`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`YEDA RESEARCH & DEVELOPMENT CO., LTD.,
`Patent Owner
`
`
`
`U.S. Patent No. 8,232,250
`
`________________________
`
`Case IPR2015
`Unassigned
`________________________
`
`
`EXPERT DECLARATION OF ARI GREEN, M.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 8,232,250
`
`
`
`
`
`
`
`
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`MYLAN INC. EXHIBIT NO. 1004 Page 1
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`TABLE OF CONTENTS
`
`Contents
`
`I.
`
`Qualifications and Background ............................................................................ 1
`
`A.
`B.
`C.
`
`Education and Experience; Prior Testimony.............................................. 1
`Bases for Opinions and Materials Considered ........................................... 6
`Scope of Work ............................................................................................ 6
`
`II.
`
`Summary of Opinions ........................................................................................... 6
`
`III. Legal Standards .................................................................................................... 8
`
`IV. Person of Ordinary Skill in the Art ..................................................................... 10
`
`V.
`
`The ’250 Patent [Ex. 1001] ................................................................................. 11
`
`VI. Background ......................................................................................................... 16
`
`D. Multiple Sclerosis ..................................................................................... 16
`E. Multiple Sclerosis Therapies .................................................................... 22
`F.
`Compliance and Adherence Rates with Disease Modifying Agents ....... 28
`
`VII. Scope and Content of the Prior Art References.................................................. 33
`
`A.
`B.
`
`C.
`
`PCT Publication No. WO 2007/081975 (“Pinchasi”) [Ex. 1005] ........... 33
`Cohen et al. “Randomized, double-blind, dose-comparison study of
`glatiramer acetate in relapsing-remitting MS” Neurology 68:939-
`44 (2007) (“Cohen”) [Ex. 1006] .............................................................. 35
`Flechter et al. “Copolymer 1 (glatiramer acetate) in relapsing forms
`of multiple sclerosis: Open multicenter study of alternate-day
`administration” Clin. Neuropharm. 29:11-15 (2002) (“Flechter
`
`MYLAN INC. EXHIBIT NO. 1004 Page 2
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`E.
`
`F.
`
`D.
`
`2002A”) [Ex. 1008] .................................................................................. 36
`D. Khan 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 (2008) (“Khan”) [Ex. 1010] ....................................................... 37
`Flechter et al. “Comparison of glatiramer acetate (Copaxone®) and
`interferon β-1b (Betaferon®) in multiple sclerosis patients: an
`open-label-2-year follow up” J. Neurological Sci. 197:51-65 (2002)
`(“Flechter 2002B”) (Ex. 1012) ................................................................. 38
`Caon 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 RRMS”
`Neurol. 72(11)(Suppl. 3):P06.141 (March 17, 2009) (“Caon”) [Ex.
`1011] ......................................................................................................... 40
`Johnson et al. “Copolymer 1 reduces relapse rate and improves
`disability in relapsing-remitting multiple sclerosis” Neurol.
`45:1268-76 (July 1995) (“Johnson”) [Ex. 1018] ..................................... 40
`G. Ge et al. “Glatiramer Acetate (Copaxone) treatment in Relapsing-
`Remitting MS Quantitative MR Assessment” Neurology 54:813-7
`(2000) (“Ge”) [Ex. 1025] ......................................................................... 41
`COPAXONE® 20 mg/ml Product Label (February 2009) (“2009
`Copaxone Product Label”) [Ex. 1052] ..................................................... 42
`Copaxone Summary Basis of Approval (NDA No. 20-622)
`“Copolymer 1 for treatment of relapsing-remitting multiple
`sclerosis” Review and Evaluation of Pharmacology Toxicology
`
`H.
`
`I.
`
`MYLAN INC. EXHIBIT NO. 1004 Page 3
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`
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`J.
`
`K.
`
`Data (“SBOA”) (1996) [Ex. A of Ex. 1007] ............................................ 43
`Jacobs et al. “Intramuscular interferon beta-1a therapy initiated
`during a first demyelinating event in multiple sclerosis” New Engl.
`J. Med 343:898-904 (“Jacobs”) (September 2000) [Ex. 1054] ............... 44
`Comi et al. “European/Canadian multicenter, double-blind,
`randomized, placebo-controlled study of the effects of glatiramer
`acetate on magnetic resonance imaging-measured disease activity
`and burden in patients with relapsing multiple sclerosis” Ann.
`Neurol. 49:290-7 (2001) (“Comi”) [Ex. 1026] ........................................ 45
`
`VIII. UNPATENTABILITY OF THE ’250 PATENT ............................................... 46
`
`A. All Claims of the ’250 Patent are Anticipated or Obvious ...................... 46
`(a) Claims 1 and 19 of the ’250 Patent are Anticipated by Pinchasi [Ex.
`1005]
`46
`(b) Claims 1, 15 and 19 are Obvious Over Pinchasi [Ex. 1005] ............ 50
`(c) Dependent Claims 2-14, 16-18 and 20 are also Anticipated or
`Obvious Over Pinchasi [Ex. 1005] ........................................................................ 58
`B. All Claims of the ’250 Patent are Obvious Over Pinchasi [Ex. 1005]
`in view of Flechter 2002A [Ex. 1008] ..................................................... 62
`
`IX. CONCLUSION ................................................................................................... 65
`
`
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`MYLAN INC. EXHIBIT NO. 1004 Page 4
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`
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`1.
`
`My name is Ari Green, M.D. I have been retained by counsel for
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`Mylan Pharmaceuticals Inc. (“Mylan”). I understand that Mylan intends to petition
`
`for inter partes review of U.S. Patent No. 8,232,250 (the ’250 patent) [Ex. 1001],
`
`which is assigned to Yeda Research & Development Co., Ltd. I also understand
`
`that Mylan will request that the United States Patent and Trademark Office cancel
`
`certain claims of the ’250 patent as unpatentable in an Inter Partes Review petition.
`
`I submit this expert declaration, which addresses and supports Mylan’s Inter Partes
`
`Review petition for the ’250 patent.
`
`I.
`
`Qualifications and Background
`A. Education and Experience; Prior Testimony
`I received my Bachelor of Arts and Science (magna cum laude) from
`2.
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`Miami University (OH) in 1994, and my M.D. from Duke University School of
`
`Medicine in 2001. I obtained my Master’s in Clinical Research from the University
`
`of California, San Francisco in 2007.
`
`3.
`
`I completed postgraduate medical training at the University of
`
`California, San Francisco, completing an internship in the Department of Medicine
`
`in 2002, and a residency in Neurology in 2004. I became the Chief Resident of
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`Neurology from 2004-2005, and a Clinical Fellow in the Departments of Neuro-
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`Ophthalmology and Neuro-Immunology from 2005-2007. In 2006, I was a Visiting
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`MYLAN INC. EXHIBIT NO. 1004 Page 5
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`Fellow in the Department of Neuropathology (Retina) at the Queen’s University in
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`Belfast.
`
`4.
`
`I am Board Certified in Psychiatry and Neurology since 2007. I have
`
`been licensed by the State of California since 2003.
`
`5.
`
`I was a Clinical Instructor in the Department of Neurology from 2005-
`
`2007, and Assistant Professor of Clinical Neurology from 2007 to 2013. I have
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`been an Associate Professor of Neurology and Associate Professor of
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`Ophthalmology since 2013. I have also served as the Medical Director of the
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`Multiple Sclerosis Center at the University of California, San Francisco since 2012,
`
`and am an attending physician in the clinic.
`
`6.
`
`My duties at University of California, San Francisco School of
`
`Medicine include teaching responsibilities for medical students and rotating
`
`residents. I currently teach a neurology course to medical students, and serve as an
`
`Attending Physician for the Neurology Service. I also serve as the Multiple
`
`Sclerosis Center Resident Education Coordinator, the Neuroimmunology
`
`Conference Coordinator, the Neuroanatomy/Neuro Radiology/Optic Neuritis
`
`teaching coordinator, the Fundoscopy/Eye movements/Optic Neuritis coordinator, a
`
`Pisces Preceptor for Neurology clinics, and participate in Professor’s Rounds at the
`
`medical school. I presently serve as a presentation mentor in the Bioengineering
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`MYLAN INC. EXHIBIT NO. 1004 Page 6
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`program at the University of California, San Francisco, and currently supervise
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`and/or mentor undergraduates, medical students and post-doctoral fellows and
`
`residents.
`
`7.
`
`I have been studying and treating patients with Multiple Sclerosis
`
`since the start of my medical career. I began doing MS research and learning about
`
`MS in 1991 at the Cleveland Clinic Mellon Center under the supervision of Drs.
`
`Rick Rudick and Donald Goodkin. I continued to perform MS research in the
`
`laboratories of Dr. Jorge Oksenberg and Stephen Hauser from 1998-2000 at UCSF.
`
`In 2005 (revised in 2007), I edited and published the Multiple Sclerosis Section of
`
`the Neurology Resident handbook in use at the medical school. I undertook to
`
`continue my research in MS after I completed my Chief Residency in 2005. I was
`
`an American Academy of Neurology Foundation Research Fellow from 2005-2007,
`
`and was awarded the Debbie and Andy Rachleff Distinguished Professor in
`
`Neurology in 2008. I received the Howard Hughes Medical Institute Physician
`
`Scientist Early Career Award in 2008, and the Harry Weaver Award, National
`
`Multiple Sclerosis Society in 2012. I was also awarded a T1 Catalyst award from
`
`the Clinical and Translational Science Institute at the University of California, San
`
`Francisco.
`
`MYLAN INC. EXHIBIT NO. 1004 Page 7
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`8.
`
`I have also been awarded research grants and fellowships from the
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`National Multiple Sclerosis Society, the American Academy of Neurology
`
`Foundation, the National Institutes of Health, the Fidelity Foundation Grant and the
`
`Howard Hughes Medical Institute. I am a member of the American Academy of
`
`Neurology and currently serve as a member of the Neuro-Ophthalmology and
`
`Multiple Sclerosis sections. I am also a member of the Society for Translational
`
`Research, the North American Neuro-Ophthalmology Society, the Transverse
`
`Myelitis Association and the Guthy Jackson Neuromyelitis Optica Research
`
`Foundation.
`
`9.
`
`I am a member of the Editorial Board for the journal Neurology, and
`
`review original abstracts and articles. I have served as a reviewer for Annals of
`
`Neurology, PLOS ONE, British Journal of Ophthalmology, IOVS, Eye, Brain,
`
`Journal of Neurology, Neurosurgery and Psychiatry, Journal of Neuro-
`
`ophthalmology, JAMA Neurology and Neurology. I am also an abstract reviewer
`
`for the European Committee for Treatment and Research in Multiple Sclerosis
`
`(ECTRIMS) and American Academy of Neurology meetings, and have served as a
`
`session chair for both the American Academy of Neurology’s Multiple
`
`Sclerosis/Neuroimmunology and Neuro-ophthalmology Highlights sections.
`
`MYLAN INC. EXHIBIT NO. 1004 Page 8
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`10. My research has resulted in peer-reviewed publications, refereed
`
`articles, conference proceedings and abstracts. I have published nearly 50 papers
`
`and have participated in more than 60 scientific abstracts presented at national and
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`international scientific meetings. I have also been invited to present my clinical and
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`research work both internationally and in the United States, and have chaired and
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`co-chaired multiple symposiums and conferences in Neuroimmunology and
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`Multiple Sclerosis.
`
`11.
`
`In all, I have more than 11 years of practicial and research experience
`
`specializing in Neurology and treating patients with Multiple Sclerosis and other
`
`neurological disorders.
`
`12.
`
`I have testified previously as an expert witness for Mylan in the
`
`following cases:
`
`• Teva Pharmaceuticals USA, Inc. v. Mylan Pharmaceuticals Inc., No.
`
`09-cv-08824-WHP (S.D. N.Y. October 16, 2009); and
`
`• Teva Pharmaceutical Industries Ltd. v. Mylan Pharmaceuticals ULC,
`
`No. T-894-13 (Federal Court, Ottawa, Canada May 17, 2013)
`
`I have also been deposed as an expert witness in Lewis v. Cach, No. CV-2010-
`
`0007613-OC (Bonneville County Court Idaho filed December 12, 2010) (Dkt.
`
`MYLAN INC. EXHIBIT NO. 1004 Page 9
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`Entry dated September 4, 2012 (Notice of Deposition Duces Tecum of Ari Green,
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`M.D.)), which was a medical malpratice case.
`
`13. My curriculum vitae is attached hereto as Exhibit A.
`
`B.
`14.
`
`Bases for Opinions and Materials Considered
`
`Exhibit B includes a list of the materials I considered, in addition to
`
`my experience, education, and training, in providing the opinions contained herein.
`
`C.
`15.
`
`Scope of Work
`
`I have been retained by Mylan as a technical expert in this matter to
`
`provide various opinions regarding the ’250 patent. I receive $1000 per hour for
`
`my services. No part of my compensation is dependent upon my opinions given or
`
`the outcome of this case. I do not have any current or past affiliation with Yeda
`
`Research & Development Co., Ltd., or any of the named inventors on the ’250
`
`patent.
`
`II.
`
`Summary of Opinions
`
`16.
`
`It is my opinion for the reasons below that claims 1-20 of the ’250
`
`patent are anticipated and obvious over Pinchasi [Ex. 1005]. Independent claims 1,
`
`15 and 19 of the ’250 patent focus on a dosage regimen of three subcutaneous
`
`injections of 40 mg glatiramer acetate with at least one day between each injection.
`
`This was disclosed in Pinchasi. Furthermore these claims would be considered
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`MYLAN INC. EXHIBIT NO. 1004 Page 10
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`obvious based on Pinchasi as evidenced by the 1996 Summary Basis of Approval
`
`for Copaxone® [Ex. A of Ex. 1007] and the Copaxone® FDA Panel Review
`
`Meeting (1996) [Ex. A of Ex. 1019] at the time of filing of the ’250 patent. The
`
`Summary Basis of Approval and Copaxone FDA Panel Review Meeting both
`
`demonstrate and support the motivation a skilled artisan had, and would have had,
`
`to utilize the recited dosing regimen as of August 2009, and provide a reasonable
`
`expectation of success in doing so. The obviousness of claims 1, 15 and 19 of
`
`the ’250 patent are made even further apparent in view of the combination of
`
`Pinchasi with Flechter 2002A [Ex. 1008], disclosing the benefits of treating patients
`
`at a lower frequency regimen, which would have provided a skilled artisan
`
`additional motivation and a reasonable expectation of success for using the claimed
`
`dosing regimen.
`
`17.
`
`The dependent claims simply add limitations or elements that would
`
`apply to all therapeutic regimens intended to be efficacious in the treatment of
`
`multiple sclerosis, as evidenced by Johnson [Ex. 1018], Ge [Ex. 1025], Jacobs [Ex.
`
`1054], Comi [Ex. 1026] and the COPAXONE® Product Label (2009) [Ex. 1052].
`
`Moreover, Pinchasi also disclosed the application of many of the dependent claim
`
`limitations. These limitations had been routinely used by skilled artisans well prior
`
`to the earliest priority date of August 2009 for the ’250 patent.
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`MYLAN INC. EXHIBIT NO. 1004 Page 11
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`18. Described above and throughout this report, the literature establishes
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`the efficacy and tolerability of an increased dose of GA, as well as reduced dosing
`
`frequency of GA. Therefore, the supposed drawbacks set out in columns 15 to 16 of
`
`the ’250 patent do not find support in any publication specific to GA and are
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`immaterial in my opinion. See ‘250 Patent [Ex. 1001] at col. 15, ln. 63 to col. 16, ln.
`
`18; Ex. 1002. It is my opinion on the basis of anticipation and obviousness that all
`
`claims of the ’250 patent are invalid.
`
`III.
`
`Legal Standards
`
`19.
`
`In preparing and forming my opinions set forth in this declaration, I
`
`have been informed regarding the relevant legal principles. I have used my
`
`understanding of those principles in forming my opinions. My understanding of
`
`those principles is summarized below.
`
`20.
`
`I have been told that Mylan bears the burden of proving
`
`unpatentability by a preponderance of the evidence. I am informed that this
`
`preponderance of the evidence standard means that Mylan must show that
`
`unpatentability is more probable than not. I have taken these principles into
`
`account when forming my opinions in this case.
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`MYLAN INC. EXHIBIT NO. 1004 Page 12
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`21.
`
`I have also been told that claims should be construed given their
`
`broadest reasonable interpretation in light of the specification from the perspective
`
`of a person of ordinary skill in the art.
`
`22.
`
`I am told that the concept of anticipation requires that each and every
`
`element of a challenged claim is present in a single reference. I also understand that
`
`an anticipatory reference does not need to explicitly describe each element because
`
`anticipation can occur when a claimed limitation is necessarily inherent or
`
`otherwise implicit in the relevant reference.
`
`23.
`
`I am told that the concept of patent obviousness involves four factual
`
`inquiries: (1) the scope and content of the prior art; (2) the differences between the
`
`claimed invention and the prior art; (3) the level of ordinary skill in the art; and (4)
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`secondary considerations of non-obviousness.
`
`24.
`
`I am also informed that when there is some recognized reason to solve
`
`a problem, and there are a finite number of identified, predictable and known
`
`solutions, a person of ordinary skill in the art has good reason to pursue the known
`
`options within his or her technical grasp. If such an approach leads to the expected
`
`success, it is likely not the product of innovation but of ordinary skill and common
`
`sense. In such a circumstance, when a patent simply arranges old elements with
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`MYLAN INC. EXHIBIT NO. 1004 Page 13
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`each performing its known function and yields no more than what one would expect
`
`from such an arrangement, the combination is obvious.
`
`IV.
`
`Person of Ordinary Skill in the Art
`
`25. As above, I have been informed by counsel that the obviousness
`
`analysis is to be conducted from the perspective of a person of ordinary skill in the
`
`art (a “person of ordinary skill”) at the time of the invention.
`
`26.
`
`I have also been informed by counsel that in defining a person of
`
`ordinary skill in the art the following factors may be considered: (1) the educational
`
`level of the inventor; (2) the type of problems encountered in the art; (3) prior art
`
`solutions to those problems; (4) rapidity with which innovations are made; and (5)
`
`sophistication of the technology and educational level of active workers in the field.
`
`27. A person of ordinary skill in the art would have had as of the priority
`
`date of the ’250 patent several years of experience as a medical professional, with
`
`direct experience administering therapeutic agents for the treatment of MS, as well
`
`as familiarity with the dosing schedules and frequencies of the different therapeutic
`
`agents available for MS treatment. A person of ordinary skill in the art would also
`
`have several years of experience working with the pharmaceutical industry, with
`
`experience in the design of studies necessary for drug development. This
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`experience may come from the person of ordinary skill in the art’s own experience,
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`MYLAN INC. EXHIBIT NO. 1004 Page 14
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`or may come through the guidance of other individual(s) with experience in the
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`pharmaceutical industry, e.g., as members of a research team or group. A person of
`
`ordinary skill in the art would also be well-versed in the world-wide literature on
`
`multiple sclerosis that was available as of the priority date.
`
`V.
`
`The ’250 Patent [Ex. 1001]
`
`28.
`
`I have read the ’250 patent and the issued claims, entitled “Low-
`
`Frequency Glatiramer Acetate Therapy.” The ’250 patent was filed on November
`
`30, 2011 and claims priority to two provisional applications: U.S. Provisional
`
`Application No. 61/247,687, filed August 20, 2009, and U.S. Provisional
`
`Application No. 61/337,612, filed February 11, 2010. See ’250 Patent File History
`
`[Ex. 1002]. The ’250 patent issued July 31, 2012, and names Ety Klinger as the sole
`
`inventor.
`
`29.
`
`I understand that Mylan is challenging claims 1-20. The ’250 patent
`
`includes 3 independent claims: claims 1, 15 and 19. I also understand that the claim
`
`terms in the ’250 patent are presumed to take on their ordinary and customary
`
`meaning based on the broadest reasonable construction in light of the specification
`
`of the patent in which they appear.
`
`30.
`
`Independent claim 1 recites: A method of alleviating a symptom of
`
`relapsing-remitting multiple sclerosis in a human patient suffering from relapsing-
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`MYLAN INC. EXHIBIT NO. 1004 Page 15
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`remitting multiple sclerosis or a patient who has experienced a first clinical episode
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`and is determined to be at high risk of developing clinically definite multiple
`
`sclerosis comprising administering to the human patient a therapeutically effective
`
`regimen of three subcutaneous injections of a 40 mg dose of glatiramer acetate over
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`a period of seven days with at least one day between every subcutaneous injection,
`
`the regimen being sufficient to alleviate the symptom of the patient.
`
`31.
`
`The phrase “alleviating a symptom of relapsing-remitting multiple
`
`sclerosis” is not a phrase that is usually referred to by clinicians to describe the
`
`therapeutic effect of glatiramer acetate treatment. Similarly, “frequency of relapses”
`
`and MRI diagnostic markers as listed in, for example, claim 4, are not usually
`
`thought of as “symptoms” of the disease, but rather clinical endpoints that indicate
`
`glatiramer acetate’s (or other disease modifying therapy’s) efficacy. However, I
`
`understand that the inventor of the ’250 patent chose to define the outcome of
`
`treating with glatiramer acetate as “alleviating a symptom,” see, e.g., ’250 patent at
`
`col. 4, ll. 3-64, and thus will follow this definition given by the inventor.
`
`32.
`
`The claim term “regimen” is not defined by the ’250 patent. In my
`
`experience, the term “regimen” refers to a dosing schedule for a therapeutic drug. It
`
`is defined with regards to the frequency, route and period of administration, among
`
`other considerations. For example, Copaxone® 20 mg dosage form is intended as a
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`MYLAN INC. EXHIBIT NO. 1004 Page 16
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`daily subcutaneous injection, and Copaxone® 40 mg dosage form is intended as a
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`subcutaneous injection given three times a week. See Copaxone 20 mg and 40 mg
`
`Product Label (dated January 28, 2014) [Ex. 1057].
`
`33.
`
`In my experience, dosing regimens are intended to guide scheduling
`
`for medication administration. However, it is important for therapies that are self-
`
`administered, such as Copaxone®, that they allow for some variability in patient
`
`compliance without sacrificing efficacy, safety or tolerability. This means that
`
`therapeutic efficacy of the drug will still be maintained even if a dose is missed.
`
`See, e.g., Boissel and Nony “Using pharmacokinetic-pharmacodynamic
`
`relationships to predict the effect of poor compliance” Clin. Pharmacol. 41:1-6
`
`(2002) (Ex. 1027). This principle is broadly appreciated in clinical practice when
`
`using GA. In my practice, I instruct patients to skip a missed dose if a patient
`
`misses the administration of the drug. This is a standard instruction. See, e.g.,
`
`https://scamparoo.wordpress.com/2008/04/11/ms-therapies-copaxone/ (dated April
`
`11, 2008 (accessed February 5, 2015)) [Ex. 1058] (“If you miss a dose, take it as
`
`soon as you remember. If you do not remember until the following day, skip the
`
`missed dose and continue with your regular dosing schedule.”).
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`MYLAN INC. EXHIBIT NO. 1004 Page 17
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`34.
`
`Claims 2 and 4-14 all depend from claim 1, and I understand that
`
`claim 3 depends from claim 1.1 Each of claims 2-14 recite various effects on
`
`clinical symptoms and post-injection site reaction, as well as pharmaceutical forms.
`
`35.
`
`Independent claim 15 recites: A method of increasing the tolerability
`
`of GA treatment in a human patient suffering from relapsing-remitting multiple
`
`sclerosis or a patient who has experienced a first clinical episode and is determined
`
`to be at high risk of developing clinically definite multiple sclerosis which
`
`comprises reducing frequency of subcutaneous injections from daily subcutaneous
`
`injections of a pharmaceutical composition comprising a 20 mg dose of glatiramer
`
`acetate to a regimen of three subcutaneous injections of a 40 mg dose of glatiramer
`
`acetate over a period of seven days with at least one day between every injection,
`
`wherein the regimen is therapeutically effective, so as to thereby increase the
`
`tolerability of GA treatment in the patient. The ’250 patent defines “tolerabilty” as:
`
`1 I understand that even though claim dependency language is missing from
`
`claim 3, however, whether claim 3 depends from claim 1 or claim 2 does not
`
`materially change or impact my analysis because all elements of claims 1 and 2 are
`
`expressly disclosed in Pinchasi.
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`MYLAN INC. EXHIBIT NO. 1004 Page 18
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`[R]elat[ing] to the level of discomfort associated with GA treatment.
`Tolerability is associated with the frequency and severity of post
`injection reactions and injection site reactions. Tolerability influences
`the period that a patient can follow GA treatment.
`
`’250 patent [Ex. 1001] at col. 7, ll. 33-37.
`
`36.
`
`In comparing claims 1 and 15, the difference is that claim 15 is
`
`directed to a method to “increas[e] the tolerability of GA treatment” in the same
`
`patient population “so as to thereby increase the tolerability of GA treatment in the
`
`patient.” The dosing regimen of “three subcutaneous injections of a 40 mg dose of
`
`glatiramer acetate over a period of seven days with at least one day between every
`
`subcutaneous injection” is otherwise identical between claims 1 and 15.
`
`37. Dependent claims 16-18, which depend from claim 15, recite the
`
`reduction of frequency of post-injection site reactions, as well as a pharmaceutical
`
`form (the pre-filled syringe of claim 18).
`
`38.
`
`Independent claim 19 recites: A method of reducing frequency of
`
`relapses in a human patient suffering from relapsing-remitting multiple sclerosis
`
`comprising administering to the human patient a therapeutically effective regimen
`
`of three subcutaneous injections of a 40 mg dose of glatiramer acetate over a period
`
`of seven days with at least one day between every subcutaneous injection, the
`
`regimen being sufficient to reduce frequency of relapses in the human patient. As
`
`MYLAN INC. EXHIBIT NO. 1004 Page 19
`
`
`
`compared to claims 1 and 15, claim 19 is directed only to a “human patient
`
`suffering from relapsing-remitting multiple sclerosis.” Claim 19 also differs from
`
`claims 1 and 15 by relating to a “method of reducing frequency of relapses,” with
`
`the “regimen being sufficient to reduce frequency of relapses in the human patient.”
`
`39. Dependent claim 20, which depends from claim 19, recites that the
`
`form of the 40 mg dose of glatiramer acetate “is in a prefilled syringe for self
`
`administration by the human patient.”
`
`VI.
`
`Background
`D. Multiple Sclerosis
`40. Multiple Sclerosis (MS) is a chronic, neurodegenerative autoimmune
`
`disease characterized early on by intermittent but potentially debilitating
`
`inflammatory and demyelinating events. See, e.g., Frohman, “Multiple Sclerosis –
`
`The Plaque and its Pathogenesis” New England J. Med. 354:942-55 (2006) [Ex.
`
`1039]. MS affects approximately 400,000 individuals in the United States, with
`
`the average age of onset estimated at 30 years of age. Miller, “The importance of
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`Early Diagnosis of Multiple Sclerosis” J. Managed Care Pharmacy 10:S4-S11
`
`(June 2004) [Ex.1013]. Because this population coincides with individuals
`
`beginning or maintaining a young family as well as with the time period that may
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`MYLAN INC. EXHIBIT NO. 1004 Page 20
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`
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`include critical career decisions and growth for afflicted patients, MS can be
`
`particularly devastating on family, social and professional relationships. Id.
`
`41. As of August 2009, while the origins of MS were under investigation,
`
`researchers generally agreed that a breach in the integrity of the blood-brain barrier
`
`in susceptible individuals contributes to a cascade of events that result in
`
`demyelination of central nervous system axons. This results in the formation of
`
`lesions in the brain. Frohman [Ex. 1039] at 942-43. The autoimmune character of
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`MS was supported by the presence of activated T-cells within MS lesions, the
`
`therapeutic efficacy of immunomodulatory drugs – especially those that block
`
`reactive T cells migration or infiltration into the central nervous system - and
`
`studies indicating that MHC class II genes, namely HLA-DR1501, amongst others,
`
`is most strongly associated with genetic susceptibility to the disease. Id. at 943;
`
`Haines et al. “Linkage of the MHC to familial multiple sclerosis suggests genetic
`
`heterogeneity. The multiple sclerosis genetics group,” Hum. Mol. Genet. 7:1229-34
`
`(Aug 1998) [Ex. 1023]. The development of myelin-reactive T-cells thus appeared
`
`to play a central role in the initiation and continued disease activity of MS in
`
`patients.
`
`42. The inflammatory damage that occurs with MS manifests itself as
`
`debilitating physical symptoms that affect a variety of neurological pathways. One
`
`MYLAN INC. EXHIBIT NO. 1004 Page 21
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`
`
`of the most common presenting clinical syndromes associated with MS is optic
`
`neuritis, which typically manifests itself as loss of vision and pain behind the eye.
`
`Frohman [Ex. 1039] at 952. Other clinical syndromes include episodes of
`
`numbness, tingling, muscle weakness and spasticity, incoordination, loss of control
`
`of bowel and bladder, general fatigue, dizziness and depression. The
`
`demyelinating injury found in MS can lead to ongoing and even permanent
`
`symptoms caused by neurological dysfunction. These lead to impairment in social
`
`engagement and work productivity, and result in economic impacts to the
`
`individual and society as a whole. See, e.g., Ziemssen et al. “Effects of Glatiramer
`
`Acetate on Fatigue and Days of Absence from Work in First-Time Treated
`
`Relapsing-Remitting Multiple Sclerosis” Hlth. & Qual. Life Outcomes 6:67 (2008)
`
`[Ex.1045] (fatigue in MS patients was the leading cause of absence from work and
`
`impaired work performance).
`
`43. Several stages in the progression of MS were recognized in August
`
`2009, including clinically-isolated syndrome (CIS), relapsing-remitting multiple
`
`sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and primary
`
`progressive multiple sclerosis (PPMS). RRMS was, and is, the most common type
`
`of MS, amounting to over 85% of patients at initial diagnosis. RRMS patients
`
`were, and are, characterized as having clearly defined relapses with at least partial
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`MYLAN INC. EXHIBIT NO. 1004 Page 22
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`
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`recovery of deficits over weeks to months. Relapses are usually characterized by
`
`the tempo of onset of the neurological deficits (subacute – meaning evolving over
`
`hours to weeks) followed by partial or complete resolution of the deficits. Patients
`
`were recognized as having fewer relapses as time went on, but were known to
`
`develop increasing insidious underlying progression of neurological dysfunction.
`
`Once patients have predominantly progressive disease with few or no relapses,
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`their disease is characterized as “secondary progressive.” The majority of patients
`
`diagnosed with RRMS will develop SPMS if followed long enough.
`
`44. A minority of patients (10-15%) at initial examination are diagnosed
`
`with primary progressive multiple sclerosis (PPMS). These patients have
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`progression of neurological dysfunction from onset without relapses. Many of
`
`these patients have significant neurological deficits, including a majority with
`
`impairment of ambulation.
`
`45.
`
` In August 2009, MS diagnosis included, and still includes, both
`
`objective and subjective analyses. Ob
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