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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS, INC.
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`Petitioner
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`v.
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`YEDA RESEARCH AND DEVELOPMENT CO. LTD.
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`Patent Owner
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`Case No. IPR2017-00195
`Patent No. 9,155,776
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`DECLARATION OF DANIEL WYNN, M.D., IN SUPPORT OF PATENT
`OWNER YEDA’S PRELIMINARY RESPONSE TO PETITION FOR
`INTER PARTES REVIEW
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`I.
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`INTRODUCTION
`1.
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`I, Daniel R. Wynn, M.D., have personal knowledge of the facts set
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`forth in this Declaration and am competent to testify to these facts.
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`2.
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`I have been retained by counsel for Teva (Teva Pharmaceuticals USA,
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`Inc., Teva Pharmaceutical Industries Ltd., Teva Neuroscience, Inc.) on behalf of
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`Yeda Research and Development Co. Ltd. (“Patent Owner”) in this proceeding
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`regarding U.S. Patent No. 9,155,776 (“the ’776 patent”).
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`3.
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`I hereby offer this Declaration in support of Patent Owner’s
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`Preliminary Response to Petition for Inter Partes Review.
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`4.
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`A list of materials that I have reviewed is attached hereto as Exhibit B.
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`II. QUALIFICATIONS AND EXPERIENCE
`5.
`I graduated from Reed College in Portland Oregon in 1977, after
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`which I attended the Chicago Medical School, receiving my M.D. in 1983.
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`6.
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`I was a Resident in the Neurology Residency Program at the Mayo
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`Graduate School of Medicine in Rochester, Minnesota from 1983 through 1988. I
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`have also held fellowships at the Mayo Graduate School of Medicine in
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`Neurophysiology.
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`7.
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`I have been a licensed medical doctor since graduating medical school
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`in 1983 and board certified in Neurology since 1988. I currently serve as Director
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`of Clinical Research of Consultants in Neurology, Ltd. in Northbrook, Illinois. I
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`am also member of the Clinical Advisory Committee of the Greater Illinois
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`Chapter of the National Multiple Sclerosis Society. I have served as a research
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`reviewer for a number of journals, including the Journal of Neuroscience and the
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`Journal of NeuroRehabilitation and Neural Repair.
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`8.
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`I have authored more than 120 journal articles, book chapters,
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`abstracts, and other publications relating primarily to the diagnosis and treatment
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`of multiple sclerosis (“MS”).
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`9.
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`I have extensive experience in the diagnosis and treatment of multiple
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`sclerosis. Over the last 25 years, I have treated thousands of patients with MS. In
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`that role, I have also gained extensive experience with the adverse events
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`associated with multiple sclerosis treatment—including those associated with
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`glatiramer acetate (“GA”) therapy—and the detrimental, unforgiving impact that
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`such adverse events have on patient treatment adherence and quality of life. As
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`such, a large amount of my MS practice has been, and remains, focused on
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`minimizing the adverse events associated with multiple sclerosis therapy and
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`maximizing the efficacy of such treatment.
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`10.
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`I have over twenty years of experience with Copaxone®, which is the
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`most commonly used MS therapy in the United States. I have used Copaxone® 20
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`mg/mL extensively in the treatment of my patients with multiple sclerosis since its
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`approval in 1996 for the treatment of relapsing forms of MS, the most common
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`forms of MS. In fact, over the last few years, Copaxone® has been the most
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`common disease modifying treatment I have prescribed to patients to treat
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`relapsing forms of MS. Moreover, since the 40 mg/mL three times weekly dosage
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`form of Copaxone® was approved by the FDA in early 2014, most of my patients
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`taking Copaxone® 20 mg/mL have switched to Copaxone® 40 mg/mL.
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`11.
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`I have been actively involved in numerous MS clinical research trials
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`involving a number of different drug therapies and have served as an investigator
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`in Phase II, III and IV studies. I have participated in more than eighty-five clinical
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`trials and extension studies as an investigator.
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`12. Many of these clinical research trials involved the drug product
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`Copaxone® or related GA therapies. For example, I took part in the following
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`clinical trials:
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` A multi-national, multi-center, randomized, double-blind, placebo-controlled
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`study to evaluate the efficacy, tolerability, and safety of two doses of
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`glatiramer acetate orally administered in Relapsing Remitting Multiple
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`Sclerosis (“CORAL”);
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` A multi-national, multi-center, double-blind, placebo-controlled study to
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`evaluate the efficacy, tolerability, and safety of glatiramer acetate for
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`injection in Primary Progressive Multiple Sclerosis patients (“PROMISE”);
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` A multi-center, randomized, double-blind, parallel group study to evaluate
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`the efficacy, tolerability and safety of 40 mg of Copaxone in the treatment of
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`relapsing remitting multiple sclerosis patients. Protocol #9006, 2003. (Phase
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`2);
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` A multi-national, multi-center, randomized, parallel-group, double-blind
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`study, to compare the efficacy, tolerability, and safety of Glatiramer Acetate
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`40 mg/ml and glatiramer Acetate 20 mg/ml administered once daily by
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`subcutaneous injection in patients with relapsing multiple sclerosis (R-MS)
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`(“FORTE”);
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` An open-label, multi-center, randomized study evaluating the tolerability
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`and safety of two formulations of glatiramer acetate (GA) for Subcutaneous
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`Injection (“SONG”);
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` A multi-national, multi-center, randomized, parallel-group, double-blind,
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`placebo-controlled study performed in subjects with relapsing-remitting
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`multiple sclerosis to assess the efficacy, safety and tolerability of glatiramer
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`acetate (GA) 20 mg/0.5 ml New Formulation Administered Daily by
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`Subcutaneous Injection (“GLOW”);
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` A multi-national, multi-center, randomized, parallel-group study performed
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`in subjects with Relapsing-Remitting Multiple Sclerosis (RRMS) to assess
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`the efficacy, safety and tolerability of Glatiramer Acetate (GA) injection 40
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`mg/ml administered three times a week compared to placebo in a double-
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`blind design (“GALA”);
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` An open-label, randomized, multi-center study to assess safety and
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`tolerability of glatiramer acetate 40 mg/1mL 3-times weekly versus 20
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`mg/1mL daily in patients with relapsing-remitting multiple sclerosis
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`(“GLACIER”); and
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` A multi-national, multi-center, randomized, parallel group, open-label study
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`to assess medication satisfaction in patients with relapsing remitting multiple
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`sclerosis (RRMS) treated with subcutaneous injections
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`of Copaxone® (glatiramer acetate) 40 mg/mL three times a week compared
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`to 20 mg/mL daily (“CONFIDENCE”).
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`13. A copy of my curriculum vitae, which provides additional information
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`about my background, experience, and publications, is attached as Exhibit A.
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`III. LEGAL PRINCIPLES
`14.
`In forming my opinions and conclusions in this report, I have been
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`provided with an overview of the prevailing principles of U.S. patent law that
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`govern the issues of patent claim interpretation and validity.
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`15.
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`I have been informed by counsel that claims should be construed by
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`giving them their broadest reasonable interpretation consistent with the
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`specification from the perspective of a person of ordinary skill in the art as of the
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`time of the invention.
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`16.
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`I have been informed by counsel that an issued patent claim is invalid
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`as obvious if it can be shown that the differences between the patented subject
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`matter and the prior art are such that the subject matter as a whole would have been
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`obvious, at the time the invention was made, to a person having ordinary skill in
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`the art. Relevant considerations include the level of ordinary skill in the art, the
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`scope and content of the prior art, any differences between the prior art and the
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`asserted claims, and the so-called objective secondary considerations of
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`nonobviousness.
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`17.
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`I have been informed by counsel that obviousness must be established
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`by a preponderance of the evidence. I understand this to mean that, for a claim to
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`be found invalid as obvious, it must be found more probable than not to be
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`obvious.
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`18.
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`I have been informed by counsel that in order to evaluate the
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`obviousness of the claims of the ’776 patent over a given prior art combination, I
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`should analyze whether the prior art references, included collectively in the
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`combination, disclose each and every element of the allegedly invalid claim as
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`those references are read by the person of ordinary skill in the art at the time of the
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`invention. Then I am to determine whether that combination makes the claims of
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`the ’776 patent obvious to the person of ordinary skill in the art by a preponderance
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`of the evidence, at the time of the invention.
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`19.
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`I have been informed by counsel that there must be some showing that
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`a person of ordinary skill in the art would have been motivated to combine such
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`prior art references and that there would have been a reasonable expectation of
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`successfully achieving the claimed invention from such combination in order to
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`support an obviousness determination.
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`20.
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`I have been informed by counsel that, in considering the obviousness
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`of a claimed invention, one should not view the invention and the prior art with the
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`benefit of hindsight. I understand that for this reason, obviousness is assessed by
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`the person of ordinary skill in the art at the time the invention was made in light of
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`the prior art as a whole. In this regard, I have been informed that the invention
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`cannot be used as a guide to selecting and understanding the prior art.
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`21.
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`I have been informed that a reference may be said to teach away when
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`a person of ordinary skill, upon reading the reference, would be discouraged from
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`following the path set out in the reference, or would be led in a direction divergent
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`from the path that was taken by the applicant.
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`22.
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`I have been informed that the “time of invention” applicable to the
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`inventions of the claims of the ’776 patent is August 20, 2009 (which I understand
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`to be the earliest priority date of the parent application resulting in the ’776 patent).
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`IV. PERSON OF ORDINARY SKILL IN THE ART
`23.
`I understand that the Patent Trial and Appeals Board has determined
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`that a person of ordinary skill in the art pertaining to the subject matter of the
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`several patents related to the ’776 patent at the time of the invention would have
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`had: (1) several years of experience in the pharmaceutical industry or in practicing
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`medicine; (2) experience with the administration or formulation of therapeutic
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`agents, dosing schedules and frequencies, and drug developmental study and
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`design; (3) a Ph.D. in pharmacology or be a physician with experience in clinical
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`pharmacology; and (4) experience with MS and GA. I agree with this definition of
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`a person of ordinary skill in the art and have applied it herein when describing my
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`opinions.
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`V.
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`SUMMARY OF OPINIONS
`24. A person of ordinary skill in the art would have understood that
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`“severity of injection site reactions” means “intensity of injection site reactions.”
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`The claim term “reduced severity of injection site reactions” is not coextensive
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`with “improved tolerability.” Rather, tolerability is a broader concept than severity
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`of injection site reactions. Improvements in tolerability of GA treatment can occur
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`without a reduction in the severity of injection site reactions.
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`25. As of August, 2009, the person of ordinary skill in the art would not
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`have possessed a reasonable expectation that GA administered at a dose of 40
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`mg/mL given three times weekly would have reduced severity of injection site
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`reactions compared with 20 mg/mL of GA administered daily.
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`VI. BACKGROUND ON MS AND COPAXONE
`A. Multiple sclerosis is a debilitating disease of the central nervous
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`26. MS is an unforgiving, chronic, progressive, irreversible, disabling
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`disease that is believed to affect over 2 million people worldwide. A diagnosis of
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`MS is a life-altering and life-long event. There is no cure for MS and its impact on
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`individual patients is often devastating, both physically and emotionally. It almost
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`invariably affects a patient’s ability to work and interact with others and can cause
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`a varied range of symptoms including paralysis, cognitive impairment, loss of
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`vision, incontinence of bowel and bladder, imbalance, spasticity, loss of sensation
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`and/or tingling, pain, fatigue, sexual dysfunction, tremors, depression, problems
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`with memory and concentration, and anxiety. (Ex. 20161.) As a consequence of
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`these and other disabilities, individuals living with MS typically experience shorter
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`lifespans with markedly reduced quality of life, affecting personal, vocational,
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`familial and spiritual goals.
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`27. MS is viewed primarily as an inflammatory disease of central nervous
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`system (“CNS”) myelin, a fatty tissue that surrounds and protects nerve axons in
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`1 Noseworthy J.H. et al., Multiple Sclerosis, N ENGL. J. MED. 2000; 343:938-952.
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`the brain, spinal cord, and optic nerves. Myelin facilitates the conduction of
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`electrochemical signals in the CNS and preserves the health of the nerves. MS
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`results in the degeneration of myelin. As myelin and the nerve fibers it protects are
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`damaged or destroyed, the ability of the nerves to conduct electrical impulses to
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`and from the brain, spinal cord and optic nerves are disrupted. These injuries
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`cause scars, or plaques, to form in the CNS, including the brain. Depending on the
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`location of the damage to the CNS, MS can cause disabling “attacks” or “relapses,”
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`which lead to one or more of the MS symptoms discussed above. The formation of
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`these lesions is what gave the disease its name—“multiple sclerosis” refers to the
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`multiple scars frequently observed in the CNS of MS patients.
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`28. MS can be categorized in two ways, relapsing onset MS and
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`progressive onset MS. Patients only have one form of the disease. Each form
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`maybe be caused by distinct biological (or pathological) mechanisms. Eighty five
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`percent (85%) of patients begin with relapsing MS. Id.
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`29. The relapsing form of the disease is defined by recurring attacks on
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`the CNS which result in a magnified disability during the relapse itself. These
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`attacks, often called “relapses,” are followed by recovery periods called
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`“remissions,” which can last from months to years, during which new symptoms
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`improve partially or completely and the patient’s neurological condition is
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`relatively stable. Even during these remission periods, however, disability can
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`progress as new lesions continue to form, even in the absence of an apparent
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`relapse of clinical symptoms. (Ex. 20172.)
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`30. Relapses are caused by lesions or scarring in the CNS that disrupt
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`nerve signals. Relapses vary in length, severity, and symptoms. There is currently
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`no way to predict the timing, frequency, or duration of relapses, thus it is important
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`for patients to adhere to continuous treatment to reduce the risk of relapses, even
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`during relapse free periods. Relapses cause new symptoms or worsening of old
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`symptoms, including common MS symptoms such as the permanent loss of vision,
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`use of limbs, and cognitive function. Such disabilities clearly disrupt personal,
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`vocational, and relationship goals.
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`31. One measure of patients’ disability is the EDSS (“Expanded
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`Disability Status Scale”), which is the most widely used and known scale to assess
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`changes in disability in MS. It was developed in the 1950s and refined in the
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`1980s to provide a standardized measure of global neurological impairment in MS.
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`It is commonly used by both clinicians and investigators in clinical studies to
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`quantify a patient’s disability. EDSS has frequently been used as a component of
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`the primary or secondary outcomes in clinical trials.
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`2 De Stefano, N. et al., Assessing brain atrophy rates in a large population of
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`untreated multiple sclerosis subtypes. NEUROLOGY 2010; 74:1868-1876.
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`32. While relapses are often significant clinical events resulting in at least
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`temporary disability of some kind, MS also works on a subclinical level to
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`gradually impair CNS function, resulting in a gradual and accumulating level of
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`disability. Up to 40% of relapses do not completely resolve, leaving patients with
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`accumulating, permanent disability. (Ex. 20183.) In addition, MS causes lesions
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`that do not result in a detectable clinical relapse or attack but that do damage or
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`destroy brain tissue, resulting in a loss of tissue known as brain atrophy. (Exhibit
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`20194.) This loss of brain tissue, which occurs during the onset of the disease even
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`before physical symptoms arise, is the closest correlate to irreversible disability
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`later in the disease. (Exhibit 20205.)
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`33. There is a disconnect between lesions and overt clinical relapses in
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`that many lesions do not cause overt symptoms when they form. Nevertheless,
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`3 Lublin, F.D. et al., Effect of relapses on development of residual deficit in
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`multiple sclerosis. NEUROLOGY 2003; 61:1528-1532.
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`4 Paolillo, A. et al., The Relationship between inflammation and atrophy in
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`clinically isolated syndromes suggestive of multiple sclerosis: A monthly MRI
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`study after triple-dose gadolinium-DTPA. J. NEUROL. (2004) 251: 432-439.
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`5 Fisniku, L.K. et al. Gray Matter Atrophy Is Related to Long-Term Disability in
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`Multiple Sclerosis. Ann. Neurol. 2008; 64:247-254.
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`these lesions still have a cumulative effect upon the CNS that ultimately leads to
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`loss of function. (Exhibit 20216; 20227.)
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`34. After a variable period of time, patients enter the progressive phase
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`where relapses decrease in frequency and they experience a steady, inexorable loss
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`of physical and cognitive function.
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`B. Copaxone is effective for treating MS
`35. Glatiramer acetate, or GA, is the active ingredient in Copaxone®, a
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`drug product first approved by the FDA in 1996 as a 20 mg daily subcutaneous
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`injection to treat relapsing-remitting multiple sclerosis. The 20 mg daily dose of
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`GA was known to reduce the frequency of relapses in patients with relapsing MS.
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`(Ex. 20048 (Johnson)) For many years, Copaxone® has been the single most
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`prescribed disease modifying therapy used by clinicians to treat MS.
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`6 Filippi, M., et al. The contribution of MRI in assessing cognitive impairment in
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`multiple sclerosis. Neurology 2010; 75: 2121-2128.
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`7 Rovaris, M. et al. Cognitive impairment and structural brain damage in benign
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`multiple sclerosis. Neurology 2008; 71:1521-1526.
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`8 Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and
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`improves disability in relapsing-remitting multiple sclerosis: Results of a phase III
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`multicenter, double-blind, placebo-controlled trial. Neurology 1995; 45: 1268-76.
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`36. GA is a complex mixture of synthetic polypeptides of varying length
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`and sequence, nearly randomly composed of four amino acids. GA is not a single
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`molecule and, due to the complexity and variability of its polypeptide mixture, a
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`clear definition of how GA functions to treat MS has not been established.
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`37.
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`In the clinical trial that led to approval of GA, administration of 20 mg
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`GA daily was shown to decrease the average relapse rate by 29%, from 0.84
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`relapses per year for patients receiving a placebo to 0.59 relapses per year for
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`treated patients. (Ex. 2004 at 1272.) And, following two years of treatment with
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`20 mg GA daily, the median time to first relapse after treatment started increased
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`from 198 days with placebo to 287 days for treated patients. (Id.) While the
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`frequency of relapses, averaged over many patients, is lower for patients on GA
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`treatment than for patients on placebo, the nature of relapses remains intermittent,
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`with unpredictable frequency and timing for each individual patient.
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`38. From its introduction in 1996 until January 2014, 20 mg daily
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`injection Copaxone® was the only approved GA treatment for the treatment of
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`relapsing MS. While the Copaxone® 20 mg dosage form was widely accepted by
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`patients due to its safety and efficacy profile, the frequency and severity of
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`injection related adverse events associated with the drug limited its tolerability.
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`This issue led some patients to discontinue treatment with GA and also impacted
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`the long-term adherence of patients prescribed the 20 mg/mL once daily
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`formulation, which in turn necessarily limited the treatment’s long-term “real-
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`world” efficacy.
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`39. Since the launch of the Copaxone® 20 mg/mL daily dose product,
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`Teva has undertaken efforts to develop alternate dosing regimens of GA. Until
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`2009, the literature reported only a few small studies explored alternate day
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`injections of 20 mg GA. But, none of those studies: (1) tested doses other than 20
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`mg; (2) tested a three times per week regimen; or (3) reported a decrease in the
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`severity of injection site reactions with an increased dose. In fact, none of these
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`studies prior to 2009 had an effect on the standard of care concerning GA. Persons
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`of ordinary skill in the art continued to advise patients to administer daily
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`injections of GA 20 mg/mL because robust clinical trial data supported the safety
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`and efficacy of daily injections of 20 mg/mL of GA. Such robust clinical data did
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`not exist for any other dosing regimens.
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`40. Additional studies studied 40 mg/mL daily administration (Cohen
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`study and the FORTE study). These 40 mg/mL studies universally concluded: (1)
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`that an increased dose did not provide any added efficacy over the 20 mg/mL GA
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`daily regimen; and (2) the increased dose resulted in increased severity of injection
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`site reactions, as was expected from a higher and more concentrated dose. None of
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`these 40mg/mL trials studied a dosing regimen less frequent than daily. Again,
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`none of these trials changed the standard of care for GA as of 2009.
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`C. Adverse events from GA therapy impacts patient adherence
`41. For a physician treating MS patients with GA, much of the day to day
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`work is actually focused upon treating the symptoms of MS, which includes
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`managing and minimizing the adverse impacts associated with MS therapy. When
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`compared with the terrible symptoms of MS, it may seem counterintuitive that the
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`tolerability of GA treatment could be so important. However, the slow and often
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`invisible progression of the disease means that the adverse events that arise from
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`GA treatment often are an initial major contributor to an MS patient’s diminished
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`quality of life during therapy.
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`42. The observable symptoms of MS are often minor during the initial
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`phases of the disease. At the outset of the disease, MS symptoms are usually
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`sensory in nature, frequently involving localized numbness or tingling or periods
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`of visual loss. Several studies have shown that the earlier a patient starts treatment
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`the better—i.e. earlier treatment leads to more efficacy in reducing patient relapse
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`rates. Therefore it is critically important that MS treatments be tolerable to
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`patients, especially in the early stages of therapy. Tolerability is important because
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`if the treatment if more tolerable it is more likely that patients will consistently
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`adhere to the prescribed regimen. Tolerability problems that cause patients to miss
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`doses can have long-term consequences for the progression of MS.
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`43. Patients who experience severe adverse events from treatment are
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`more prone to switch to a different therapy or discontinue treatment, either
`
`temporarily or permanently. Severe adverse events are the most serious and cause
`
`the most disruption in a patient’s life. Severe adverse events are therefore the most
`
`intolerable adverse events and most likely to lead to a decision that a patient cannot
`
`sustain GA treatment. In other words, the number of subjects discontinuing GA
`
`therapy correlates to the severity of adverse events associated with GA injections.
`
`44. Moreover, patients who are having difficulty adhering to GA therapy
`
`often refrain from reporting relapses or other complications associated with MS to
`
`their physician due to their unwillingness to disclose that they are not adhering to
`
`the prescribed treatment. This silence can lead to a worsening of the disease and
`
`continued irreversible damage to the central nervous system. The fact that, as
`
`noted above, the majority of patients on MS disease modifying therapies exhibit
`
`cognitive deficits means that the negative psychological impact of such adverse
`
`events can also exceed what a treating physician might initially expect.
`
`45. Due to the importance of patient adherence, it is therefore critical that
`
`MS therapies be both tolerable in addition to safe and efficacious. Because MS is
`
`currently an incurable disease patients often receive MS treatment for decades.
`
`Therefore, a physician deciding on an MS treatment for their patient must balance
`
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`safety and efficacy with tolerability to ensure the patient adheres to the treatment
`
`over the long-term.
`
`46.
`
`In addition to the problems of adherence associated with severe
`
`adverse reactions, there remains the long term impacts—both physical and
`
`emotional—on patient quality of life that such adverse events can cause. In my
`
`experience, patients talking once daily Copaxone® to treat their MS often suffer
`
`acute injection related adverse events. Many of these once daily patients
`
`complained more of the side effects of such treatment than of any symptoms
`
`arising early in the course of the disease. Even when those patients maintained
`
`their adherence to the therapeutic regimen, it was clear to me that more was needed
`
`to be done to improve the tolerability of treatment.
`
`47. The most common adverse events associated with Copaxone®
`
`therapy are injection site reactions. 90% of patients taking 20 mg of GA daily in
`
`the original Phase III trial that led to approval of Copaxone experienced injection
`
`site reactions. (Ex. 2004 at 1272.) Injection site reactions can vary, with some
`
`reactions resulting in redness or swelling around the injection site, prolonged pain,
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`masses at the site of injection, permanent scaring with hardness, discoloration, or
`
`loss of subcutaneous tissue in or around the injection site.
`
`
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`48. For example, many patients experience large urticarial reactions,
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`which commonly present as a burning sensation, often followed by raised welts
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`and localized stinging which may last for days.
`
`49. Patients can also often suffer erythema, or areas of skin redness and
`
`flushing, that can extend far beyond the injection site. While these flushed areas
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`are often not directly painful, many of my patients have reported self-
`
`consciousness from such marks, especially those who hoped to keep their disease
`
`private. Some have reported that they were questioned at work, or threatened with
`
`loss of employment based on the misunderstanding that such marks might be
`
`associated with illegal drug use.
`
`50. Possibly the most disfiguring injection site reaction is lipoatrophy, or
`
`the localized loss of fatty tissue. Lipoatrophy presents in the creation of permanent
`
`cavities or hollows beneath a patient’s skin in areas where injections are given.
`
`Because the damage is irreversible, the physical and psychological impact of
`
`lipoatrophy cannot be overstated.
`
`51.
`
`In my experience treating MS, the impact of such injection site
`
`reactions is nontrivial. In addition to often being painful and disfiguring, some
`
`injection site reactions become necrotic and infected. Some injection site reactions
`
`can become so severe as to require extended antibiotic courses, surgical drainage,
`
`debridement, and surgical closure. These injection site reactions also can lead to
`
`
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`significant physical and emotional discomfort for patients. In some instances the
`
`discomfort for patients is so severe the patient completely discontinues treatment,
`
`allowing the disease to progress. I have had a number of patients describe to me
`
`the psychological impact of living with such reactions, and the effect of injection
`
`site reactions on their desire not to broadcast their diseased condition to others
`
`including co-workers, bosses, friends, and family. Therefore, as of 2009 there was
`
`a clinical need for an MS treatment that reduced the severity of these adverse
`
`events but maintained the efficacy of GA.
`
`52.
`
`Immediate post-injection reactions (“IPIRs”) are distinct from
`
`injection site reactions. IPIRs generally occur within a few minutes of injecting
`
`Copaxone®, are systemic in nature, and can involve flushing (feeling of warmth
`
`and/or redness), chest pain, heart palpitations, panic or anxiety, and trouble
`
`breathing. In some instances these symptoms may last only 15 minutes or may
`
`persist for hours.
`
`53. The shortness of breath associated with IPIRs may lead to reflex
`
`hyperventilation. Hyperventilating patients unknowingly fill their stomachs with
`
`air which in turn causes acute chest pain, leading many to feel they are
`
`experiencing a heart attack. This leads some patients to call paramedics and other
`
`healthcare professionals. Additionally, as many patients schedule their
`
`
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`Copaxone® injections often early in the morning or late at night, IPIRs lead many
`
`patients into emergency wards.
`
`54. Although less common than injection site reactions, IPIRs are often
`
`extremely frightening to patients. Thus, patients may discontinue therapy entirely
`
`after suffering even a single IPIR, and the severity of IPIRs is a significant concern
`
`for patients and physicians.
`
`55. For these reasons, and others, the promise of less severe side effects
`
`by a change in product formulation and schedule without a compromise in product
`
`efficacy is a highly sought after goal, promising increased real world benefit
`
`through increased adherence to therapy and increased patient quality of life.
`
`VII. DISCUSSION AND OPINIONS
`A. The ’776 Patent
`1.
`Claims
`56. The claims of the ’776 patent relate to methods of treating MS or
`
`improving the tolerability of GA by administering a new dosing regimen that has
`
`reduced severity of adverse events associated with GA treatment while maintaining
`
`effectiveness for treating MS. The new dosing regimen is 40 mg of GA
`
`administered three times per week with at least one day between doses.
`
`57. Claim 1 of the ’776 patent states:
`
`1. A method of treating a human patient suffering from a
`relapsing form of multiple sclerosis, while inducing reduced
`severity of injection site reactions in the human patient relative to
`22
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`Page 22 of 9
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