an amendment and general correspondence concerning the New
`Drug Application (“NDA”) for Copaxone® (NDA 20-622). Teva is providing herein all
`information from the May 23, 2014 submission, as well as additional findings from Teva’s
`
`is a global pharmaceutical company specializing in the development,
`' Teva Pharmaceutical Industries Ltd.
`production, and marketing of generic, proprietary, and branded pharmaceuticals, and active pharmaceutical
`ingredients. Teva is among the top 20 pharmaceutical companies and is the leading generic pharmaceutical
`company in the world. Teva Neuroscience is the branded neurological products subsidiary of Teva Phannaceutical
`Industries Ltd. and is responsible for the clinical development, registration, and marketing of Teva’s branded
`neurological products in North America, including Copaxone®.
`
`Teva Pharmaceuticals
`
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`
`1
`
`Mylan Pharms. Inc.
`Mylan Pharlns Inc
`Exhibit 1009 Page 1
`Exhibit 1009 Page 1
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`

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`ongoing research. Teva continues to study Copaxone® and other glatiramoids, publishing the
`findings as rapidly as possible in the peer-reviewed literature in order to advance scientific
`understanding of these complex medicines, and ensure the safe and efficacious treatment of
`multiple sclerosis (“MS”) patients worldwide.
`
`I.
`
`Actions Requested
`
`Copaxone® is a non-biologic complex drug (“NBCD”) and first-generation nanomedicine
`composed of an uncharacterized mixture of immunogenic polypeptides in a colloidal suspension.
`The active ingredient in Copaxone(cid:147) – glatiramer acetate – is not a single molecular entity but
`rather a heterogeneous mixture of potentially millions of distinct, synthetic polypeptides of
`varying lengths, some containing up to 200 amino acids, with structural complexity comparable
`to that of proteins. The complexity of glatiramer acetate is amplified by the fact that its exact
`mechanisms of action are unknown, and the specific amino acid sequences (epitopes) responsible
`for its efficacy and safety cannot be identified. Accordingly, like many biological products,
`glatiramer acetate is defined, in large part, by its well-controlled manufacturing process, which
`has been used by Teva for more than twenty years.
`
`As part of its ongoing commitment to better characterize Copaxone®, Teva continues to
`evaluate the physicochemical and biological properties of Copaxone® using state-of-the-art
`technology. In a prior Petition, Teva submitted the results of new gene expression studies
`comparing Copaxone® and purported, foreign, generic glatiramer acetate products.2 Those
`studies produced multiple lines of evidence suggesting that purported “generic” products have a
`significantly more variable biological impact than Copaxone®, particularly with respect to
`immune cells associated with inflammatory response and beneficial tolerance. The results from
`these recent tests thus raise significant concerns that proposed generic products manufactured via
`different processes and using different starting materials may have undetected structural and
`compositional differences from Copaxone(cid:147) that could compromise safety, immunogenicity, and
`effectiveness.
`
`In its May 2, 2014, response to Teva’s most recent Petition, FDA expressed interest in
`ongoing research conducted by Teva and others, stating that “FDA continues to actively consider
`the issues you have raised and the information you have included in your Petition” and that
`“scientific information regarding this complex drug continues to accumulate, which in turn
`means that FDA continues to update the information available to it … ”.3 FDA also noted that
`some specific details associated with the gene expression studies conducted by Teva in order to
`characterize similarities and differences between Copaxone® and purported “generics” were
`missing from the Petition. These include references that characterize the genetic pathways
`postulated, documentation of those pathways themselves, in-depth analysis of the 98 genes
`
`
`2 See Docket No. FDA-2013-P-1641 (Dec. 5, 2013) (Exhibit 2). In an earlier petition, Teva submitted the results of
`traditional colloidal assessment experiments to confirm that Copaxone® is a colloidal suspension rather than a true
`solution. See Docket No. FDA-2013-P-1128 (Sept. 12, 2013) (Exhibit 3).
`
`3 FDA Response to Sixth Copaxone Petition, FDA-2013-P-1641, pp. 5-6 (note20) (May 2, 2014) (Exhibit 4).
`
`
`
`2
`
`Mylan Pharms. Inc.
`Exhibit 1009 Page 2
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`

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`identified, and additional evidence that the observed differences are clinically significant to the
`treatment of MS patients.
`
`Some of the Agency’s feedback has been addressed by recent material provided by Teva
`and deposited by the FDA under the same docket, including Teva’s peer-reviewed publication in
`PLOS ONE,4 as well as the briefing document and powerpoint slides shared with the FDA in a
`Type C Meeting that took place on February 25, 2014.5 These documents outline in detail the
`experimental design, analytical approach and the clinical relevance associated with the gene
`expression studies pursued by Teva. In order to address the specific feedback from the Agency,
`provide the latest findings (including investigations conducted further to the May 23 NDA
`submission), and allow FDA an in-depth review of the methodology and full set of results, this
`document summarizes the available data gathered to date by Teva and analyzed by Immuneering
`Corporation.6
`
`In brief, as part of Teva’s ongoing commitment to better understand Copaxone®, Teva
`studied its effect at the level of gene expression across the entire genome (unbiased, without
`prior hypothesis about the genes for which expression pattern may be altered and without
`choosing which genes to focus on or study) in a variety of immunologically relevant model
`systems, including mouse splenocytes, human monocytes, and peripheral blood mononucleated
`cells (“PBMCs”) from MS patients. The genome-wide approach is critical, because two
`glatiramoids can appear identical based on a small panel of genes, yet differ significantly in
`their impact on other genes that are potentially highly relevant to safety and/or efficacy (as
`illustrated in Section II.B below and on slides 49-50 of the powerpoint presentation at the
`February 25, 2014 Type C meeting (Exhibit 6)). Using multiple model systems is equally
`critical, since acting as an antigen, Copaxone® significantly impacts a variety of
`immunological cell types. The unbiased approach allows identification of genes and pathways
`with subtle, yet robust, differential expression patterns following stimulation by different
`glatiramoids in different experimental contexts. The functionality of identified genes and
`pathways is then described based on experimental data reported in the peer-reviewed literature.
`As described below, the research has also shown that various model systems capture different
`aspects of Copaxone®’s mechanism of action, such that no single cell type or system tested was
`sufficient to fully characterize the biological impact of this medicine.
`
`The core analysis methods used for these studies are validated and considered standard in
`the field (experimental design methodologies: Churchill, Nat. Genet., 2002; microarray data
`normalization method: Quackenbush, Nat. Genet., 2002; batch correction methodology: Johnson
`et al, Biostat, 2007; differential expression methodology: Smyth, Stat Appl Genet Mol Biol.,
`
`
`4 Towfic, F. et al. Comparing the Biological Impact of Glatiramer Acetate with the Biological Impact of a Generic.
`PLOS ONE. (Jan. 8, 2014) (Exhibit 5).
`
` 5
`
` Teva Presentation at FDA Type C Meeting (Feb. 25, 2014) (Exhibit 6).
`
`6 This submission also addresses comments filed to the prior docket (Docket No. FDA-2013-P-1641) by Mylan
`Pharmaceuticals, Inc. dated April 29, 2014, which (a) dismisses potential safety issues and batch-to-batch
`manufacturing variability identified in a similar product from the company Mylan selected to manufacture the API
`for their ANDA, and (b) raises inaccurate and outdated objections to an older subset of Teva’s scientific
`communications. For completion, a detailed response to this comment is supplied in Appendix 3.
`3
`
`
`
`Mylan Pharms. Inc.
`Exhibit 1009 Page 3
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`

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`2004). Novel, innovative approaches were developed by Immuneering Corporation so as to
`address particular questions, such as methods
`to determine enrichment for specific
`immunological cell types.
`
`The null hypothesis in traditional gene-expression studies, including Teva’s studies with
`the glatiramoids, is that there are no significant gene expression differences induced between the
`treatments. As such, the expectation is that regardless of the biological system used for testing,
`genes would show no statistically significant, nor biologically meaningful, differences among the
`various treatments. Only in cases where the treatments induce significant observable effects,
`genes differentially expressed between treatments will pass the stringent statistical tests, and
`false discovery rate (FDR) correction for multiple hypotheses.7 These stringent requirements
`were imposed a priori across all tests to ensure robustness of results and minimizing of spurious
`findings. Such statistically significant differences, if biologically meaningful (e.g., related to the
`disease biology or any of the drug’s known or putative targets and downstream pathways),
`warrant further studies, as two drugs that have identical activities in biological systems should
`not induce statistically observable and biologically enriched differences when compared against
`each other.
`
`It should be emphasized that these studies were not designed to establish a particular set
`of genes in a specific model system as a panel to evaluate “sameness” between differently
`manufactured glatiramoids. Instead, these were designed to assess the degree of similarity in the
`impact of two glatiramoids on relevant biological pathways. The application of robust
`methodology (high number of replicates, conditions and time-points, where relevant) was aimed
`to describe pathways changed by different treatments out of the entire milieu of genomic
`patterns. The results obtained across the tested experimental models revealed statistically
`significant differences between glatiramoids, which were intended to be similar and to perform
`the same function, despite stringent statistical threshold requirements. This was noteworthy
`particularly in genes highly relevant to disease processes and drug response mechanisms. In
`addition, the differences observed revealed a complex interplay between immunological
`pathways, such that some differences were common to multiple systems, while many others were
`dependent on the specific model system (for example, some key genes modulated in T cells were
`not the same as in monocytes). This is not surprising for a process that involves multifaceted
`interactions between many immune system components, and is also exemplified in experimental
`studies of Copaxone®’s mechanism of action. Thus, no single model system, characterization
`method, or set of genes tested was sufficient to comprehensively capture the differences (or
`“sameness”) between the drugs. These observations indicate a need for in-depth investigation of
`comparative gene expression profiles in several relevant pre-clinical systems as key indicators of
`similarity and/or sameness between generic candidates and the original drug within the context
`of NBCDs.
`Ideally, the concordance between high-resolution physicochemical measures (e.g.
`ion motility mass spectrometry, IMMS), gene expression profiling and clinical trials would allow
`a more definitive assessment of equivalence in terms of patient benefit and safety.
`
`The challenges inherent in combining and interpreting data from the wide range of
`characterization methods currently available for complex drugs are well recognized in FDA’s
`
`
`7 Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to
`multiple testing. Journal of the Royal Statistical Society Series B (Methodological): 289–300.
`4
`
`
`
`Mylan Pharms. Inc.
`Exhibit 1009 Page 4
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`

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`recently announced funding opportunity for a research project entitled “Development of an
`Integrated Mathematical Model for Comparative Characterization of Complex Molecules.”8 The
`Agency’s announcement recognizes
`the need for
`innovative approaches, seeking
`the
`development of novel methods to “determine whether the type and number of in vitro chemical
`and biological characterization assays employed are sufficient to establish the sameness or
`similarity between the reference and follow-on (or generic) drug products for the complex
`molecules.” Teva is in full support of the Agency’s efforts in this area, and encourages
`exhaustive scientific research to address the important, unanswered questions described in the
`announcement.
`
`The potential of biological characterization assays, such as gene expression, to yield
`information relevant to patient safety is exemplified most strikingly by findings from studies in a
`human monocyte (THP-1) cell line comparing Copaxone(cid:147) with Probioglat (sold in Mexico by
`Probiomed), described below in section II.B.3. The tests revealed that genes significantly
`upregulated by Probioglat relative to Copaxone(cid:147) were significantly enriched for inflammatory
`pathways and included key pro-inflammatory genes that could be harmful to MS patients. At the
`same time, Probioglat downregulated several anti-inflammatory genes, thus reducing the
`beneficial effects of these genes, compared to Copaxone®. Results were corroborated by gene-
`level, pathway-level and independent qRT-PCR analyses. These findings may provide clues to
`prediction of the serious clinical reports from Mexico post introduction of this purported generic
`to the market (January 2013). The suffering of MS patients in Mexico reflected in reports on
`adverse reactions and exacerbated disease progression may be due to a biological imbalance
`between anti-inflammatory and pro-inflammatory processes, which may be discernible in gene
`expression differences such as those described herein.
`
`Teva previously has raised the above issues regarding active ingredient sameness,
`immunogenicity and bioequivalence with FDA in a series of Citizen Petitions dating back to
`2008.9
`In its responses to Teva’s prior Petitions, FDA has taken the position that it would be
`“premature and inappropriate” to provide a substantive decision on the approval requirements for
`ANDAs for glatiramer acetate while FDA is still reviewing pending applications.10 Teva’s prior
`Petitions thus remain largely unanswered.
`
`On May 23, 2014, Teva submitted the new scientific evidence described above as an
`amendment and general correspondence to the NDA for Copaxone®. On June 9, 2014, the
`Agency issued a letter to Teva requesting that “if [Teva] wish[es] the Agency to consider the
`
`8 Available at: http://grants.nih.gov/grants/guide/rfa-files/RFA-FD-14-082.html.
`
`9 The prior Citizen Petitions were submitted in 2008, 2009, 2010, 2012 and 2013, respectively, and are incorporated
`herein by reference. See FDA-2008-P-0529 (Sept. 26, 2008) (Exhibit 7); FDA-2009-P-0555 (Nov. 13, 2009)
`(Exhibit 8); FDA-2010-P-0642 (Dec. 10, 2010) (Exhibit 9); FDA-2012-P-0555 (June 4, 2012) (Exhibit 10); FDA-
`2013-P-1128 (Sept. 12, 2013) (Exhibit 3); FDA-2013-P-1641 (Dec. 5, 2013) (Exhibit 2). Teva also incorporates by
`reference any exhibits to those petitions although, for efficiency’s sake, such exhibits are not being re-submitted
`because they are either FDA documents that are routinely available to the public (e.g., approved labeling, guidance
`documents and petition responses) or recognized medical or scientific textbooks or articles that are readily available
`to the agency. See 21 C.F.R. § 10.20(c)(1)(iii), (iv).
`
`10 See, e.g., FDA’s Response to Sixth Copaxone Petition, FDA-2013-P-1641 (May 2, 2014).
`
`
`
`5
`
`Mylan Pharms. Inc.
`Exhibit 1009 Page 5
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`

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`information and arguments set forth in your May 23, 2014 letter and white paper, that you submit
`these documents as a citizen petition in accordance with section 505(q) of the FD&C Act.”11
`Although Teva believes the Agency can consider the information submitted to the Copaxone®
`NDA outside the context of a new citizen petition, Teva nevertheless has decided to comply with
`the Agency’s request. Accordingly, Teva is hereby renewing and supplementing the arguments
`made in its prior Petitions regarding active ingredient sameness, immunogenicity and
`bioequivalence testing and presenting new scientific data and information to support those
`arguments.12 At bottom, Teva believes it would be contrary to the public health for FDA to
`approve a purported generic glatiramer acetate product that, based on current analytical
`technologies, can only be shown to be similar, rather than identical, to Copaxone® – particularly
`without any clinical
`testing whatsoever
`to address
`residual uncertainty
`regarding
`immunogenicity, bioequivalence, safety or effectiveness.
`
`Consequently, Teva respectfully requests that the Commissioner:
`
`Review and consider the new scientific data and information contained in this
`1.
`Petition prior to approving any ANDA that relies upon Copaxone® as the reference listed drug
`(“RLD”); and
`
`Based upon the additional scientific information and data contained in this
`2.
`Petition, as well as the information and arguments set forth in Teva’s prior Petitions (which are
`incorporated herein by reference), refrain from approving any ANDA that relies upon
`Copaxone® as the RLD unless and until the ANDA contains:
`
`a.
`
`Information demonstrating that the proposed generic product contains the
`identical active ingredient as Copaxone®, not merely an active ingredient
`that is similar (or even highly similar) to Copaxone®’s, including data
`from high-resolution physicochemical, biological and genome-wide
`expression methods;
`
`b. Results of non-clinical and clinical investigations, including in-depth
`analyses of comparative gene expression profiles in several relevant
`preclinical systems, demonstrating
`that
`the
`immunogenicity risks
`associated with the proposed generic product are no greater than the risks
`associated with Copaxone(cid:147), including a demonstration that the risks of
`alternating or switching between use of the proposed product and
`Copaxone(cid:147) are not greater than the risks of using Copaxone(cid:147) without such
`alternation or switching; and
`
`
`11 Letter from Nancy K. Hayes, Acting Director, Office of Regulatory Policy, CDER, FDA, to Dennis Ahern, MS,
`Senior Director, Regulatory Affairs, Teva Pharmaceuticals USA, at 2 (June 9, 2014) (Exhibit 1).
`
`12 Because this submission contains new scientific information, Teva is required to file it as a new Citizen Petition
`rather than as a Petition for Reconsideration. See 21 C.F.R. § 10.33(e).
`
`
`
`6
`
`Mylan Pharms. Inc.
`Exhibit 1009 Page 6
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`

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`c. Results of comparative clinical investigations in RRMS patients using
`relevant safety and effectiveness endpoints demonstrating that the
`proposed generic drug is bioequivalent to Copaxone(cid:147).
`
`II.
`
`Statement of Grounds
`
`A.
`
`Factual Background
`
`1.
`
`Development of Copaxone®
`
`In the 1960’s, Israeli scientists at the Weizmann Institute were attempting to develop a
`synthetic copolymer that would mimic myelin basic protein, an autoantigen attacked by the
`immune system in MS pathoetiology, resulting in destruction of myelin. Their goal was to use
`the synthetic copolymer to induce an MS-like disease in animals so as to develop a model
`mimicking the disease and useful in evaluating possible treatment options for MS. Rather than
`induce the disease, however, one of the copolymers they synthesized (known as “copolymer-1”)
`actually suppressed the disease in animals. The Weizmann scientists immediately recognized
`the potential of this copolymer mixture to treat MS.
`
`Through intense development efforts in the 1980’s, the Weizmann scientists finally were
`able to conduct a limited clinical trial of copolymer-1 in MS patients, but the results were mixed.
`While some patients responded favorably, others experienced local injection site reactions and,
`on rare occasions, adverse side effects including difficulty breathing, palpitations, severe flush,
`sweating, and anxiety. Since copolymer-1 was being developed for daily injection, those side
`effects posed a serious health hazard to prospective patients.
`
`In November 1987, Teva partnered with Weizmann’s commercial affiliate to develop
`copolymer-1 into a useful pharmaceutical product. Among other things, the team of scientists
`working on the drug eventually discovered on the basis of certain laboratory tests that the
`toxicity of a copolymer-1 mixture was related in part to its molecular weight: the higher the
`average molecular weight of the product, and the higher the percentage of high-molecular weight
`polypeptides in the mixture, the more likely it was to be toxic. They also discovered that at
`lower molecular weights, copolymer-1 mixtures were likely to remain therapeutically active.
`Having discovered a new lower molecular weight product with improved tolerability
`characteristics, Teva conducted a new clinical trial for a copolymer-1 mixture. That trial found
`that daily injections of copolymer-1 yielded a statistically significant reduction in relapse rates
`for patients with RRMS.
`
`FDA approved Copaxone® for commercial marketing in the United States in late 1996
`and it remains widely prescribed to this day. Copaxone® is “indicated for reduction of the
`frequency in relapses in patients with RRMS, including patients who have experienced a first
`clinical episode and have MRI features consistent with multiple sclerosis.” To be effective in the
`20 mg version at issue here, patients administer the drug by subcutaneous injection (i.e., under
`the skin, rather than into a vein or artery) every single day; tens of thousands of patients have
`been doing so for almost two decades.
`
`
`
`7
`
`Mylan Pharms. Inc.
`Exhibit 1009 Page 7
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`

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`Clinical studies and extensive experience with Copaxone® in patients diagnosed with
`RRMS have demonstrated its consistent therapeutic efficacy. The cumulative exposure to
`Copaxone® is approximately 2 million patient-years, with some patients effectively treated with
`Copaxone® for more than 20 consecutively years.
`
`As FDA long has recognized, Copaxone® “is not a conventional drug, either in chemical
`composition or in its presumed mechanism of action.”13 Rather than consisting of a single
`molecular entity, Copaxone® is a heterogeneous polypeptide mixture containing millions of
`distinct synthetic polypeptides of varying lengths (up to an estimated 200 amino acids),
`sequences, and molecular weights, with a structural complexity that exceeds that of some
`proteins. In that respect, Copaxone® has almost nothing in common with typical small-molecule
`drugs like the therapeutically active ingredients in Tylenol® (acetaminophen) or Advil®
`(ibuprofen), where scientists have been able to map every atom of those products and their
`precise structural arrangements.
` Given
`the
`lack of clear pharmacokinetic and
`pharmacodynamic markers and mapping of molecular structure for Copaxone®, it remains a
`unique sub-class within NBCDs, described as a heterogeneous mixture of polymeric molecules.
`Given the uncertainty in accurate characterization of Copaxone®, it is no surprise that the drug’s
`therapeutically active components—the specific amino acid sequences (acting effectively as
`immunological “epitopes”, or antigenic motifs that uniquely activate certain aspects of the
`immune system, analogous to a vaccine) responsible for its clinical efficacy—have yet to be
`identified.
`
`Not only does Copaxone® remain a challenge for complete physicochemical
`characterization; its precise mechanism of action (i.e. the manner in which the drug exerts its
`therapeutic activity), and associated pharmacodynamics biomarkers, are not fully understood.
`Yet, intense research over almost two decades indicates both direct and indirect immunological
`effects, attributed to the fact that Copaxone® is an antigen. As such, it is highly immunogenic,
`meaning that exposure to the product generates a complex cascade of immune events that is
`difficult to fully characterize. Immunogenicity is generally a potential concern, because anything
`that impacts how the body’s immune system functions has potentially significant health
`consequences. A delicate balance between pro- and anti-inflammation is crucial to MS
`pathoetiology and conversely to its successful management. It is thus particularly concerning in
`the case of MS patients, who have a diagnosed inflammatory immune system disorder.
`Copaxone® induces immune reactions that are favorable and beneficial to patients as has been
`consistently demonstrated over more than two decades: The product functions like a therapeutic
`vaccine (defined by FDA as “an immunogen, the administration of which is intended to stimulate
`the immune system to result in the prevention, amelioration or therapy of any disease or
`infection”),14 eliciting beneficial responses in treated subjects by modulating the patient’s
`immune system over an extended period of time. Even so, Copaxone®’s package insert warns
`
`13 Letter from P. Leber (former Director, Division of Neuropharmacological Drug Products) to B. Mackler (Dec. 10,
`1992) (Exhibit 11).
`
`14 Guidance for Industry: Content and Format of Chemistry, Manufacturing and Controls Information and
`Establishment Description Information for a Vaccine or Related Product, January 1999, available at:
`http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/vaccines/ucm076
`612.htm.
`
`
`
`8
`
`Mylan Pharms. Inc.
`Exhibit 1009 Page 8
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`

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`that chronic use has the potential to alter healthy immune function, as well as induce pathogenic
`immune mechanisms (though no such effects have been observed with Copaxone® over 2 million
`patient-years of exposure).
`
`To this end, Copaxone® has been linked by the FDA to white blood (immunological)
`cells’ function as reflected in the FDA’s Division of Neurology Products recent decision to
`require Teva to conduct a clinical trial as a condition of approving an application for a more
`concentrated version of the product—one that included the same 20 mg of Copaxone® as the
`first version marketed since 1996, made using Teva’s same precise manufacturing process and
`controls, but presented in 0.5 mL of water rather the 1.0 mL of water with Copaxone®’s existing
`formulation—based on concerns that removing just 0.5 mL of water (half a milliliter of
`water!) might render the product unsafe or ineffective.15 Similarly, the recently approved 40
`mg dosage of Copaxone® (in 1 mL, used 3 times per week) was approved based on clinical trials
`(i.e. GALA and GLACIER). Specifically, the GALA trial was a multinational, multicenter,
`randomized, parallel-group study performed in subjects with RRMS to assess the efficacy, safety
`and tolerability of Glatiramer Acetate (“GA”) injection 40 mg administered three times a week
`compared to placebo in a double-blind design. A total of 1404 patients were randomized at a 2:1
`ratio between active and placebo treatment arms across 17 different countries and a total of 155
`recruitment centers.
`
`Precisely because the product’s chemical makeup cannot be fully characterized, carefully
`regulating the manufacturing process is the only way Teva can ensure that the product it
`produces is an unaltered and consistent Copaxone®. Teva prepares Copaxone® using a precise,
`well-controlled manufacturing process which results in a heterogeneous mixture of literally
`millions of distinct, synthetic polypeptides in a liquid colloid mixture. Teva routinely conducts
`extensive quality testing to ensure consistency among various batches of Copaxone®. These
`tests verify that each batch of Copaxone® possesses certain specific characteristics as measured
`by an array of proprietary and confidential specifications, including: (1) a specific molecular
`weight distribution profile; (2) complex reproducible patterns in its amino-acid sequences; (3) a
`characteristic ratio of molecules with C-terminal carboxylates to diethylamides; (4) a
`characteristic electrophoretic profile; (5) specific hydrophobic interactions due to unique charge
`dispersion; (6) a specific proteolytic digestion profile; (7) a specific affinity to glatiramer acetate
`antibodies; and (8) a specific potency as determined by its biorecognition by glatiramer acetate-
`specific T cells. The precise battery of testing protocols that Teva uses (including these and
`many others), and the precise specifications Teva applies in evaluating the results of those tests,
`is proprietary, confidential, and subject to trade-secret protection.
`
`Despite Teva’s ability to reproduce Copaxone® with consistency and efficacy over the
`last several decades, it bears repeating that Teva has not been able to fully characterize the drug
`despite extensive efforts to do so. Current analytical methods are not capable of individually
`separating and then fully characterizing the millions of individual polypeptides in the Copaxone®
`
`
`15 Letter from R. Katz to D. Ahern, NDA 20-622/S-077, at 1 (Dec. 21, 2010) (“The uncertainty about
`[Copaxone®’s] mechanism of action, and the fact that some of the effect may be related to the activation of
`lymphocytes in the periphery, raise questions about a possible impact of a high concentration/lower volume
`formulation on the safety and efficacy of the product.”).
`
`
`
`9
`
`Mylan Pharms. Inc.
`Exhibit 1009 Page 9
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`

`
`mixture. While Teva’s proprietary analytical methods thus help to ensure that Teva’s
`manufacturing process has been properly implemented by identifying potential differences
`between batches of Copaxone®, they cannot conclusively demonstrate that the clinically relevant
`polypeptide sequences in two putative versions of Copaxone® that are manufactured by different
`processes are identical in all material respects.
`
`In fact, underscoring the complexity of these challenges, FDA has recently issued a
`request for proposals regarding this class of drugs, entitled “Development of an Integrated
`Mathematical Model for Comparative Characterization of Complex Molecules.”16 The Agency’s
`initiative seeks innovative approaches for the dev