UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Mylan Pharmaceuticals Inc.
`
`v.
`
`Patent Owner
`
`Patent No. 8,399,413
`
`IPR2015-00644
`
`CORRECTED DECLARATION OF STEPHEN J. PEROUTKA,
`M.D., PH.D.
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`MYLAN INC. EXHIBIT NO. 1003 Page 1
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`TABLE OF CONTENTS
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`I.
`
`QUALIFICATIONS AND BACKGROUND..............................................4
`
`A.
`
`B.
`
`C.
`
`Education and Experience.....................................................................4
`
`Materials Considered.............................................................................9
`
`Scope of Work.......................................................................................9
`
`II.
`
`SUMMARY OF OPINIONS.......................................................................10
`
`III. LEGAL STANDARDS................................................................................17
`
`IV. PRIORITY DATE .......................................................................................20
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART....................................21
`
`VI. BACKGROUND OF GLATIRAMER ACETATE..................................22
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`VII. PRIOR ART GLATIRAMER ACETATE DOSING STUDIES ............25
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`Overview of Dose Range Studies........................................................25
`
`Early Dosing Studies of Glatiramer Acetate Established a
`Minimum Effective Dosing in Multiple Sclerosis (5 mg 5 times
`per week or 25 mg/week)....................................................................28
`
`A Clinically Effective Dose of GA for Treating MS Has Been
`Known Since 1984 (20 mg Daily Dosing or 140 mg/week)...............29
`
`Flechter 2002 (A & B) and Khan 2008: Alternate Day Dosing
`of GA 20 mg Effective to Treat MS (60 to 80 mg/week)...................32
`
`Cohen 2007: 40 mg Daily Dosing of Glatiramer Acetate (i.e.,
`280 mg per week) Also Effective to Treat MS (i.e. 280
`mg/week).............................................................................................39
`
`Rasmussen 2005 Every Other Day and Three Times Per Week
`Dosing in the Treatment of MS (preferably 10-40 mg GA every
`48 hours or 30-120 mg GA per week) ................................................40
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`G.
`
`H.
`
`Pinchasi 2007: Every Other Day Dosing of 40 mg GA (i.e.,
`120 or 160 mg GA per 7-Day Period) Effective to Treat MS ............42
`
`Summary of Prior Art Teaching of Dosing Ranges and
`Frequency ............................................................................................45
`
`VIII. THE MAJORITY OF THE ’413 PATENT’S CLAIMS ARE
`ANTICIPATED BY PINCHASI 2007.......................................................48
`
`A.
`
`Independent Claim 1 of the ’413 Patent Is Disclosed in Pinchasi
`2007 .....................................................................................................48
`
`1.
`
`2.
`
`3.
`
`“reducing the frequency of relapses in a human patient
`suffering from relapsing-remitting multiple sclerosis”.............49
`
`“comprising administering to the human patient a
`therapeutically effective dosage regimen of three
`subcutaneous injections of 1 ml of a pharmaceutical
`composition comprising 40 mg of glatiramer acetate over
`a period of seven days with at least one day between
`every subcutaneous injection” ..................................................49
`
`“the regimen being sufficient to reduce the frequency of
`relapses in the patient.”.............................................................51
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`Dependent Claims 2, 3, 5, 8, 12 and 13 of the ’413 Patent Are
`Disclosed in Pinchasi 2007 .................................................................51
`
`Dependent Claims 4, 6 and 9-11 Are Disclosed in Pinchasi
`2007 .....................................................................................................54
`
`Dependent Claims 14-18 Are Disclosed in Pinchasi 2007 .................56
`
`Independent Claim 19 Is Disclosed in Pinchasi 2007.........................62
`
`Independent Claim 20 of the ’413 Patent Is Disclosed in
`Pinchasi 2007 ......................................................................................62
`
`IX. EACH CLAIM OF THE ’413 PATENT IS INVALID AS
`OBVIOUS.....................................................................................................63
`
`A.
`
`Overview of Petitioner’s Obviousness Challenge ..............................63
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`B.
`
`Compliance, Side Effect, and Commercial Considerations
`Motivated Less Frequent GA Dosing .................................................66
`
`1.
`
`2.
`
`3.
`
`Patient Compliance ...................................................................66
`
`Side Effects of Daily Injections ................................................68
`
`Financial and Market Forces.....................................................71
`
`C.
`
`D.
`
`E.
`
`The Prior Art Provides a Reasonable Expectation of Success in
`Administering the Claimed Dosing Regimen .....................................73
`
`Pinchasi 2007, Alone or in View of the 1996 FDA SBOA
`Renders Each Claim of the ’413 Patent Obvious................................76
`
`Each Claim of the ’413 Patent is Obvious over Pinchasi 2007 in
`view of Flechter 2002A.......................................................................89
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claim 1 of the ’413 Patent Is Obvious......................................90
`
`Claims 2, 3, 5, 8, 12 and 13 of the ’413 Patent Are
`Obvious .....................................................................................93
`
`Claims 4, 9-11 Are Obvious .....................................................95
`
`Claim 6 of the ’413 Patent Is Obvious......................................96
`
`Claim 7 of the ’413 Patent Is Obvious......................................97
`
`Claim 16 of the ’413 Patent Is Obvious..................................100
`
`Claims 14 and 17 of the ’413 Patent Are Obvious .................103
`
`Claims 15 and 18 of the ’413 Patent Are Obvious .................105
`
`Claim 19 of the ’413 Patent ....................................................108
`
`10. Claim 20 of the ’413 Patent ....................................................109
`
`X.
`
`CONCLUSION ..........................................................................................111
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`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A.
`
`1.
`
`Education and Experience
`
`My name is Stephen J. Peroutka. I am a physician and
`
`pharmacologist with over thirty years of experience. Throughout my career I have
`
`practiced as a clinician in the field of neurology, conducted research in multiple
`
`neurological disorders, including multiple sclerosis (MS)1, and held a number of
`
`relevant positions in the biotechnology and pharmaceutical industries. My full
`
`curriculum vitae (CV) is attached hereto as Exhibit A and is incorporated herein.
`
`2.
`
`I received my A.B. degree in neurobiology and psychology from
`
`Cornell University in 1975, where I was a College Scholar in the School of Arts
`
`and Sciences and graduated Phi Beta Kappa. In 1979, I received an M.D. degree
`
`from the Johns Hopkins University School of Medicine. I earned my Ph.D. from
`
`the Department of Pharmacology and Experimental Therapeutics at the Johns
`
`Hopkins University School of Medicine in 1980.
`
`3.
`
`I currently serve as Chief Medical Officer of Semnur Pharmaceuticals,
`
`1 In this declaration, I use several abbreviations for certain well known terminology
`
`in the art, including for example “MS” for multiple sclerosis, “RRMS” for relapse-
`
`remitting multiple sclerosis, “GA” for the glatiramer acetate active ingredient, and
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`“SC” for the subcutaneous route of injection.
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`Inc. where I am responsible for all medical activities including relevant pre-
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`clinical, clinical, and regulatory affairs of the company. Semnur develops
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`innovative therapies for the treatment of neurological conditions, and our team is
`
`currently focusing our efforts on therapeutic products for pain management.
`
`4.
`
`From 1980-1981, I served as an intern in the Department of Internal
`
`Medicine at Stanford University Hospital. I returned to the Johns Hopkins
`
`Hospital from 1981-1984 to complete my residency and fellowship in the
`
`Department of Neurology. I also conducted research and taught at Stanford
`
`University as an Assistant Professor in the Neurology and Pharmacology
`
`Departments from 1984-1990. From 1988-1990, I served as Chief Physician of the
`
`Neurology Service at the Palo Alto Veteran’s Administration Hospital. In my
`
`clinical practice as a neurologist (1981-1990), I evaluated numerous multiple
`
`sclerosis patients on a day-to-day basis.
`
`5.
`
`I also have extensive experience working in the biotechnology and
`
`pharmaceutical industries. I served as the first Director of Neuroscience at
`
`Genentech, Inc. from 1990 to 1993. While at Genentech, one of my major
`
`responsibilities was to determine appropriate dosing for recombinant human nerve
`
`growth factor in humans. This was an extremely complicated problem because it
`
`was a biological agent that had never before been administered to humans. I also
`
`have determined appropriate dosages in the case of new uses for approved
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`compounds. As an example, a team I led balanced safety versus efficacy to
`
`determine the appropriate dose for nifedipine in migraine patients. Additionally, I
`
`have investigated and determined appropriate dosages for new formulations,
`
`including a novel formulation of diclofenac for postoperative dental pain. In
`
`addition, in my role as CMO at various biotechnology companies, I have evaluated
`
`clinical trial dosing parameters for capsaicin2, hydrocodone,3 and other analgesic
`
`products.4
`
`6.
`
`I was also the Vice President of the CNS group at PRA International
`
`from 2008 to 2011. At PRA, I was the therapeutic expert advising and supporting
`
`both the operations and business development groups. In this role, I was
`
`responsible for providing therapeutic expert advice on the design and development
`
`of human clinical trials for numerous neuropharmacological treatment therapies,
`
`including over 30 clinical trials for multiple sclerosis. This work involved, in part,
`
`assessing the inclusion and exclusion criteria of multiple sclerosis studies to assure
`
`appropriate subject enrollment, evaluating the clinical trial endpoints such as
`
`relapse rates and the presence of lesions on MRI scans, and assessing the global
`
`evolution in the ethical acceptability of placebo arms in MS trials.
`
`2 In my work as CMO at NeurogesX. See CV, Exhibit A.
`
`3 In my work as CMO at Zogenix. See id.
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`4 Name of active ingredient withheld as confidential to Semnur. See id.
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`7.
`
`I have founded two companies: Spectra Biomedical, Inc. and Synergia
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`Pharma, Inc. I have also served as a consultant to several companies and assisted
`
`with various aspects of these companies’ product portfolios directed to treatment of
`
`neurological conditions.
`
`8.
`
`I have extensive experience in optimizing dosage treatment regimens
`
`for clinical efficacy and titrating pharmaceuticals for commercial products,
`
`including new drugs for neurological conditions, new neurological uses for known
`
`compounds, new formulations of known compounds, and dosing in clinical trials.
`
`9.
`
`I have also participated in academic studies on dosing. I investigated
`
`the binding of neuroleptic drugs to different neurotransmitter receptors in
`
`evaluating both clinical efficacy and known side effects. More recently, I received
`
`a grant to develop an opioid taper regimen, to minimize or eliminate opioid
`
`withdrawal symptoms, which required quantitative analysis of opioid
`
`pharmacokinetics and dosing schedules.5
`
`10. Related to my work in designing dosing schedules, I also have
`
`experience with evaluating local site reactions for a variety of administration
`
`routes. In connection with my work with the subcutaneous (SC) injection of
`
`recombinant human nerve growth factor, as one example, I addressed the unique
`
`local site reaction characterized by hyperalgesia. As another example, I
`
`5 See id.
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`participated in a local site reaction study for another injectable, Sumavel DosePro.6
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`In addition to subcutaneous (SC) injectables, I also have experience with local site
`
`reactions for epidural products.7 I have also evaluated local site reactions related to
`
`topical products.8
`
`11.
`
`I have received a number of awards and honors for my work. In 1993,
`
`I won the Syntex Award for Receptor Pharmacology, was elected to the Scientific
`
`Committee of the International Headache Society, and received the Harold G.
`
`Wolff Award from the American Association for the Study of Headache for the
`
`best research paper of that year. I also received the Daniel H. Efron Award from
`
`the American College of Neuropsychopharmacology for excellence in basic
`
`neuropharmacology research.
`
`12.
`
`I have published my work extensively, having been named as author
`
`or co-author on over 400 articles, books, book chapters, and abstracts. I have been
`
`an invited lecturer on numerous occasions to address topics in the field of
`
`neuroscience. I have served as an editor and/or referee and on the editorial boards
`
`6 During my time a CMO at Zogenix. See id.
`
`7 Name of active ingredient withheld as confidential to Semnur. Id.
`
`8 Specifically, the topical analgesic product, Qutenza, as well as a second
`
`generation liquid product during my time as CMO at NeurogesX. Id.
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`of numerous peer-reviewed journals in the field of neurology, including Annals of
`
`Neurology, Neurochemistry, Clinical Neuropharmacology, Neuropharmacology,
`
`New England Journal of Medicine, and Peptides. I currently serve on the editorial
`
`board of Molecular Diagnosis & Therapy.
`
`B.
`
`13.
`
`Materials Considered
`
`In connection with forming my opinions and drafting this declaration,
`
`I considered the materials identified in this declaration and listed in Exhibit B,
`
`attached hereto, in addition to my experience, education and training.
`
`C.
`
`14.
`
`Scope of Work
`
`I have been retained by counsel for Mylan Pharmaceuticals Inc.
`
`(“Mylan”) in connection with this matter. I am being compensated at a rate of
`
`$500 per hour for my work on this matter. My compensation does not in any way
`
`depend on the outcome of this proceeding.
`
`15.
`
`I have been admitted as an expert in federal court (District of
`
`Delaware). My expertise is in the pharmaceutical sciences, and more specifically
`
`in pharmacological aspects of dosing (including amounts of agent and frequency of
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`administrations), and in and to the medical aspects of the treatment of neurological
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`conditions, including clinical pharmacology.
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`II.
`
`SUMMARY OF OPINIONS
`
`16.
`
`U.S. Pat. No. 8,399,413 (“the ’413 patent”) (Exh. 1001) relates to the
`
`use of the drug glatiramer acetate (GA) to treat certain forms of multiple sclerosis
`
`(MS). GA is the active ingredient in the branded pharmaceutical Copaxone®,
`
`marketed and sold by Teva Pharmaceuticals. As of August 2009 (the ’413 patent’s
`
`earliest possible priority date), Copaxone® had been approved to treat MS for more
`
`than a decade, and studied in patients for almost three decades. It was first
`
`approved by the FDA for clinical use in 1996 in a dosing regimen of 20 mg daily
`
`administered by subcutaneous injection.
`
`17.
`
`The ’413 patent claims a modified, less frequent dosing regimen for
`
`GA in the treatment of MS. In general, the claims have in common the step of
`
`administering a therapeutically effective regimen of three SC injections of 40 mg
`
`of GA over a seven day period in which the three injections are separated by at
`
`least one day. The recited dosing regimen is administered to reduce the frequency
`
`of relapses or to alleviate a symptom in patients suffering from certain forms of
`
`MS, including relapsing-remitting multiple sclerosis (RRMS).
`
`18.
`
`In my opinion, the method recited in the ’413 patent offers nothing
`
`inventive. International Publication Number WO 2007/081975 (Exh. 1005,
`
`“Pinchasi 2007”) is a 2007 Teva patent application that taught the administration
`
`of 40 mg of GA in an alternate day dosing regimen for the treatment of MS
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`symptoms, including RRMS. The publication, titled Method of Treating Multiple
`
`Sclerosis, “provides a method of alleviating a symptom of a patient suffering from
`
`a relapsing form of multiple sclerosis which comprises periodically administering
`
`to the patient by subcutaneous injection a single dose of a pharmaceutical
`
`composition comprising 40 mg of glatiramer acetate so as to thereby alleviate the
`
`symptom of the patient,”9 and states that “periodic administration” includes “every
`
`other day” dosing.10 The disclosed alternate day dosing regimen necessarily
`
`requires that during each seven day period, GA will be administered as three SC
`
`injections with at least one day between every SC injection. This disclosure and
`
`others in Pinchasi 2007 renders unpatentable every claim of the ’413 patent.
`
`19. All claims of the ’413 patent are also obvious. As long ago as 1996,
`
`in the course of reviewing the New Drug Application for Copaxone®, the FDA
`
`questioned whether daily SC injections of GA were necessary and explicitly
`
`suggested investigation of less frequent dosing regimens. Specifically, in a
`
`document that I understand became publically available before the earliest priority
`
`9 Pinchasi 2007, Exh. 1005 at Abstract & 8, ll. 1-8.
`
`10 Id. at 8, ll. 10-11.
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`date,11 an FDA reviewer stated that “it is unclear to me why it is necessary to inject
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`the drug on a daily basis. This dosing regimen seems like it would subject the
`
`patient to an excessive amount of discomfort if it is not necessary to maintain
`
`efficacy.”12 The reviewer “recommend[ed] that [Teva] evaluate the necessity of
`
`daily s.c. injections as opposed to more infrequent intermittent administration of
`
`the drug.”13
`
`20.
`
`To those familiar with this art, the FDA reviewer’s suggestion was a
`
`natural one for several reasons. One reason relates to patient compliance with a
`
`dosing regimen. In general, the more frequently a medication is administered, the
`
`less likely the patient will adhere to the prescribed schedule. With injections in
`
`particular, the need for minimizing administrations is even greater; the less
`
`frequent the injection schedule the better. As one prior art study of alternate day
`
`GA dosing regimens explained, “[t]here is considerable interest in alternate dosing
`
`11 Exh. 1007, Affidavit of Marlene S. Bobka dated December 9, 2014 (“Bobka
`
`December 9, 2014 Affidavit”), attaching as Exh. A, John J. Jessop, Review and
`
`Evaluation of Pharmacology Toxicology Data: Original NDA Review (1996) (Exh.
`
`1007A “1996 FDA SBOA”). The 1996 FDA SBOA was disclosed to the public,
`
`and to Mylan, more than one year before the earliest possible priority date.
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`12 1996 FDA SBOA, Exh. 1007A at 121.
`
`13 Id.
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`regimens of GA in RRMS. Daily SC injectable therapy can be challenging for
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`long-term patient compliance.”14
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`21. Another reason to adopt less frequent alternatives to daily dosing of
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`GA has to do with the side effects associated with daily injections. Since its
`
`marketing approval in 1996 and as of the priority date, injection site reactions
`
`remained the most frequently reported side effect associated with the daily
`
`administration of Copaxone®. For example, as described in a 1995 pivotal trial of
`
`Copaxone®, “the most commonly recognized adverse event was a localized
`
`injection-site reaction consisting of mild erythema and induration, which
`
`sometimes persisted for several days. It was observed at least once during 730
`
`days of treatment in 90% of the copolymer 1-treated patients.”15 A person of
`
`ordinary skill would have understood that fewer injections of GA would likely
`
`14 See Exh. 1010, Khan O., et al., Randomized, prospective, rater-blinded, four-
`
`year, pilot study to compare the effect of daily versus every-other-day glatiramer
`
`acetate 20 mg subcutaneous injections in relapsing-remitting multiple sclerosis,
`
`MULTIPLE SCLEROSIS 14:S296, P902 (2008) (“Khan 2008”).
`
`15 See Exh. 1018, Johnson K.P., et al., Copolymer 1 reduces relapse rate and
`
`improves disability in relapsing-remitting multiple sclerosis, NEUROLOGY,
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`45:1268-76 (1995) (“Johnson 1995”) at 1272.
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`reduce the frequency of such adverse reactions, which would have motivated such
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`person to minimize the total number of injections. In short, well before the priority
`
`date there were ample suggestions in the publically available literature that would
`
`motivate a person of ordinary skill in the art to investigate less frequent than daily
`
`dosing regimens for GA.
`
`22. Considering this, it is unsurprising that well before August 2009,
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`researchers in the MS field had in fact successfully investigated decreasing the
`
`number of doses per week of GA administered to patients. It was reported that
`
`alternate-day treatment with GA was safe, well tolerated, and was expected to be
`
`as effective as daily SC injections in reducing relapse rate and slowing neurologic
`
`deterioration.16 At least two prior art clinical studies suggested that 20 mg of GA
`
`administered on alternating days to patients with RRMS is at least equally effective
`
`as and more tolerable than treatment with 20 mg of GA administered daily.17
`
`Based on these studies, those in the art would have reasonably expected a dosing
`
`regimen of three times per week with 40 mg GA to be effective and tolerable in
`
`16 See Exh. 1008, Flechter S., et al., Copolymer 1 (Glatiramer Acetate) in
`
`Relapsing Forms of Multiple Sclerosis: Open Multicenter Study of Alternate-Day
`
`Administration, CLINICAL NEUROPHARMACOLOGY, 25:11-15 (2002) (“Flechter
`
`2002A”) at 15.
`
`17 Khan 2008, Exh. 1010 & Flechter 2002A, Exh. 1008 at 15.
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`MS patients, and patients with MS symptoms.
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`23.
`
`In addition to investigating alternative dosing schedules, before
`
`August 2009 researchers had also performed successful studies comparing
`
`different dosage amounts of GA to the traditional dose of 20 mg.18 One prior art
`
`study published in 2007 in Neurology, a widely read and highly cited peer-
`
`reviewed neurology journal, compared 20 mg daily and 40 mg daily doses of GA
`
`in terms of safety, tolerability and efficacy. It concluded that “[g]latiramer acetate
`
`(GA) 40 mg was safe and well tolerated. The overall efficacy results suggested
`
`that a 40-mg dose of GA may be more effective than the currently approved 20-mg
`
`daily dose in reducing MRI activity and clinical relapses.”19 The Neurology study
`
`18 See, e.g., Exh. 1012, Flechter S., et al., Comparison of glatiramer acetate
`
`(Copaxone) and interferon β-1b (Betaferon) in multiple sclerosis patients: an
`
`open-label 2-year follow up, 197 JOURNAL OF THE NEUROLOGICAL SCIENCES 51-55
`
`(2002) (“Flechter 2002B”) at 52 (“[s]ince the decision of injecting Copaxone 20
`
`mg sc on a daily basis was an arbitrary one based on pre-clinical studies, we have
`
`decided to compare the effect of alternate day injection vs. daily injection.”)
`
`19 Exh. 1006, Cohen, J.A., et al., Randomized, double-blind, dose-comparison
`
`study of glatiramer acetate in relapsing-remitting MS, NEUROLOGY, 68:939-44
`
`(2007) (“Cohen 2007”) at 939.
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`data appears to be the same dataset as that reported in Pinchasi 2007 which, as
`
`discussed above, discloses alternate day dosing with 40 mg of GA to treat RRMS
`
`and MS symptoms in patients.
`
`24.
`
`The specification of the ’413 patent sets out four supposed drawbacks
`
`from changing the Copaxone® 20 mg daily therapy: acceptable injection volume;
`
`drug degradation at the injection site resulting in reduced bioavailability; increased
`
`potential for local irritation, precipitation of the drug and concentration-dependent
`
`adverse reactions; and the unpredictability of dosing frequency due to the
`
`“complex pharmacokinetic behavior of a drug” (emphasis added).20 Notably, none
`
`of the references cited in support of these purported challenges relate to GA. Teva
`
`did not discuss any of the publications discussed above, such as Pinchasi, Flechter,
`
`Khan or the SBOA in the patent specification, which demonstrate the safety,
`
`efficacy and tolerability of increased dose and decreased dosing frequency of GA.
`
`I do not find the arguments set forth in column 15, line 52 through column 16, line
`
`8, of the patent to have any bearing on my opinion that the ’413 patent is invalid.
`
`25.
`
`In summary, as of August 2009, Copaxone® had been in widespread
`
`use to treat MS for more than a decade. It had been successfully studied clinically
`
`in numerous ways, including in dosing regimens of 20 mg daily, 40 mg daily, and
`
`20 ’413 patent, Ex. 1001 at col. 15, l. 63-col. 16, l. 18.
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`20 mg on alternate days, all of which showed similar efficacy, safety and
`
`tolerability. Moreover, publications before August 2009 explicitly taught 40 mg
`
`alternate day dosing of GA. These disclosed dosing regimens taught a weekly dose
`
`of GA ranging from 60 mg (i.e., 20 mg alternate day dosing) to 280 mg (i.e., 40 mg
`
`daily dosing), and included three 40 mg injections of GA, which is 120 mg, in one
`
`7-day period. The ’413 patent includes a 120 mg dose per 7-day period (i.e., three
`
`40 mg doses in a seven day period with at least one day between doses) which falls
`
`squarely in the middle of the effective, safe and tolerable dosing range established
`
`in the prior art. In my opinion, there is nothing inventive about the claimed dosing
`
`regimen, which merely selects a weekly dosage amount in the middle of a range of
`
`dosage amounts previously shown to be safe, tolerable and effective.
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`III.
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`LEGAL STANDARDS
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`26.
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`In forming my opinions, I have been advised of certain legal
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`principles that are relevant here. My understanding of these principles is
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`summarized below.
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`27.
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`I have been advised that Mylan bears the burden of proving
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`unpatentability of the challenged claims of the patent under discussion by a
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`preponderance of the evidence. It is my understanding that this standard means
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`that Mylan must show that unpatentability is more probable than not.
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`28.
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`I have also been advised that, in this proceeding, the patent claims are
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`to be given their broadest reasonable interpretation in view of the specification
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`from the perspective of a person of ordinary skill in the art as of the priority date
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`and that this standard differs from that used in the district court proceedings in
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`which I have been involved. I have followed these principles in my analysis
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`presented in this declaration.
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`29. Additionally, I have been informed that in order to be patentable,
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`claims of a patent must meet a legal standard known as novelty. It is my
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`understanding that a claim is unpatentable if, in light of the prior art, the subject
`
`matter of that claim was disclosed to the public before the priority date. I
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`understand that in order for a claim to be anticipated, every element of the claim
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`must be disclosed either expressly or inherently in a single prior art reference in a
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`manner that teaches, or enables, a person of ordinary skill in the art how to use the
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`claimed methods. A reference may anticipate inherently if a claim limitation that
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`is not expressly disclosed in a prior art reference is necessarily present, or inherent,
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`in the single anticipating reference. I also understand that extrinsic evidence may
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`be used to explain but not expand the meaning of terms and phrases used in a prior
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`art reference relied upon as anticipatory of the claimed subject matter.
`
`30.
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`I understand that, in a patentability analysis, a claimed result of a
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`method step is inherent in a prior art teaching if the result is a natural result of the
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`claimed method step that is explicitly disclosed in the prior art reference. The
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`inherent characteristics or functioning of the prior art need not be explicitly
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`recognized by the person of ordinary skill.
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`31.
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`I have been informed that, in order to be patentable, a patent claim
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`must also meet a legal standard known as non-obviousness. It is my understanding
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`that a claim is unpatentable if the differences between the claimed subject matter
`
`and the prior art are such that the subject matter as a whole would have been
`
`obvious at the time of invention to a person having ordinary skill in the art.
`
`32.
`
`In addition, to establish that a patent claim is obvious, Mylan must
`
`prove by a preponderance of the evidence that a person of ordinary skill in the art
`
`would have had a reason to combine the teaching of the prior art, or modify a
`
`single prior art reference, to achieve the claimed invention, and that the person of
`
`ordinary skill would have had a reasonable expectation of success in doing so. I
`
`understand that multiple pieces of prior art may be combined to establish the
`
`obviousness of a claim and that in order for a claim to be obvious, every element of
`
`the claim must be found either expressly or inherently in the teachings of the prior
`
`art. As discussed above, inherency, in a patentability analysis, is present when the
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`limitation at issue, for example, is the “natural result” of practicing the prior art.
`
`33.
`
`Further, I am also informed that when there is some recognized reason
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`to solve a problem, and there are a finite number of identified, predictable and
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`known solutions, a person of ordinary skill in the art has good reason to pursue the
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`known options within his or her technical grasp. If such an approach leads to the
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`expected success, it is likely not the product of innovation but of ordinary skill and
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`common sense. In such a circumstance, when a patent simply arranges old
`
`elements with each performing its known function and yields no more than one
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`would expect from such a modification, the combination is likely obvious.
`
`34.
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`I have also been informed that the term “comprising” that is used in
`
`the ’413 patent has a very specific meaning: it is inclusive or open-ended and does
`
`not exclude additional, unrecited elements or method steps.
`
`IV.
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`PRIORITY DATE
`
`35. The ’413 patent reports that it stems from applications claiming the
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`benefit of U.S. Provisional Application Serial No. 61/274,687 filed August 20,
`
`2009. Thus, I understand that the earliest possible effective filing date to which
`
`the ’413 patent can claim any sort of priority is August 20, 2009. The named
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`inventor on the face of the’413 patent is Ety Klinger.
`
`36.
`
`I understand that any reference by an author other than Ety Klinger
`
`that published prior to August 20, 2009 qualifies as prior art under 35 U.S.C.
`
`§ 102(a) to each claim of the’413 patent.
`
`I also understand that any reference
`
`published by anyone prior to August 20, 2008 qualifies as prior art to the ’413
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`patent under 35 U.S.C. § 102(b).
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`V.
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`PERSON OF ORDINARY SKILL IN THE ART
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`37.
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`I have reviewed the ’413 patent and its respective file history.21 The
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`’413 patent relates to therapeutic methods of administering GA. Each claim
`
`requires the step of “administering to the human patient a therapeutically effective
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`regimen of three subcutaneous injections of a 40 mg dose of glatiramer acetate
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`over a period of seven days with at least one day between every subcutaneous
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`injection.”22 The ’413 patent’s specification provides a single example that I
`
`understand had not actually been completed as of the filing date, but instead
`
`expressed a hypothesis. There are no data reported in the Example with respect to
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`the methods claimed in the patent.
`
`38. A person of ordinary skill in the art in the field of the ’413 patent as
`
`of the priority date would have had several years of experience in the
`
`pharmaceutical industry and/or practicing medicine. Such a person would have
`
`direct experience with the administration or formulation of therapeutic agents,
`
`dosing schedules and frequencies, and/or drug development study design. Such a
`
`person would also be well versed in the literature that was available as of the
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`21 ’413 patent, Exh. 1001; Exh. 1002, file history for Appl. Ser. No. 12/806,684
`
`(which issued as the ’413 patent).
`
`22 See section VIII and IX, infra (the ’413 patent is anticipated by Pincha