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. 8,399,413
`
`________________________
`
`Case IPR2015 Unassigned
`________________________
`
`
`EXPERT DECLARATION OF ARI GREEN, M.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 8,399,413
`
`
`
`
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`________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`YEDA RESEARCH & DEVELOPMENT CO., LTD.,
`Patent Owner
`
`
`
`U.S. Patent No. 8,399,413
`
`________________________
`
`Case IPR2015 Unassigned
`________________________
`
`
`EXPERT DECLARATION OF ARI GREEN, M.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 8,399,413
`
`
`
`
`
`
`
`
`
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`TABLE OF CONTENTS
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`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 ’413 Patent [Ex. 1001] ................................................................................. 11
`
`VI. Background ......................................................................................................... 14
`
`D. Multiple Sclerosis ..................................................................................... 14
`E. Multiple Sclerosis Therapies .................................................................... 20
`F.
`Compliance and Adherence Rates with Disease Modifying Agents ....... 26
`
`VII. Scope and Content of the Prior Art References.................................................. 31
`
`A.
`B.
`
`C.
`
`PCT Publication No. WO 2007/081975 (“Pinchasi”) [Ex. 1005] ........... 31
`Cohen et al. “Randomized, double-blind, dose-comparison study of
`glatiramer acetate in relapsing-remitting MS” Neurology 68:939-
`44 (2007) (“Cohen”) [Ex. 1006] .............................................................. 32
`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
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`E.
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`F.
`
`D.
`
`2002A”) [Ex. 1008] .................................................................................. 33
`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] ....................................................... 35
`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) ................................................................. 36
`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] ......................................................................................................... 37
`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] ..................................... 38
`G. Ge et al. “Glatiramer Acetate (Copaxone) treatment in Relapsing-
`Remitting MS Quantitative MR Assessment” Neurology 54:813-7
`(2000) (“Ge”) [Ex. 1025] ......................................................................... 39
`COPAXONE® 20 mg/ml Product Label (February 2009) (“2009
`Copaxone Product Label”) [Ex. 1052] ..................................................... 39
`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.
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`J.
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`K.
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`Data (“SBOA”) (1996) [Ex. A of Ex. 1007] ............................................ 40
`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] ............... 41
`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] ........................................ 42
`
`VIII. UNPATENTABILITY OF THE ’413 PATENT ............................................... 43
`
`A.
`
`The Challenged Claims of the ’413 Patent Are Anticipated and
`Obvious Over Pinchasi [Ex. 1005] ........................................................... 43
`(a)
`Independent Claims 1, 19 and 20 of the ’413 Patent are Anticipated
`by Pinchasi [Ex. 1005] ........................................................................................... 43
`(b) Claims 1, 19 and 20 of the ’413 Patent are Obvious Over Pinchasi
`[Ex. 1005] 53
`(c) Dependent Claims 2-18 of the ’413 Patent are also Anticipated and
`Obvious in View of Pinchasi [Ex. 1005] ............................................................... 58
`B. All Claims of the ’413 Patent are Obvious Over Pinchasi [Ex. 1005]
`in view of Flechter 2002A [Ex. 1008] ..................................................... 62
`
`IX. CONCLUSION ................................................................................................... 65
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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 Inc. (“Mylan”). I understand that Mylan intends to petition for inter partes
`
`review of U.S. Patent No. 8,399,413 (the ’413 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 ‘413 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 ‘413 patent.
`
`I.
`
`Qualifications and Background
`A. Education and Experience; Prior Testimony
`I received my Bachelor of Arts and Science (magna cum laude) from
`2.
`
`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
`
`Neurology from 2004-2005, and a Clinical Fellow in the Departments of Neuro-
`
`Ophthalmology and Neuro-Immunology from 2005-2007. In 2006, I was a Visiting
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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
`
`been an Associate Professor of Neurology and Associate Professor of
`
`Ophthalmology since 2013. I have also served as the Medical Director of the
`
`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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`program at the University of California, San Francisco, and currently supervise
`
`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.
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`8.
`
`I have also been awarded research grants and fellowships from the
`
`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.
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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
`
`international scientific meetings. I have also been invited to present my clinical and
`
`research work both internationally and in the United States, and have chaired and
`
`co-chaired multiple symposiums and conferences in Neuroimmunology and
`
`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
`
`Pharmaceuticals Inc. 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
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`Entry dated September 4, 2012 (Notice of Deposition Duces Tecum of Ari Green,
`
`M.D.)), which was a medical malpratice case.
`
`13. My curriculum vitae is attached here 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 ’413 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 ’413
`
`patent.
`
`II.
`
`Summary of Opinions
`
`16.
`
`It is my opinion for the reasons below that claims 1-20 of the ’413
`
`patent are anticipated and obvious over Pinchasi [Ex. 1005]. Independent claims 1,
`
`19 and 20 of the ’413 patent each 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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`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 ’413 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 claimed dosing regimen in August 2009, and provide a reasonable
`
`expectation of success in doing so. The obviousness of claims 1, 19 and 20 of
`
`the ’413 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 ’413 patent.
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`18. Described above and throughout this report, the literature establishes
`
`the efficacy and tolerability of an increased dose, and reduced dosing frequency of
`
`GA. Therefore the supposed drawbacks set out in columns 15 to 16 of the ’413
`
`patent do not find support in any publication specific to GA and are immaterial in
`
`my opinion. See ’413 Patent [Ex. 1001] at col. 15, l. 53 to col. 16, l. 8. For example,
`
`the reference to volume raised by the Kansara reference is irrelevant because the
`
`ultimate total volume of drug + vehicle is identical between the product described in
`
`the patent and the 1-2 ml volume recited in this passage. ’413 Patent at col. 15, ll.
`
`56-58. It is my opinion on the basis of anticipation and obviousness that all claims
`
`of the ’413 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
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`unpatentability is more probable than not. I have taken these principles into
`
`account when forming my opinions in this case.
`
`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)
`
`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
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`sense. In such a circumstance, when a patent simply arranges old elements with
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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 and ’413 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.
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`This experience may come from the person of ordinary skill in the art’s own
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`experience, or may come through the guidance of other individual(s) with
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`experience in the 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 ’413 Patent [Ex. 1001]
`
`28.
`
`I have read the ‘413 patent and the issued claims, also entitled “Low-
`
`Frequency Glatiramer Acetate Therapy.” The ’413 patent was filed August 19,
`
`2010, 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 id at 1. The ’413 patent
`
`issued March 19, 2013, and names Ety Klinger as the sole inventor.
`
`29.
`
`I understand that Mylan is challenging claims 1-20. The ’413 patent
`
`includes 3 independent claims, claims 1, 19 and 20. I understand that the claim
`
`terms in the ’413 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 reducing the frequency of
`
`relapses in a human patient suffering from relapsing-remitting multiple sclerosis or
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`a patient who has experienced a first clinical episode and has MRI features
`
`consistent with multiple sclerosis 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,
`
`the regimen being sufficient to reduce the frequency of relapses in the patient.
`
`31. Dependent claims 2-18 all ultimately depend on claim 1, and recite
`
`the effect of the claimed treatment on various markers, e.g., lesions on T1-weighted
`
`images and T2 lesions, as well as pharmaceutical compositions and the effect on
`
`clinical symptoms.
`
`32.
`
`Independent claim 19 of the ’413 patent recites: A method of reducing
`
`the frequency of relapses in a human patient suffering from relapsing-remitting
`
`multiple sclerosis 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, wherein
`
`the pharmaceutical composition is in a prefilled syringe for self administration by
`
`the patient, wherein the pharmaceutical composition further includes mannitol, and
`
`wherein the pharmaceutical composition has a pH in the range of 5.5 to 7.0, the
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`regimen being sufficient to reduce the frequency of relapses in the patient. Claim
`
`19 differs from claim 1 by relating only to a “patient suffering from relapsing-
`
`remitting multiple sclerosis,” and also by specifying that the glatiramer acetate
`
`pharmaceutical formulation is “in a prefilled syringe ... further compris[ing]
`
`mannitol, and has ... a pH of 5.5 to 7.0.”
`
`33.
`
`Independent claim 20 of the patent recites: A method of reducing the
`
`frequency of relapses in a human patient who has experienced a first clinical
`
`episode and has MRI features consistent with multiple sclerosis 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, wherein the pharmaceutical composition is
`
`in a prefilled syringe for self administration by the patient, wherein the
`
`pharmaceutical composition further includes mannitol, and wherein the
`
`pharmaceutical composition has a pH in the range of 5.5 to 7.0, the regimen being
`
`sufficient to reduce the frequency of relapses in the patient. Claim 20 differs from
`
`claim 19 by being directed only to “a human patient who has experienced a first
`
`clinical episode and has MRI features consistent with multiple sclerosis,” but is
`
`otherwise identical.
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`VI.
`
`Background
`D. Multiple Sclerosis
`34. Multiple Sclerosis (MS) is a chronic, neurodegenerative autoimmune
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`disease characterized early on by intermittent but potentially debilitating
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`inflammatory and demyelinating events. See, e.g., Frohman, “Multiple Sclerosis –
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`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
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`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
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`(June 2004) [Ex.1013]. Because this population coincides with individuals
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`beginning or maintaining a young family as well as with the time period that may
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`include critical career decisions and growth for afflicted patients, MS can be
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`particularly devastating on family, social and professional relationships. Id.
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`35. While the origins of MS were under investigation in August 2009,
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`researchers generally agreed that a breach in the integrity of the blood-brain barrier
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`in susceptible individuals contributes to a cascade of events that result in
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`demyelination of central nervous system axons. This results in the formation of
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`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
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`therapeutic efficacy of immunomodulatory drugs–especially those that block
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`reactive T cells migration or infiltration into the central nervous system-and studies
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`indicating that MHC class II genes, namely HLA-DR1501, amongst others, is most
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`strongly associated with genetic susceptibility to the disease. Id. at 943; Haines et
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`al., “Linkage of the MHC to familial multiple sclerosis suggests genetic
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`heterogeneity. The multiple sclerosis genetics group,” Hum. Mol. Genet. 7:1229-34
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`(1998) [Ex. 1023]. The development of myelin-reactive T-cells thus appeared to
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`play a central role in the initiation and continued disease activity of MS in patients.
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`36. The inflammatory damage that occurs with MS manifests itself as
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`debilitating physical symptoms that affect a variety of neurological pathways. One
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`of the most common presenting clinical syndromes associated with MS is optic
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`neuritis, which typically manifests itself as loss of vision and pain behind the eye.
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`Frohman [Ex. 1039] at 952. Other clinical syndromes include episodes of
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`numbness, tingling, muscle weakness and spasticity, incoordination, loss of control
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`of bowel and bladder, general fatigue, dizziness and depression. The
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`demyelinating injury found in MS can lead to ongoing and even permanent
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`symptoms caused by neurological dysfunction. These lead to impairment in social
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`engagement and work productivity, and result in economic impacts to the
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`individual and society as a whole. See, e.g., Ziemssen et al., “Effects of Glatiramer
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`Acetate on Fatigue and Days of Absence from Work in First-Time Treated
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`Relapsing-Remitting Multiple Sclerosis” Hlth. & Qual. Life Outcomes 6:67 (2008)
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`[Ex.1045] (fatigue in MS patients was the leading cause of absence from work and
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`impaired work performance).
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`37. Several stages in the progression of MS were recognized in August
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`2009, including clinically-isolated syndrome (CIS), relapsing-remitting multiple
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`sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and primary
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`progressive multiple sclerosis (PPMS). RRMS was, and is, the most common type
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`of MS, amounting to over 85% of patients at initial diagnosis. RRMS patients
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`were, and are, characterized as having clearly defined relapses with at least partial
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`recovery of deficits over weeks to months. Relapses are usually characterized by
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`the tempo of onset of the neurological deficits (subacute – meaning evolving over
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`hours to weeks) followed by partial or complete resolution of the deficits. Patients
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`were recognized as having fewer relapses as time went on, but were known to
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`develop increasing insidious underlying progression of neurological dysfunction.
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`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
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`diagnosed with RRMS will develop SPMS if followed long enough.
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`38. A minority of patients (10-15%) at initial examination are diagnosed
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`with primary progressive multiple sclerosis (PPMS). These patients have
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`progression of neurological dysfunction from onset without relapses. Many of
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`these patients have significant neurological deficits, including a majority with
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`impairment of ambulation.
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`39.
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` In August 2009, MS diagnosis included, and still includes, both
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`objective and subjective analyses. Objective analyses, including clinical
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`examination – as well as formalized clinical evaluations scored as Expanded
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`Disability Status Scale (EDSS) or ambulation index (AI) – magnetic resonance
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`imaging (MRI) scans, extended clinical assessments (e.g., neuropsychological
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`assessments, neurovisual assessments and assessments of bladder function), and
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`relapse frequency assessments, were routinely combined with patient
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`questionnaires targeting measurement of clinical progression in domains
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`incompletely measured at the bedside, including cognitive, visual,
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`psychological/social state as well as activities of daily living and subjective
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`assessment of ambulation. Clinical MRI measurements typically included lesion
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`detection and measurement on T2-weighted images, as well as assessment of areas
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`of active demyelination on T1-weighted images after the administrations of
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`paramagnetic contrast agents such as gadolinium (Gd). See, e.g., Comi et al.,
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`“European/Canadian multicenter, double-blind, randomized, placebo-controlled
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`study of the effects of glatiramer acetate on magnetic resonance imaging-measured
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`disease activity and burden in patients with relapsing multiple sclerosis” Annals
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`Neurol. 49:290-297 (2001) [Ex.1026]. In 2009, some attention was paid to the T1-
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`hypointense lesions as a measure of neuroprotection. See id. at Abstract. Within
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`research studies, brain atrophy measures were also employed as a potential means
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`of monitoring subclinical neuroaxonal loss. Ge et al., “Glatiramer acetate
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`(Copaxone) treatment in relapsing-remitting MS, Quantitative MR assessment”
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`Neurol. 54:813-17 (February 2000) [Ex. 1025].
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`40. MRI was also used to monitor disease activity in August 2009, and
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`played a role in the longitudinal management of MS. See, e.g., Rich et al.,
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`“Stepped-care approach to treating MS: A managed care treatment algorithm,” J.
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`Managed Care Pharm. 10(3)(Suppl. S-b):S26-S32 (June 2004) [Ex. 1031]. MRI
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`lesions, e.g., hyperintense lesions on T2-weighted images and Gd-enhanced T1-
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`weighted images, were typically used to assess disease activity. Id. at S29. In
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`addition, CNS atrophy, lesion load, number and volume of hypointense T1 lesions
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`and whole brain atrophy measures with MRI images were also used. Id. MRI
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`detection was, and is, ofte
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