UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS, INC.
`
`Petitioner
`
`v.
`
`YEDA RESEARCH AND DEVELOPMENT CO. LTD.
`
`Patent Owner
`
`Case No. IPR2015-00644
`
`Patent No. 8,399,413
`
`DECLARATION OF TJALF ZIEMSSEN, M.D., Ph.D IN SUPPORT OF
`PATENT OWNER YEDA’S RESPONSE TO PETITION FOR INTER
`PARTES REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`TABLE OF CONTENTS
`
`Contents
`
`Page
`
`3. 
`
`Introduction ..................................................................................................... 1 
`I. 
`II.  Qualifications And Experience ...................................................................... 2 
`III.  Legal Standard ................................................................................................ 6 
`IV.  Person Of Ordinary Skill In The Art ............................................................ 9 
`V.  Summary Of Opinions .................................................................................. 10 
`VI.  Overview Of Multiple Sclerosis And Glatiramer Acetate ........................ 13 
`A.  Multiple Sclerosis Is Associated With A Wide Variety Of Different Symptoms That
`Can Affect The Ability Of Patients To Carry Out Normal Activities Of Daily Living
`........................................................................................................................................... 13 
`B.  The Underlying Causes of MS are Complex and Not Fully Established ................... 15 
`C.  Glatiramer Acetate Is A Complex Drug That Is Unlike Traditional Drugs ............. 17 
`1. 
`The Active Molecule in Glatiramer Acetate Remains Unknown ................... 18 
`2. 
`While Not Definitively Characterized, Certain Principles Concerning GA’s
`Mechanism of Action Were Established in the Prior Art as of 2009. ............ 19 
`Standard Pharmacokinetics Cannot Predict the Effects of Glatiramer
`Acetate .................................................................................................................. 29 
`VII.  The Cited References .................................................................................... 32 
`A.  Pinchasi (Ex. 1005) .......................................................................................................... 32 
`B.  SBOA (Ex. 1007A) .......................................................................................................... 35 
`C.  Flechter (Ex. 1008) .......................................................................................................... 39 
`VIII. Discussion And Opinions .............................................................................. 41 
`A.  The ’413 Patent ............................................................................................................... 41 
`B.  Ground 3: The Combination Of Pinchasi In View Of SBOA Would Not Have
`Rendered Obvious The Invention Claimed In The ’413 Patent ................................. 43 
`A POSA Would Not Have been Motivated to Increase the Dose of Glatiramer
`1. 
`Acetate from 20 mg to 40 mg. ............................................................................ 44 
`A POSA Would Not Have been Motivated to Decrease the Dosing Frequency
`of Glatiramer Acetate in 2009. ........................................................................... 51 
`Pinchasi In View Of The SBOA Would Not Motivate The POSA To Dose 40
`mg Of GA Three Times Weekly With At Least A Day Between Doses With A
`Reasonable Expectation Of Success. ................................................................. 65 
`
`2. 
`
`3. 
`
`
`
`i
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`2. 
`
`C.  Ground 4: The Combination Of Pinchasi In View Of Flechter Would Not Have
`Rendered Obvious The Invention Claimed In The ’413 Patent ................................. 68 
`Flechter does not disclose or suggest using 40 mg of GA three times weekly
`1. 
`with at least a day between doses....................................................................... 68 
`Pinchasi In View Of Flechter Would Not Motivate The POSA To Dose 40 mg
`Of GA Three Times Weekly With At Least A Day Between Doses With A
`Reasonable Expectation Of Success. ................................................................. 71 
`D.  Other Prior Art Does Not Support an Obviousness Finding. ..................................... 72 
`1. 
`The Khan 2008 Abstract (Ex. 1010) .................................................................. 73 
`2. 
`The Rasmussen Patent Application (Ex. 1036) ................................................ 74 
`3. 
`Interferon Prior Art Would be Considered Irrelevant by the POSA for
`Purposes of Developing a Dosing Regimen for GA. ......................................... 75 
`IX.  Unexpected Results Confirm The Nonobviousness Of The Invention .... 76 
`X.  Conclusion ...................................................................................................... 76 
`
`
`
`ii
`
`
`
`
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`
`
`Abbreviation
`
`’250 patent
`
`’413 patent
`
`’302 patent
`
`Yeda
`
`Mylan
`
`Teva
`
`Pinchasi
`
`The SBOA
`
`Flechter
`
`TABLE OF ABBREVIATIONS
`
`Description
`
`U.S. Pat. No. 8,232,250
`
`U.S. Pat. No. 8,399,413
`
`U.S. Pat. No. 8,969,302
`
`Patent Owner Yeda Research & Development Co. Ltd.
`
`Petitioner Mylan Pharmaceuticals, Inc.
`
`Teva Pharmaceuticals Industries Ltd. is the exclusive
`licensee of the ’250, ’302, and ’413 patents. Teva
`Pharmaceuticals USA, Inc. is the holder of the New
`Drug Application for Copaxone®, a drug for which the
`’250, ’302, and ’413 patents are listed in the FDA
`publication “Approved Drug Products with Therapeutic
`Equivalence Evaluations,” commonly referred to as
`“the Orange Book.” Teva Neuroscience, Inc. markets
`and sells Copaxone® in the United States.
`
`Ex. 1005, Pinchasi, WO 2007/081975 A2, published
`July 19, 2007.
`
`Ex. 1007, Summary Basis of Approval for the New
`Drug Application for 20 mg daily Copaxone® (NDA
`#20-622).
`
`Ex. 1008, S. Flechter et al., Copolymer 1 (Glatiramer
`Actetate) in Relapsing Forms of Multiple Sclerosis:
`Open Multicenter Study of Alternate-Day
`Administration, 25(1) CLIN.
`NEUROPHARMACOLOGY, 11-15 (2002).
`
`GA
`
`MS
`
`Glatiramer acetate
`
`Multiple sclerosis
`
`iii
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`RRMS
`
`Relapsing-remitting multiple sclerosis
`
`Green Decl.
`
`Peroutka Decl.
`
`Cohen
`
`PK
`
`PD
`
`Ex. 1004
`
`Ex. 1003
`
`Ex. 1006
`
`pharmacokinetics
`
`pharmacodynamics
`
`POSA
`
`Person of ordinary skill in the art
`
`iv
`
`
`
`
`
`
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`I.
`
`Introduction
`1.
`
`I, Tjalf Ziemssen, have personal knowledge of the facts set forth in
`
`this Declaration and am competent to testify to the same.
`
`2.
`
`I have been retained by counsel for Yeda Research and Development
`
`Co. Ltd. (“Yeda”) in this proceeding regarding U.S. Patent No. 8,399,413 (“the
`
`’413 patent”).
`
`3.
`
`I have been informed by counsel for Teva that the Patent Trial and
`
`Appeal Board (“PTAB”) has granted the petition of Mylan Pharmaceuticals Inc.
`
`(“Mylan”) regarding the purported obviousness of claims 1-20 of the ’413 patent.
`
`I understand from counsel that Mylan’s petition was instituted on the following
`
`grounds:
`
`a.
`
`Ground 3: Claims 1-20 as obvious over Pinchasi (Ex. 1005)
`
`and SBOA (Ex. 1007); and
`
`b.
`
`Ground 4: Claims 1-20 as obvious over Pinchasi and Flechter
`
`(Ex. 1008).
`
`4.
`
`I hereby offer this Declaration in support of Patent Owner’s Response
`
`to Petition for Inter Partes Review of the ’413 patent regarding the state of the art
`
`as of August 20, 2009, the relevant scientific and technical information available to
`
`the person of ordinary skill in the art (“POSA”) at that time, and my opinions
`
`concerning the nonobviousness of the claims of the ’413 patent.
`
`
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`5.
`
`In forming my opinions, I have relied upon my knowledge and
`
`experience, the references identified in Attachment A, and any other references
`
`identified herein.
`
`II. Qualifications And Experience
`6.
`I am currently the Director of the Center of Clinical Neuroscience,
`
`Professor of Clinical Neuroscience and Vice Chair of the Department of Neurology
`
`at the Carl Gustav University Hospital in Dresden, Germany, positions I have held
`
`since 2011. As Director, I am responsible for heading its four groups: the
`
`Multiple Sclerosis Center, the Neuroimmunological Laboratory, and the
`
`Autonomic and Neuoroendocrine Function Laboratory and the Ehealth Group. I
`
`personally established each of these three groups and have been the head of each
`
`since inception.
`
`7.
`
`The Multiple Sclerosis Center was founded by me in 2004 after my
`
`return from a postdoctoral fellowship at the Max Planck Institute in Munich. It is
`
`the largest teaching MS Center in Germany with active involvement in numerous
`
`clinical studies. The MS Center offers a comprehensive approach to treatment and
`
`research, with five physicians on staff, 9 specialized nurses and 10 research
`
`assistants and data managers, all housed within a dedicated building on the hospital
`
`campus. We currently offer service to 800 MS patients per month and have a total
`
`of 200 MS patients are participating in clinical trials at the moment. In addition to
`
`
`
`2
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`clinical studies funded by the pharmaceutical industry, several academic scientific
`
`studies are performed in our center, including a current study examining gait
`
`function in patients with MS. Many of the clinical studies our center has
`
`participated in have involved glatiramer acetate (“GA”).
`
`8.
`
`In my role as a Professor, I currently oversee a lab of 12 researchers at
`
`the Neuroimmunological Laboratory. Our work there includes both clinical and
`
`basic research in the field of immunology. One area of focus has been research
`
`concerning biomarkers of treatment responses for MS. For example, our research
`
`has included investigation of links between immunological effects and clinical
`
`outcomes with GA treatment in thousands of MS patients as part of the
`
`CopImmunoNet study.
`
`9.
`
`The Autonomic and Neuoroendocrine Function Laboratory provides
`
`analytical techniques for the non-invasive assessment of the function of the
`
`autonomic nervous system and of the cardiovascular system.
`
`10.
`
`I treat patients on a daily basis, with roughly 70% of my time
`
`dedicated to clinical practice or study. I currently have approximately 1,500 MS
`
`patients under my care, with approximately 250 of these patients participating in
`
`clinical trials that I supervise.
`
`11.
`
`I earned my M.D. from the University of Bochum, Germany, in 1998.
`
`I earned my Ph.D. (summa cum laude) in 1999 after completing my doctoral thesis
`
`
`
`3
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`in the laboratory of Professor Michael Krieg (Institute of Clinical Chemistry,
`
`Laboratory Medicine and Transfusion Medicine, University of Bochum). I
`
`received several awards for this work, including the Young Investigator award at
`
`the NIH symposium on Biology of Prostate Growth, the research award at the
`
`German Society of Laboratory Medicine and the award from the medical faculty of
`
`the Ruhr-University in Bochum for the best doctoral thesis in 1999.
`
`12. From 1998 to 2000, I worked as a Fellow in Neurology at the
`
`Department of Neurology, University Clinic Carl-Gustav, Technical University of
`
`Dresden, Germany. I became involved with MS treatment at this time by
`
`participating in the University clinic.
`
`13. From 2000 to 2003, I worked as a Research Fellow of the Deutsche
`
`Forschungsgemeinschaft (DFG) and Max-Planck-Society (MPG) at the Max-
`
`Planck Institute of Neurobiology, Department of Neuroimmunology, within the
`
`groups of Professor Reinhard Hohlfeld, Professor Hartmut Wekerle and
`
`Dr. Antonio Iglesias. At this time my research focused on neuroimmunology and
`
`included work studying the mechanism of action of GA.
`
`14.
`
`In 2004, upon completing my fellowships, I returned to Dresden,
`
`where I have continued my work on neuroimmunology, with a specific focus on
`
`multiple sclerosis ever since.
`
`
`
`4
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`15. My research interests currently include several aspects of MS,
`
`including, for example, examining the dual role of inflammation in the brain,
`
`identifying mechanisms of action of immunomodulatory therapies, studying
`
`autoimmunity and tolerance in MS and Experimental Autoimmune
`
`Encephalomyelitis (EAE), and MS patient documentation and management. As
`
`part of my research, I have studied the effects of glatiramer acetate (“GA”) on
`
`human patients suffering from MS.
`
`16. During my professional career, I have worked as a Clinical
`
`Investigator on several clinical trials focused on MS, several of which studied the
`
`administration of GA, including the FORTE, COPTIMIZE and QualiCOP trials. A
`
`full listing of the clinical trials in which I have participated as an investigator is
`
`attached hereto as Exhibit 2132. I have been trained in the proper conduct and
`
`design of clinical trials, including pharmacological principles related to clinical
`
`trial design.
`
`17.
`
`I have also published extensively on topics including MS and
`
`neurology. I have more than 194 papers published in peer-reviewed scientific
`
`journals, including more than a dozen articles relating specifically to GA and its
`
`mechanism of action.
`
`18.
`
`I am a member of several medical societies, including the German
`
`Neurological Society, European Academy of Neurology, American Academy of
`
`
`
`5
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`Neurology, German Autonomic Society, and the European Federation of
`
`Autonomic Societies.
`
`19.
`
`I have also received several honors and awards for my research. For
`
`example, I was awarded the Charcot Award of the European Charcot Foundation in
`
`2003, which recognizes a lifetime of achievement in outstanding research in the
`
`understanding or treatment of MS. More recently, the MS Center I lead in Dresden
`
`was recognized as the best MS center in Germany by FOCUS magazine.
`
`20. A copy of my current curriculum vitae is attached hereto as Exhibit
`
`2131.
`
`III. Legal Standard
`21.
`I have been informed by counsel that claims should be construed by
`
`giving them their broadest reasonable interpretation consistent with the
`
`specification from the perspective of the POSA as of the time of the invention.
`
`22.
`
`I have been informed by counsel that an issued patent claim is invalid
`
`as obvious if it can be shown that the differences between the patented subject
`
`matter and the prior art are such that the subject matter as a whole would have been
`
`obvious, at the time the invention was made, to a person having ordinary skill in
`
`the art. Relevant considerations include the level of ordinary skill in the art, the
`
`scope and content of the prior art, any differences between the prior art and the
`
`
`
`6
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`asserted claims, and the so-called objective secondary considerations of
`
`nonobviousness.
`
`23.
`
`I have been informed by counsel that obviousness must be established
`
`by a preponderance of the evidence. I understand this to mean that, for a claim to
`
`be found invalid as obvious, it must be found more probable than not to be
`
`obvious.
`
`24.
`
`I have been informed by counsel that in order to evaluate the
`
`obviousness of the claims of the ’413 patent over a given prior art combination, I
`
`should analyze whether the prior art references, included collectively in the
`
`combination, disclose each and every element of the allegedly invalid claim as
`
`those references are read by the person of ordinary skill in the art at the time of the
`
`invention. Then I am to determine whether that combination makes the claims of
`
`the ’413 patent obvious to the person of ordinary skill in the art by a preponderance
`
`of the evidence, at the time of the invention.
`
`25.
`
`I have been informed by counsel that the obviousness inquiry requires
`
`that the prior art be considered in its entirety. I am further informed and I
`
`understand that an invention cannot be obvious to try where the breadth of the
`
`choices and the numerous combinations indicate that the disclosures would not
`
`have rendered the claimed invention obvious to try.
`
`
`
`7
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`26.
`
`I have been informed by counsel that there must be some showing that
`
`a person of ordinary skill in the art would have been motivated to combine such
`
`prior art references and that there would have been a reasonable expectation of
`
`successfully achieving the claimed invention from such combination in order to
`
`support an obviousness determination.
`
`27.
`
`I have been informed by counsel that, in considering the obviousness
`
`of a claimed invention, one should not view the invention and the prior art with the
`
`benefit of hindsight. I understand that for this reason, obviousness is assessed by
`
`the person of ordinary skill in the art at the time the invention was made in light of
`
`the prior art as a whole. In this regard, I have been informed that the invention
`
`cannot be used as a guide to selecting and understanding the prior art.
`
`28.
`
`I have been informed that a reference may be said to teach away when
`
`a person of ordinary skill, upon reading the reference, would be discouraged from
`
`following the path set out in the reference, or would be led in a direction divergent
`
`from the path that was taken by the applicant.
`
`29.
`
`I have been informed that the “time of invention” applicable to the
`
`inventions of the claims of the ’413 patent is August 20, 2009 (which I understand
`
`to be the earliest priority date of the parent application resulting in the ’413 patent).
`
`
`
`8
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`IV. Person Of Ordinary Skill In The Art
`30.
`I have been informed that the claims of a patent are judged from the
`
`perspective of a “person of ordinary skill in the art” (or “POSA”) at the time of the
`
`invention. The “art” is the field of technology to which the patent is related.
`
`31.
`
`I understand that the Patent Trial and Appeals Board has determined
`
`that a POSA pertaining to the subject matter of the ’413 patent at the time of the
`
`invention would have had: (1) several years of experience in the pharmaceutical
`
`industry or in practicing medicine; (2) experience with the administration or
`
`formulation of therapeutic agents, dosing schedules and frequencies, and drug
`
`developmental study and design; and (3) a Ph.D. in pharmacology or be a
`
`physician with experience in clinical pharmacology. Further, the POSA would
`
`have experience with MS and GA. I have applied this definition of a POSA herein
`
`when describing my opinions.
`
`32. My opinions in this case, however, would not change if the level of
`
`ordinary skill in the art is defined similarly, though not identically, or is as
`
`proposed by Petitioner or by Patent Owner. See Petition at 13 (Paper No. 2);
`
`Peroutka Decl. at ¶¶ 37-8 (Ex. 1003); Patent Owner Preliminary Response (Paper
`
`No. 12) at pp. 33-34.
`
`
`
`9
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`33. As of August, 2009, I was qualified as a person of at least ordinary
`
`skill in the art, and my qualifications enable me to provide opinions regarding the
`
`’413 Patent from the perspective of the POSA.
`
`V.
`
`Summary Of Opinions
`34. As of August, 2009, the POSA would not have been motivated to
`
`develop GA for the treatment of MS at a dose of 40 mg given three times weekly
`
`with at least one day between doses. Furthermore, the POSA would not have had a
`
`reasonable expectation of success for such a regimen.
`
`35. As of August, 2009, the POSA would have been aware that the results
`
`from a large Phase III clinical trial demonstrated that 40mg of GA was no more
`
`efficacious than 20 mg, while leading to greater side effects, including a greater
`
`incidence of injection site reactions. Teva press release, Teva provides update on
`
`FORTE TRIAL (July 7, 2008), http:www.tevapharm.com (Ex. 2001); Giancarlo
`
`Comi, Results from a Phase III, 1-year Randomized, Double-Blind, Parallel-
`
`Group, Dose-Comparison Study with Glatiramer Acetate in Relapsing-Remitting
`
`Multiple Sclerosis, 2008 Joint Meeting of the American, European, and Latin
`
`American Committees on Treatment and Research in Multiple Sclerosis,
`
`http://www.multiwebcast.com/wctrims/2008/msmontreal/2448/chair.giancarlo.com
`
`i.results.from.a.phase.iii.one-year. randomized.double-blind.html (Ex. 2028). In
`
`view of these results, the POSA would not have been motivated to develop a 40
`
`
`
`10
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`mg dose of GA rather than the 20 mg dose of GA, which had been used in clinical
`
`practice with thousands of patients for over 12 years and was considered the
`
`“optimal dose” of the drug. This is particularly true given the commonly-held
`
`belief that the lowest effective dose of a drug should be administered unless an
`
`increase in efficacy coupled with an acceptable increase in toxicity could be
`
`expected from a dosage increase. The information available at the time would
`
`have instead taught away from increasing the dose of GA beyond 20 mg because
`
`no increase in efficacy or duration of action could be expected from increasing the
`
`dose to 40 mg.
`
`36. A POSA also would not have been motivated to change the dosing
`
`regimen of 20 mg GA given once daily to a less frequent regimen of three
`
`injections per week. In 2009, a POSA would have been aware of prior art
`
`establishing that GA’s efficacy was in part due to its promotion of a shift from pro-
`
`inflammatory immune cells that attack MS patients’ nervous systems to anti-
`
`inflammatory immune cells that help ameliorate such attacks. The prior art as of
`
`2009 taught that the daily administration of GA was critical to ensuring that an
`
`adequate population of activated, anti-inflammatory immune cells were available
`
`to enter a patient’s central nervous system (“CNS”) to counter the constant attack
`
`of inflammatory cells that occurs in patients with MS. A POSA would not have
`
`
`
`11
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`been motivated to reduce dosing frequency and thereby reduce the number of anti-
`
`inflammatory immune cells available to provide a therapeutic effect.
`
`37. A POSA in 2009 also would not have possessed a reasonable
`
`expectation that a 40 mg, three times per week dosing regimen would maintain
`
`GA’s efficacy and improve the tolerability of the drug. As of 2009, GA’s active
`
`molecule, specific mechanism of action and pharmacokinetic/pharmacodynamic
`
`profile remained unknown. What was known, however, actually suggested that
`
`less frequent dosing would reduce efficacy and that increasing the dose of GA to
`
`40 mg would provide no additional benefit in terms of efficacy. In short, there was
`
`no basis for a POSA to form a reasonable expectation that a 40 mg, three times a
`
`week regimen would succeed.
`
`38. As of August, 2009, it would not have been obvious to the POSA to
`
`administer GA at a dose of 40 mg three times per week with at least one day in
`
`between doses.
`
`39.
`
`I have reviewed Mylan’s Petition for Inter Partes Review (“IPR”) and
`
`Dr. Peroutka’s and Dr. Green’s declarations, as well as the references cited therein.
`
`See Mylan’s Petition for Inter Partes Review of U.S. Patent No. 8,399,413
`
`(IPR2015-00644) (Paper No. 2) (“Petition”); Declaration of Stephen J. Peroutka
`
`(Ex. 1003) (“Peroutka Decl.”); Declaration of Ari Green, M.D. (Ex. 1004).
`
`Nothing in the petition or declarations changes my opinion concerning the
`
`
`
`12
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`nonobviousness of the claimed regimen. Furthermore, none of the cited
`
`references, either alone or in combination, would have motivated the POSA to
`
`administer 40 mg of GA three times per week with at least one day between doses.
`
`Nor would those references have provided the POSA with a reasonable expectation
`
`of success in so doing.
`
`VI. Overview Of Multiple Sclerosis And Glatiramer Acetate
`A. Multiple Sclerosis Is Associated With A Wide Variety Of
`Different Symptoms That Can Affect The Ability Of Patients To
`Carry Out Normal Activities Of Daily Living
`40. MS is a condition of the central nervous system (“CNS”). It is an
`
`autoimmune disease, meaning the immune system mistakenly recognizes a protein
`
`of a patient’s body as foreign and attacks it. T. Menge, et al., Disease-modifying
`
`agents for multiple sclerosis: recent advances and future prospects, 68(17)
`
`DRUGS, 2445-68 (2008) (Ex. 2077 at 2). In a patient suffering from MS, the
`
`body’s immune system attacks myelin, a protective sheath wrapped around the
`
`body’s nerve fibers. PW Duda, et al., Glatiramer acetate (Copaxone) induces
`
`degenerate, Th2-polarized immune responses in patients with multiple sclerosis,
`
`105(7) J. CLIN. INVESTIGATION, 967-76 (2000) (Ex. 2069 at 1).
`
`41. Without this outer myelin shell, nerves become damaged, impairing
`
`the body’s ability to facilitate transmission of nerve impulses. T. Ziemssen,
`
`Modulating processes within the central nervous system is central to therapeutic
`
`
`
`13
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`control of multiple sclerosis, 252 Suppl 5 J. NEUROL., v38-45 (2005) (Ex. 2084 at
`
`3). The pathological hallmark of MS is the formation of demyelinating plaques or
`
`lesions. Ex. 2003 at 1. Symptoms of MS are varied and severe, and include
`
`paralysis, sensory and cognitive disturbances, spasticity, tremor, lack of
`
`coordination and visual impairment. Id.
`
`42. MS is the most common neurological disease affecting young adults.
`
`MS typically begins in early adulthood, and has a variable, unpredictable
`
`prognosis. Id. There are several distinct subtypes of MS, including relapsing-
`
`remitting (“RR”) MS, secondary progressive (“SP”) MS and primary progressive
`
`(“PP”) MS. Id. Patients with RRMS exhibit symptomatic exacerbations (relapses)
`
`followed by periods of recovery (remission), although the recovery is usually not
`
`complete. Id. Patients with progressive forms of MS may have disease
`
`progression without specific relapses. Id. Worldwide, the most common subtype
`
`of the disease is RRMS, which affects about 85% of patients at the time of
`
`diagnosis. Id.
`
`43. The figure below, taken from one of my publications, shows the
`
`relationship of relapsing-remitting and progressive symptoms in a typical MS
`
`patient:
`
`
`
`14
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`
`
`As adopted from Ex. 2084 at 3.
`
`B.
`
`The Underlying Causes of MS are Complex and Not Fully
`Established
`44. As mentioned above, MS is characterized by inflammation and
`
`destruction of myelin—an insulating sheath that surrounds parts of neurons to
`
`facilitate the transmission of nerve impulses—in discrete spot-like areas of the
`
`brain (“multi-focal”). Id. At the same time, progressive neurodegeneration—loss
`
`of axons—occurs. Id.
`
`45. The exact order of events leading to the loss of myelin and axons is
`
`not completely understood, but T helper cells (Th cells), immune cells involved in
`
`conveying immune signals, are considered to play a pivotal role in the self-reactive
`
`
`
`15
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`immune response of the CNS. It is believed that in MS patients Th1 cells become
`
`reactive against the body’s own nervous system (i.e., proinflammatory), and attack
`
`myelin causing demyelinating lesions.
`
`46.
`
` As of August 20, 2009, I and others had published literature
`
`describing the pathological events that were believed to result in demyelinating
`
`lesions:
`
`47.
`
`
`
`
`
`As adopted from T Ziemssen and W. Schrempf, Glatiramer acetate: mechanisms
`
`of action in multiple sclerosis, 79 INT’L REV. NEUROBIOLOGY, 537-570
`
`(2007) (Ex. 2083 at 3).
`
`48. This diagram explains how in patients with MS the body’s Th1 cells
`
`are activated in the periphery, travel to the CNS, and attack the nervous system’s
`
`
`
`16
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`insulating sheath (myelin). Id. First, T helper cells become mistakenly activated
`
`against components of the brain by an interaction with antigen presenting cells (or
`
`“APCs”). Id. Second, because they are activated, the Th1 cells can now migrate
`
`through the blood-brain barrier into the brain. Id. (step 3). Once in the CNS, the
`
`Th1 cells recognize the same or similar protein that caused them to be activated
`
`(the “APCs”) in the brain, and the APCs reactivate the Th1 cells, which causes
`
`them to release pro-inflammatory factors. Id. (steps 4 and 5). This pro-
`
`inflammatory action and the further recruitment of immune attack cells lead to
`
`damage in the brain. Id. at 4.
`
`49. Due in large part to the complex pathology of MS, a cure continues to
`
`elude scientists. Indeed, very few drugs have been developed to this day that
`
`effectively treat the disease. One of the first of these drugs is known as
`
`Copaxone® or glatiramer acetate.
`
`C. Glatiramer Acetate Is A Complex Drug That Is Unlike
`Traditional Drugs
`50. Glatiramer acetate is an extremely complex drug that exerts its
`
`therapeutic effect by modulating the immune system response in patients with
`
`multiple sclerosis. While the discovery and development of GA has revolutionized
`
`the treatment and care of MS patients, GA’s unique properties continue to
`
`confound researchers to the present day.
`
`
`
`17
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`1.
`
`The Active Molecule in Glatiramer Acetate Remains
`Unknown
`51. GA is a standardized yet mostly random mixture of synthetic
`
`polypeptides consisting of four amino acid building blocks: L-glutamic acid, L-
`
`lysine, L-alanine, and L-tyrosine. These four amino acids appear in a defined ratio
`
`(0.14:0.34:0.43:0.09, respectively) and have an average length from 45 to 100
`
`amino acids. Ex. 2012 at 3. Thus, the mixture of polypeptides has a variable
`
`length of amino acids, variable sequence of amino acids, and a variable molecular
`
`weight. This variation creates an enormous number of potential polypeptide
`
`sequences found in GA. H. Varkony, et al., The glatiramoid class of
`
`immunomodulator drugs, 10(4) EXPERT OPINION PHARMACOTHERAPY,
`
`656-68 (2009) (Ex. 2046 at 1).
`
`52. Due to the complexity and variability of its polypeptides mixture, a
`
`clear definition of the active component, the “active species”, has not been
`
`established. Id. Some researchers have postulated it is the overall “pool” of
`
`various amino acid sequences that facilitates multiple actions in the human body,
`
`and therefore, these “pools” may be required for Copaxone’s therapeutic activity.
`
`M. Fridkis-Hareli, et al., Binding motifs of copolymer 1 to multiple sclerosis- and
`
`rheumatoid arthritis-associated HLA-DR molecules, 162(8) J. IMMUNOLOGY,
`
`4697-704 (1999) (Ex. 2036 at 7). In short, as of August, 2009, the POSA would
`
`not have known which molecule or group of molecules within the vast array of
`
`
`
`18
`
`YEDA EXHIBIT NO. 2135
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`
`
`polypeptides known as GA was responsible for its clinical effects. Even today we
`
`are struggling to obtain an understanding in this regard.
`
`2. While Not Definitively Characterized, Certain Principles
`Concerning GA’s Mechanism of Action Were Established in
`the Prior Art as of 2009.
`53. Despite extensive research, the mechanism or mechanisms by which
`
`GA works is still not fully understood today. However, as of August 20, 2009, the
`
`prior art, including research I conducted with my colleagues, had established
`
`several generally accepted principles concerning how GA worked to treat multiple
`
`sclerosis.
`
`a. Glatiramer Acetate Acts in the Periphery and
`Indirectly on the CNS
`54. By August, 2009, the prior art taught that GA had an indirect
`
`therapeutic effect. Traditional drug products treat a disease or condition by
`
`directly targeting, for example, an enzyme or receptor, at the site where the
`
`pathological process occurs. P. Imming, et al., Drugs, their targets and the nature
`
`and number of drug targets, 5(10) NATUR