Case No. IPR2015-00644
`Yeda’s Patent Owner Response
`
`
`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
`
`YEDA’S PATENT OWNER RESPONSE
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`Case No. IPR2015-00644
`Yeda’s Patent Owner Response
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`TABLE OF CONTENTS
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`I.
`II.
`
`Page
`INTRODUCTION ......................................................................................... 1
`THE BOARD’S DECISION ON INSTITUTION ...................................... 6
`A.
`Claim Construction................................................................................ 6
`B.
`Instituted Grounds. ................................................................................ 7
`III. PATENT OWNER’S EXPERT DECLARATIONS ................................ 10
`A. Dr. Tjalf Ziemssen ............................................................................... 10
`B.
`Dr. Edward Fox ................................................................................... 11
`C.
`Dr. Robert Gristwood .......................................................................... 11
`D. Dr. Henry Grabowski .......................................................................... 12
`IV. TECHNICAL BACKGROUND ................................................................. 13
`A. Multiple Sclerosis ................................................................................ 13
`B.
`The Active Molecule In GA Is Unknown ........................................... 14
`C. What Was Known About The Mechanism of Action of GA
`Taught Away From Less Frequent Administration ............................ 15
`D. No PK/PD Correlation Exists For GA ................................................ 16
`V. CLAIMS 1-20 ARE NOT OBVIOUS OVER PINCHASI AND
`THE SBOA OR FLECHTER ..................................................................... 16
`A.
`The Prior Art Would Have Discouraged a POSA From Using A
`40 mg Dose of GA On Any Schedule ................................................. 17
`1.
`After the FORTE trial, a POSA would not have
`used a 40 mg dose of GA to treat MS. ........................... 17
`The prior art taught that a 40 mg dose would be
`associated with increased side effects which would
`have discouraged a POSA from using a 40 mg
`dose. ................................................................................ 20
`The Prior Art Would Have Discouraged a POSA From Using A
`Three Times Weekly Dosing Regimen ............................................... 22
`1.
`The POSA’s understanding of the mechanism of
`action of GA taught away from three times weekly
`dosing. ............................................................................. 22
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`2.
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`B.
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`Case No. IPR2015-00644
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`2.
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`3.
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`2.
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`Flechter actually teaches away from less frequent
`dosing. ............................................................................. 29
`No other prior art would have motivated three
`times weekly dosing. ...................................................... 31
`A POSA Would Not Have Been Motivated To Combine
`Pinchasi With The SBOA To Make The Claimed Invention.............. 32
`D. A POSA Would Not Have Been Motivated To Combine
`Pinchasi With Flechter To Make The Claimed Invention .................. 35
`A POSA Would Not Have Had A Reasonable Expectation That
`A 40mg Three Times Weekly Regimen Would Work for Its
`Intended Purpose ................................................................................. 36
`1.
`The monkey data PK are entirely irrelevant to the
`activity of GA. ................................................................ 39
`The monkey data do not support the conclusion
`that GA has an 80 hour half-life in human patients. ...... 41
`3. Modifying the alternate day dosing schedule to
`three times weekly is not “routine optimization”. .......... 46
`VI. THE DEPENDENT CLAIMS ARE PATENTABLE .............................. 51
`A. Mylan Has Failed To Meet Its Burden of Proving That The
`Limitations of Dependent Claims 6 and 14-18 Are “Inherent” In
`Pinchasi................................................................................................ 51
`B. Mylan Has Failed To Meet Its Burden of Proving That The
`Limitations of Dependent Claim 7 Are Disclosed By The Prior
`Art ........................................................................................................ 52
`VII. OBJECTIVE INDICIA SUPPORT THE NONOBVIOUSNESS
`OF THE ’413 PATENT CLAIMS .............................................................. 53
`A.
`The Unexpected Efficacy Of The Claimed Dosing Regimen
`Supports A Finding That The Claims Are Not Obvious ..................... 53
`The Unexpected Tolerability Of The Claimed Dosing Regimen
`Supports A Finding That The Claims Are Not Obvious ..................... 55
`Commercial Success Supports A Finding That The Claims Are
`Not Obvious ........................................................................................ 57
`The Claimed Invention Met A Long-Felt But Unmet Need ............... 59
`D.
`VIII. CONCLUSION ............................................................................................ 60
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`C.
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`E.
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`B.
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`C.
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`Case No. IPR2015-00644
`Yeda’s Patent Owner Response
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955) ....................................................................... 48,49
`
`In re Antonie,
`559 F.2d 618 (C.C.P.A. 1977) ............................................................................ 46
`
`In re Boesch,
`617 F.2d 272 (Fed. Cir. 1980) ............................................................................ 48
`
`DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co.,
`464 F.3d 1356 (Fed. Cir. 2006) .......................................................................... 48
`
`Eurand, Inc. v. Mylan Pharmaceutics, Inc.,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 38
`
`Interconnect Planning Corp. v. Feil,
`774 F.2d 1132 (Fed. Cir. 1985) .......................................................................... 34
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 38
`
`Merck & Co., Inc. v. Biocraft Labs., Inc.,
`874 F.2d 804 (Fed. Cir. 1989) ...................................................................... 48, 49
`
`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988) ............................................................................ 46
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) .......................................................................... 48
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 48
`
`Sandoz, Inc. v. EKR Therapeutics, LLC,
`IPR2015-00005, Paper 20 (P.T.A.B. 2015) ........................................................ 52
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`Case No. IPR2015-00643
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`Other Authorities
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`M.P.E.P. § 716.04(I) ................................................................................................ 59
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`iv
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`Abbreviation
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`’250 patent
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`’413 patent
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`’302 patent
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`Yeda
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`Mylan
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`Teva
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`Pinchasi
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`The SBOA
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`Flechter
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`Case No. IPR2015-00644
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`TABLE OF ABBREVIATIONS
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`Description
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`U.S. Pat. No. 8,232,250
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`U.S. Pat. No. 8,399,413
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`U.S. Pat. No. 8,969,302
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`Patent Owner Yeda Research & Development Co. Ltd.
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`Petitioner Mylan Pharmaceuticals, Inc.
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`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
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`MS
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`Glatiramer acetate
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`Multiple sclerosis
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`RRMS
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`CNS
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`Relapsing-remitting multiple sclerosis
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`Central nervous system
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`Green Decl.
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`Ex. 1004
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`Green Tr.
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`Peroutka Decl.
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`Peroutka Tr.
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`Cohen
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`Meiner
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`PK
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`PD
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`POSA
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`MRI
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`NDA
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`FDA
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`CNS
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`IPIR
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`ISR
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`TCA
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`Ex. 1065
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`Ex. 1003
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`Ex. 1066
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`Ex. 1006
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`Ex. 1009
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`pharmacokinetics
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`pharmacodynamics
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`person of ordinary skill in the art
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`Magnetic Resonance Imaging
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`New Drug Application
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`United States Food & Drug Administration
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`central nervous system
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`immediate post-injection reaction
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`injection site reaction
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`trichloroacetic acid
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`Case No. IPR2015-00644
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`I.
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`INTRODUCTION
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`Petitioner has failed to meet its burden of proving that a person of skill in the
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`art, knowledgeable about glatiramer acetate (“GA”), would have been motivated to
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`develop a 40 mg, three times per week dosing regimen of GA as claimed in the
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`’413 patent, and would have had a reasonable expectation of success in doing so.
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`The prior art as a whole in 2009 taught that 20 mg, not 40 mg, was the optimal
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`dose of GA and that no additional therapeutic benefit would be provided by
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`increasing the dose. The prior art as a whole also taught that daily administration
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`of GA at the approved 20 mg dose was necessary to maintain the efficacy of the
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`drug in treating multiple sclerosis.
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`At the time that it decided to institute this IPR, the Board did not have the
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`benefit of any expert testimony from Patent Owner. Based on the one-sided record
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`at that time, the Board found that “[a]lthough Patent Owner’s arguments are
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`compelling, they generally amount to a difference in opinion as to the evidence set
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`forth by Petitioner.” (Paper 14 at 15; IPR2015-00643, Paper 13 at 14.) Patent
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`Owner respectfully submits that the evidence provided here, including (i)
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`declarations from experts with real experience studying and using GA and its
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`effect on MS; (ii) admissions by Mylan’s experts; and (iii) prior art ignored by
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`Mylan, demonstrates that Mylan cannot meet its burden of proving that the claimed
`
`invention would have been obvious to a POSA.
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`Mylan’s arguments are fundamentally flawed because they are based on an
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`inaccurate and over-simplified depiction of the state of the art at the priority date.
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`First, Mylan ignores the post-Pinchasi prior art that established that a 40 mg
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`dose was not more effective than a 20 mg dose. As Mylan’s expert acknowledged
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`at his deposition, the large, Phase III FORTE trial demonstrated 40 mg of GA was
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`no more effective than 20 mg. Based on the FORTE results, the 20 mg daily dose,
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`which had been used in thousands of patients for over 12 years, remained the
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`“optimal dose.” This would have discouraged a POSA from using a 40 mg dose
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`on any schedule and would have caused a POSA to reject the results of the earlier,
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`smaller Phase II Cohen study reported in the Pinchasi reference.
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`The FORTE Phase III results also demonstrated that the 40 mg dose of GA
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`was associated with more frequent adverse events than 20 mg GA—a result
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`consistent with other prior art suggesting that more frequent and severe side
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`effects would result from a larger dose. Again, these results would have
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`discouraged further development of a 40 mg dose.
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`Second, Mylan’s position that less frequent administration of GA would
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`have been obvious to a POSA is based on an oversimplified argument that ignores
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`GA’s mechanism of action and the complexities and uncertainties associated with
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`the drug. As Patent Owner’s expert Dr. Ziemssen, a researcher and physician who
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`has extensive experience with the treatment of MS using GA and who has been
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`extensively involved in researching GA’s mechanism of action, explains, the prior
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`art indicated that daily administration of the drug was important to GA’s efficacy
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`because it ensured that an adequate population of activated, anti-inflammatory
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`immune cells (“Th2 cells”) were crossing into the brain and reducing the
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`inflammation associated with MS. Thus, the prior art suggested that less frequent
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`administration would not be as effective as daily administration because it would
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`not provide the same constant activation of anti-inflammatory cells provided by
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`daily GA therapy. This expectation is consistent with the data set out in Flechter,
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`which reports that patients on alternate day dosing of Copaxone® exhibited a
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`relapse rate twice as high as the comparator patients taking Copaxone® daily. On
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`this basis, a POSA (1) would have expected less frequent dosing to decrease
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`efficacy, and (2) would have found it surprising and unexpected that a 40 mg,
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`three times weekly regimen has the same safety and efficacy as 20 mg daily with
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`improved tolerability.
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`Third, even if a POSA would have ignored this teaching of the prior art and
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`gone forward with development of a 40 mg, three times per week regimen, there
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`would have been no basis for a reasonable expectation of success with such a
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`regimen. Here, undisputed facts show that at the priority date, the cause of MS
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`was unknown, the active molecule(s) in and mechanism of action of GA were
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`unknown, and the drug had no known or even measurable PK/PD relationship.
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`Despite its complexity and incompletely understood mechanism of action,
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`Mylan’s expert Dr. Peroutka analogized changing the dose of Copaxone® from 20
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`mg to 40 mg to buying breakfast at Starbucks. (Ex. 1066 at 166:3-166:5) (“If 20
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`[dollars] lasts two days, common sense would say 40 [dollars], as a base common
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`sense assumption, should last twice as long.”) Dr. Peroutka may have chosen his
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`“common sense” breakfast analogy because he has no experience studying the
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`makeup or mechanism of action of GA, nor even with its administration. He last
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`worked as a treating physician in 1990—years before GA was approved. Without
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`the aid of hindsight, Mylan cannot plausibly assert that the POSA would have had
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`a basis for forming a reasonable expectation that the claimed regimen would both
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`maintain the efficacy of 20 mg GA and improve the tolerability of the drug.
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`Patent owner’s experts also explain why Dr. Peroutka’s opinion that GA
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`was known to have an 80-hour half-life, and that it would therefore not be
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`expected to lose efficacy in patients during the three to four day gaps between
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`injections in a three injections weekly regimen, is scientifically flawed. First and
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`foremost, PK parameters, such as plasma half-life, which are useful with ordinary
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`small molecule pharmaceuticals, are inapplicable to GA because GA does not act
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`through the systemic circulation. For this reason, a POSA would have understood
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`that GA’s plasma “half-life,” even if it could be measured, would be irrelevant to
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`how the drug worked, and the POSA would not have looked to such data in
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`evaluating a GA treatment regimen. Moreover, even if “half-life” of GA was
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`considered, the POSA would have understood it to be very short, as the drug was
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`known to be broken down in the subcutaneous tissues almost immediately and
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`there was little or no evidence demonstrating that intact drug reached the blood
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`plasma. Finally, if the POSA had reviewed the monkey data on which Dr.
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`Peroutka bases his opinions, they would have recognized that they were not a
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`reliable basis upon which to form expectations concerning modifications to GA’s
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`dose and administration because of, e.g., internal inconsistences within the data.
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`Fourth, Mylan fails to address the fact that the claimed regimen exhibits
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`unexpected results, satisfied a long-felt but unmet need, and that it has enjoyed
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`immense commercial success that has a clear nexus to its novel three times weekly
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`treatment regimen. As Patent Owner’s experts explain, the prior art suggests that
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`decreasing the frequency of administration of GA would decrease the efficacy of
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`the drug and that increasing the dose would increase the side effects and provide
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`no added efficacy benefit. That the claimed regimen of 40 mg three times weekly
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`actually worked (as demonstrated by the GALA trial and others) and was
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`associated with fewer and less severe side effects, was therefore unexpected. The
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`blockbuster-level sales of the 40 mg, three times weekly product—which plainly
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`fall within the scope of the ’413 patent claims—also support a finding that the
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`claims are not obvious. The Copaxone® 40 mg product was launched in January
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`2014, and it has been an enormous commercial success, capturing approximately
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`67% of the Copaxone® market. And Mylan itself concedes there was a long-felt
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`need for a less frequently administered GA product for the “ease” of the patient.
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`This evidence rebuts Mylan’s obviousness arguments.
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`In sum, Mylan has failed to demonstrate by a preponderance of the evidence
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`that the claims of the patent ’413 patent are obvious over the prior art, and the
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`Board should reject Mylan’s challenge.
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`II. THE BOARD’S DECISION ON INSTITUTION
`The claims of the ’413 patent are directed to methods of treating RRMS
`
`comprising administering a regimen of three subcutaneous injections of a 40 mg
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`dose of GA weekly. (Ex. 1001.) The dependent claims are directed to, inter alia,
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`alleviating specific RRMS symptoms. See infra at Section VI.
`
`A. Claim Construction
`In its Institution Decision, the Board properly rejected Mylan’s contention
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`that the transitional claim term “comprising” changes the scope of the claims,
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`making them “open ended” such that the claimed regimen can cover four, instead
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`of three, administrations in a week. (IPR2015-00643, Paper 13 at 6-7.). As the
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`Board recognized, during prosecution, Yeda expressly limited the claims to a three
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`40 mg injections per week regimen, and made clear that the claims do not cover
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`alternate day (or any other) administration. (Id. at 7.) The Board further correctly
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`found that claim 3 merely contains a typographical error and properly depends
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`from claim 2. (Id.) Mylan’s unreasonable interpretations should similarly be
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`rejected.
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`Instituted Grounds
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`B.
`In its Institution Decision (Paper 14), the Board instituted review of claims
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`1-20 as obvious over (1) Pinchasi and the SBOA and (2) Pinchasi and Flechter.
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`Pinchasi. The Pinchasi application describes daily administration of a 40 mg
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`dose of GA and reports the same data from the 40 mg daily versus 20 mg daily trial
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`reported by Cohen.1 The Board stated in its Institution Decision that Pinchasi
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`“comprises periodically administering by subcutaneous injection a 40 mg dose of
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`GA” and “discloses that the GA can be administered daily or every other day.”
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`1 In 2007, Cohen et al. reported the results of a small trial carried out in 90 patients
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`that compared 20 mg of GA daily to 40 mg daily. (Ex. 1006.) The primary
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`endpoint being examined in the study was the total number of certain types of
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`lesions that can be detected in patients’ brains using MRI. (Id. at Abstract; 5.) The
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`primary endpoint did not reach statistical significance, but Cohen reports “a trend”
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`favoring the 40 mg dose. (Id. at 4-5) Cohen reports, however, that the 40 mg dose
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`was associated with “a greater incidence of certain adverse effects,” thus teaching
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`away from the 40 mg dose. (Id. at 6.)
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`(IPR2015-00643, Paper 13 at 9.) However, while Pinchasi briefly mentions an
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`embodiment of the invention where “the periodic administration is every other
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`day,” this was not based on work actually conducted or results actually achieved.
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`(Ex. 1005 at 22:11-12.) The only data in Pinchasi is the Cohen once-daily data.
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`Pinchasi cites no data whatsoever to demonstrate the efficacy of an every other day
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`regimen, or any regimen other than daily administration.
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`The Pinchasi application was eventually abandoned following the FORTE
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`trial, a much larger scale Phase III trial that compared 40 mg GA daily with 20 mg
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`GA daily in 1,155 patients. (Ex. 2001 at 1.) Unlike Cohen, which measured
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`lesions in the brain using MRI, the primary clinical outcome measured in FORTE
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`was rate of confirmed relapses of MS. (Id.) The results of the FORTE trial were
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`announced on July 7, 2008, after the publication of the Pinchasi application. The
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`trial results showed that “[t]he 40 mg dose did not demonstrate increased efficacy”
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`compared to the 20 mg dose. (Ex. 2001 at 1 (emphasis added).) The press release
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`announcing the FORTE results stated that the study “reaffirms” that Copaxone®
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`20 mg daily “remains the optimal treatment dose.” (Id. (emphasis added).)
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`Further, data from the study provided to POSAs in the wake of its completion
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`showed that the 40 mg dose was associated with a statistically significant increase
`
`in treatment discontinuation due to adverse reactions compared to the 20 mg dose.
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`(Ex. 2028 at 5, 9.)
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`The SBOA. The Summary Basis of Approval relied on by Mylan is a
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`compilation of some of the FDA’s communications with Teva during the review
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`and approval process for the NDA for the Copaxone® 20 mg daily product. Mylan
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`hangs its hat on an isolated query from an FDA toxicology reviewer as to whether
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`“daily s.c. injections [are] really necessary” and the reviewer’s comment that “the
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`Sponsor evaluate the necessity of daily s.c. injections as opposed to more
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`infrequent intermittent administration of the drug.” (Ex. 1007 at 252.) But, as
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`described below, the SBOA does not teach a three times weekly regimen or a 40
`
`mg dose of Copaxone®. In fact, the reasoning behind the question to which Mylan
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`clings teaches away from the use of a unit dose of GA larger than 20 mg.
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`Flechter. Flechter addresses the alternate day administration of the 20 mg
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`GA product. (Ex. 1008.) The data in Flechter were generated in 68 patients
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`administered 20 mg of GA every other day in an open-label study. (Id. at 2.) Data
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`from those patients were then compared to data gathered in a separate study
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`(“Meiner”) of 20 mg of GA administered daily. (Ex. 1065 at 132:8-10.)
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`According to Flechter, the results “suggest” that alternate-day treatment is
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`“probably” as effective as daily administration. (Ex. 1008 at 5.) He concludes,
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`however, that his “preliminary observations will have to be examined in larger
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`studies…in a blinded manner.” (Id.) As discussed further below, Flechter teaches
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`away from less-than-daily administration of GA as the data suggest that decreasing
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`the frequency of administration of GA led to a decrease in efficacy. (Ex. 1008 at 4,
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`Table 5) (showing a mean relapse rate twice as high for patients undergoing
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`alternate day administration of 20 mg GA as compared to daily administration of
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`the same dosage) In addition, Flechter does not mention the administration of
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`higher unit doses of GA or of any dosage schedule other than daily or every other
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`day administration.
`
`III. PATENT OWNER’S EXPERT DECLARATIONS
`A. Dr. Tjalf Ziemssen
`Dr. Ziemssen has extensive experience treating MS patients, and currently
`
`leads a clinic and neuro-immunological laboratory that cares for approximately
`
`3,000 MS patients. In addition, he presently has about 1,500 MS patients under his
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`personal care as part of his medical practice. He has worked on several clinical
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`trials for MS, including trials investigating the use of GA. (Ex. 2132; Ex. 2135 at ¶
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`16.) Dr. Ziemssen has published extensively on topics including MS and
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`neurology, with more than a dozen articles specifically relating to Copaxone® and
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`its mechanisms of action. (Id. at ¶ 17.) Dr. Ziemssen published a seminal article
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`on the activity of GA in causing an anti-inflammatory shift in T cells, which is
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`thought to be one of the central mechanisms by which GA works. (Ex. 2066.)
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`This article has been cited in the scientific literature more than 300 times. Among
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`other things, Dr. Ziemssen offers the opinion that a 40 mg three times weekly
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`regimen would not have been obvious over the prior art.
`
`B. Dr. Edward Fox
`Dr. Fox holds an M.D. and a Ph.D. in immunology. He is the Director of the
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`MS Clinic of Central Texas and was named Clinical Assistant Professor of
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`Neurology at the University of Texas Medical Branch in 2004. (Ex. 2129 at ¶ 6.)
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`For the past 25 years, Dr. Fox has specialized in the diagnosis and treatment of
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`MS. (Id. at ¶ 7.) He currently has approximately 1,000 MS patients under his care.
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`(Id.) Dr. Fox has authored articles and abstracts related to neurology, MS, and the
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`treatment of MS with pharmaceutical agents, including GA. (Id. at ¶ 11.) He has
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`also participated in more than one hundred clinical trials and extensions as
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`principal investigator, including several major trials involving Copaxone®. (Id. at
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`¶ 12.) Dr. Fox offers, e.g., the opinion that the claimed invention has unexpected
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`results and satisfies a long-felt but unmet need.
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`C. Dr. Robert Gristwood
`Dr. Gristwood holds a Ph.D. in Pharmacology and has nearly 40 years of
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`experience working in the pharmacology and biology departments in several
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`pharmaceutical companies. (Ex. 2134 at ¶¶ 4-5.) Dr. Gristwood is currently a
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`pharmacology consultant at Cambridge BioConsultants Ltd., which he founded,
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`and which provides biological consulting services to pharmaceutical companies.
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`Dr. Gristwood co-founded the pharmaceutical companies Arachnova Limited,
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`Arachnova Therapeutics, and Acacia Pharma Ltd. (Id. at ¶¶ 8-11.) Dr. Gristwood
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`worked in the pharmacology department as SmithKline & French for 12 years,
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`ultimately becoming Associate Director of Pharmacology. He also directed the
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`pharmacology and biology departments at Laboratorios Almirall and Chiroscience
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`Limited. (Id. at ¶ 7.) Dr. Gristwood has experience with the analysis and
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`interpretation of pharmacological data from animal models, and he offers opinions
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`on those issues here. (Id. at ¶¶ 13, 16.) Dr. Gristwood offers the opinion that a
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`skilled pharmacologist would not have relied on the monkey data provided in the
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`SBOA to make predictions about the efficacy of a GA regimen.
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`D. Dr. Henry Grabowski
`Dr. Grabowski is Professor Emeritus of Economics and the Director of the
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`Program in Pharmaceuticals and Health Economics at Duke University. (Ex. 2133
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`at ¶ 2.) Dr. Grabowski holds a Ph.D. in economics from Princeton University. (Id.
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`at ¶ 2.) Dr. Grabowski has studied and published on the economics of the
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`pharmaceutical industry. (Id. at ¶ 3.) He has extensive experience studying the
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`economic issues related to patents and pharmaceuticals, and he offers the opinion
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`here that the invention claimed in the ’413 patent has enjoyed commercial success
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`attributable to novel features of the claimed invention. (Id. at ¶¶ 5, 12-19.)
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`IV. TECHNICAL BACKGROUND
`A. Multiple Sclerosis
`MS is a neurological disease characterized by an autoimmune attack on the
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`CNS. (Ex. 2002 at 1; Ex. 2135 at ¶¶ 40-43.) The disease results in damage to the
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`myelin sheaths (the insulation surrounding nerve fibers) and injury to the axons
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`(long arm-like extensions) of the nerve cells. (Id.) This damage interferes with the
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`neurons’ ability to conduct electrical signals, and it is believed that the clinical
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`symptoms seen in MS patients result from the blockade of electrical conduction
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`that follows the damage to the myelin sheaths and the loss of axons. (Id.) A
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`variety of symptoms characterize MS, among them are visual and motor problems,
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`changes in sensation in the arms and legs, and weakness. Greater than 80% of the
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`patients present with RRMS, which is characterized by discrete attacks of
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`disability followed by periods of partial or total recovery. (Id.)
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`Because of the complex and chronic nature of MS, there are significant
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`obstacles to developing safe and effective therapies for treating the disease. (Ex.
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`2003.) The precise cause of MS is unknown. Lack of a complete understanding of
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`the causative entity, or the precise target associated with instigation of the disease,
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`undermines any expectation of success concerning therapies proposed to interrupt
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`the disease by focusing on its cause. (Id.) In addition, the shortcomings of existing
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`animal models and the lack of a reliable biomarker for assessing therapeutic
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`efficacy make it difficult, if not impossible, to predict the efficacy of any particular
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`MS drug or treatment regimen absent clinical testing. (Id.)
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`The inflammation in the brains of MS patients is derived, at least in part,
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`from the activity of a specific type of T cell known as the Th1 cell, which is
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`associated with inflammation. Under normal circumstances, these Th1 cells are
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`prevented from accessing the CNS and causing inflammation by the “blood brain
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`barrier.” In MS, however, Th1 cells are repeatedly activated in the periphery and
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`are then able to cross the blood brain barrier into the CNS. Once there, the Th1
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`cells react against “self” nervous tissue and cause the inflammation that leads to
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`the disability in MS. It is not known what causes the Th1 cells to become reactive
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`against the patient’s tissues. (Ex. 2135 at ¶¶ 40-49.)
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`The Active Molecule In GA Is Unknown
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`B.
`Unlike virtually all other active pharmaceutical ingredients, GA is not made
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`up of just a single type of molecule. Rather, GA is a complex mixture of linear
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`synthetic polypeptides of varying length and sequence that are made by
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`polymerizing the amino acids L-glutamic acid, L-alanine, L-lysine, and L-tyrosine
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`in an almost random fashion. (Ex. 2135 at ¶ 50-53.) This polymerization process
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`results in an incredible number of different polypeptides that vary in their length,
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`sequence, and molecular weight. It has been estimated that any of >1030 different
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`potential polypeptide sequences could be found in Copaxone®. (Ex. 2007,
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`Abstract.) Because the molecules in GA cannot be separated and fully
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`characterized, and because the target molecules in MS remain unidentified, the
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`specific molecules in GA that are responsible for its activity remain unknown. (Ex.
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`2135 at ¶¶ 50-53.) In fact, it is unknown whether it is the smaller peptide
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`degradation products or the polypeptides found in the GA drug product itself (or
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`both) that are responsible for the clinical effect of the drug. (Ex. 2025 at 2.)
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`C. What Was Known About The Mechanism of Action of GA Taught
`Away From Less Frequent Administration
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`Although the specific mechanism by which GA works has still not been
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`established, at the priority date some generally accepted principles had emerged in
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`the prior art. (Ex. 2135 at ¶¶ 53-64.) As discussed in further detail below, one
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`central understanding of the mechanism of action was that GA activated anti-
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`inflammatory Th2 cells, which are able to cross into the CNS and decrease the
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`inflammation associated with MS. (Ex. 2135 at ¶¶ 58-64.) The prior art suggested
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`that “constant” (i.e., daily) administration of GA allowed these Th2 cells to enter
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`the CNS. (Ex. 2084 at 1.) “Current theories propo