Case No. IPR2015-00643
`
`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. IPR2015-00643
`Patent No. 8,232,250
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`YEDA’S PRELIMINARY PATENT OWNER RESPONSE
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`
`
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`YEDA EXHIBIT NO. 2013
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`Case No. IPR2015-00643
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`TABLE OF CONTENTS
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`Page
`INTRODUCTION ........................................................................................... 1
`I.
`THE ʼ250 PATENT ......................................................................................... 6
`II.
`III. BACKGROUND FACTS ................................................................................ 9
`A. Multiple Sclerosis .................................................................................. 9
`B.
`COPAXONE® - Glatiramer Acetate ..................................................11
`1.
`The Active Molecule In GA Is Unknown ......................11
`2.
`GA’s Mechanism Of Action Is Unknown ......................13
`3.
`No PK/PD Correlation Exists For GA............................15
`IV. THE PRIOR ART ..........................................................................................17
`V. MYLAN’S PROFFERED GROUNDS OF UNPATENTABILITY ............23
`VI. MYLAN’S PROPOSED CONSTRUCTION OF “COMPRISING” IS
`UNREASONABLE AND SHOULD BE REJECTED .................................24
`A. Yeda Expressly Disclaimed Coverage of Alternate Day
`Administration During Prosecution ....................................................24
`B. Mylan’s Proposed Claim Construction Conflicts With The Intrinsic
`Record..................................................................................................27
`“Comprising” Should Not Be Interpreted To Render the “Regimen”
`Method Step Open-Ended ...................................................................28
`VII. MYLAN’S IPR PETITION SHOULD BE REJECTED ...............................31
`A. Ground 1 Fails: Pinchasi Does Not Anticipate Claims 1-13 And 19-20
` .............................................................................................................31
`Grounds 2, 3, And 4 Fail: The Claims Would Not Have Been Obvious
`Over Pinchasi Alone Or Pinchasi In View Of The SBOA Or Flechter
` .............................................................................................................32
`1. Mylan’s Definition Of The Person Of Ordinary Skill
`Should Be Rejected ........................................................33
`A POSA Would Not Have Had A Reasonable
`Expectation Of Success In Using A 40 mg Three Times
`Per Week Regimen Because The Active Molecule And
`Mechanism Of Action Were Unknown, And There Was
`No PK/PD Correlation ....................................................34
`
`C.
`
`B.
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`2.
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`i
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`Case No. IPR2015-00503
`Yeda’s Preliminary Response
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`3.
`
`4.
`
`5.
`
`A Skilled Artisan Would Not Have Been Motivated To
`Dose GA Three Times Weekly ......................................37
`It Would Not Have Been Obvious To Use A 40 mg Dose
` ........................................................................................44
`The Person Of Skill Would Not Have Been Motivated To
`Combine Pinchasi With The SBOA And/Or Flechter....45
`6. Mylan Has Failed To Prove That The SBOA Document
`Is Available As Prior Art ................................................47
`VIII. IF IPR IS INSTITUTED, IT SHOULD NOT BE INSTITUTED FOR ALL
`CLAIMS ........................................................................................................49
`A.
`The Board Should Not Institute Review Of Dependent Claims 5 And
`9-11 Where Mylan’s Only Argument Is An Insufficiently Supported
`Assertion That The Claim Limitations Are “Inherent” In The Prior Art
` .............................................................................................................49
`The Board Should Not Institute Review Of Claims 15-18 .................51
`B.
`IX. UNEXPECTED RESULTS AND OBJECTIVE INDICIA SUPPORT THE
`PATENTABILITY OF THE ’250 PATENT CLAIMS ................................52
`A. Unexpected Results Support The Patentability Of The ’250 Patent’s
`Claims ..................................................................................................52
`Commercial Success Supports The Patentability Of The ’250 Patent’s
`Claims ..................................................................................................54
`The Claimed Invention Met A Long Felt But Unmet Need ...............54
`C.
`CONCLUSION ..............................................................................................56
`
`B.
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`X.
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`Case No. IPR2015-00643
`Yeda’s Preliminary Response
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Cedarapids, Inc. v. Nordberg, Inc.,
`No. 95-1529, 1997 WL 452801 (Fed. Cir. Aug. 11, 1997) ................................ 34
`
`Dippin’ Dots, Inc. v. Mosey,
`476 F.3d 1337 (Fed. Cir. 2007) .......................................................................... 28
`
`Elkay Mfg. Co. v. Ebco Mfg. Co.,
`192 F.3d 973 (Fed. Cir. 1999) ............................................................................ 27
`
`ERBE Elektromedizin GmbH v. Canady Tech. LLC,
`629 F.3d 1278 (Fed. Cir. 2010) .......................................................................... 26
`
`Ericsson, Inc. v. D-Link Sys., Inc.,
`773 F.3d 1201 (Fed. Cir. 2014) .................................................................... 31, 32
`
`In re Fritch,
`972 F.2d 1260 (Fed. Cir. 1992) .......................................................................... 39
`
`Gillette Co. v. Energizer Holdings, Inc.,
`405 F.3d 1367 (Fed. Cir. 2005) .................................................................... 30, 31
`
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) .................................................................... 36, 37
`
`Interconnect Planning Corp. v. Feil,
`774 F.2d 1132 (Fed. Cir. 1985) .................................................................... 45, 46
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 36
`
`Mass. Inst. of Tech. v. Harman Int’l Indus.,
`584 F. Supp. 2d 297 (D. Mass. 2008) ................................................................. 47
`
`In re McLaughlin,
`443 F.2d 1392 (C.C.P.A. 1971) .......................................................................... 55
`
`Spectrum Int’l, Inc. v. Sterilite Corp.,
`164 F.3d 1372 (Fed. Cir. 1998) .......................................................................... 29
`
`iii
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`SRI Int’l Inc. v. Internet Sec. Sys., Inc. et al.,
`511 F.3d 1186 (Fed. Cir. 2008) .................................................................... 48, 49
`
`Std. Oil Co. v. Am. Cyanamid Co.,
`774 F.2d 448 (Fed. Cir. 1985) ............................................................................ 27
`
`Syntex (U.S.A.) LLC v. Apotex Inc.,
`No. C 01-02214 MJJ, 2006 WL 1530101 (N.D. Cal. June 2, 2006) .................. 55
`
`U.S. v. Telectronics, Inc.,
`857 F.2d 778 (Fed. Cir. 1988) ............................................................................ 34
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) .......................................................................... 35
`
`VirnetX, Inc. v. Cisco Sys., Inc.,
`767 F.3d 1308 (Fed. Cir. 2014) .......................................................................... 32
`
`W.L. Gore & Assocs., Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) .......................................................................... 39
`
`Warner Chilcott Co., LLC v. Teva Pharms. USA, Inc.,
`594 Fed. Appx. 630 (Fed. Cir. Nov. 18, 2014) ............................................. 36, 37
`
`Zhejiang Med. Co. v. Kaneka Corp.,
`No. H-11-1052, 2012 WL 4795623 (S.D. Tex. Aug. 23, 2012)......................... 28
`
`Statutes & Regulations
`35 U.S.C. § 102 .................................................................................................passim
`
`35 U.S.C. § 312(a)(3) ............................................................................................... 49
`
`Other Authorities
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`M.P.E.P. § 2141.03(I) .............................................................................................. 34
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`Case No. IPR2015-00643
`Yeda’s Preliminary Response
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`I.
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`INTRODUCTION
`
`In 1996, Yeda’s commercial partner Teva obtained approval from the FDA
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`for Copaxone®, a multiple sclerosis (“MS”) treatment administered by injection at
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`a dose of 20 mg every day. After more than a decade of additional research,
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`including many failed attempts at alternate dosing regimens, Teva discovered that
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`Copaxone® could be administered on the very specific regimen of 40 mg/three
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`times per week. Upon the launch of this new dose and schedule last year, doctors
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`and patients quickly adopted it. Mylan’s argument that U.S. Pat. No. 8,232,250
`
`(“the ’250 patent”), which covers Teva’s blockbuster 40 mg/three times per week
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`MS treatment, is anticipated or obvious should be rejected. No prior art reference
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`disclosed the claimed treatment regimen, and Mylan’s obviousness argument is
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`tainted by hindsight and ignores the teaching of the entire prior art.
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`Mylan focuses on a handful of prior art references it deems “close” to the
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`claimed invention and simplistically suggests it would have been obvious to arrive
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`at a method of treating MS using a regimen of glatiramer acetate three times per
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`week. But nothing about treating MS with glatiramer acetate is simple or obvious.
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`At the relevant time, no one fully understood what causes the onset of MS and no
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`one fully understood why or how glatiramer acetate (“GA”) works to treat the
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`disease. This remains true today.
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`1
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`GA is fundamentally different from typical “small molecule” drugs. Unlike
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`most drugs, GA is not a single type of molecule; it is a complex mixture of many
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`millions of different peptide chains of varying lengths and amino acid sequences.
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`It is unknown which of those millions of molecules is active in the body or
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`whether the active molecule is created by degradation of GA in the body after
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`administration. Also unknown is the mechanism by which GA works to treat MS;
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`scientists have not fully elucidated the various means by which the drug exerts its
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`therapeutic effect. GA molecules cannot be detected in the bloodstream after it is
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`administered and there is no known dose-response relationship for the drug.
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`With no certainty on any of these issues, a person of ordinary skill could not
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`have predicted in advance whether dosing 40 mg of GA three times per week
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`would prove safe, effective and more tolerable than daily treatment with 20 mg
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`GA. A full scale clinical trial—like the one commissioned and successfully
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`completed by Teva in 2013—was necessary to determine whether such a regimen
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`would work. Mylan’s suggestion to the contrary overlooks the complexity of the
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`relevant art and the teachings of references cited in its own petition that would
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`have discouraged a skilled artisan from even attempting a 40 mg/three times a
`
`week regimen.
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`Mylan first posits that some, but not all, of the inventions claimed in the
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`’250 patent were already disclosed in the prior art. But Mylan has not identified a
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`single prior art reference disclosing three times per week dosing of GA. And
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`Mylan’s attempt to conceal this fundamental flaw in its argument by improperly
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`altering the scope of the claim under the guise of claim construction should be
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`rejected. As the patent makes clear, the claims cover a very specific dosing
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`regimen of three, and only three, administrations per week—a regimen that was
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`proven by clinical trial to be safe and effective. Contrary to Mylan’s assertions,
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`the claim term “comprising” cannot be used to change the scope of this specific
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`claimed regimen from three times per week to four times per week. Significantly,
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`during prosecution, Yeda expressly amended its claims in order to disclaim any
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`dosing regimen that was not limited to three and only three administrations per
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`week in order to overcome a rejection under 35 U.S.C. §102. Mylan’s proposed
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`construction, which is the lynchpin of its anticipation argument, is not reasonable
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`and should be rejected.
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`Mylan’s obviousness arguments, like its anticipation arguments, raise issues
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`that were already considered and rejected by the Examiner during prosecution.
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`For example, Mylan relies on reports of some small studies that had experimented
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`with either a 40 mg daily dose or alternate day dosing of a 20 mg of GA to argue
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`that a person of skill would have pursued a 40 mg/three times a week regimen.
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`But these studies were all before the Examiner during prosecution, and Mylan
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`3
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`ignores teachings from the prior art that would have expressly discouraged pursuit
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`of a 40 mg/three times a week regimen.
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`For example, the Phase III FORTE clinical trial, which is prior art to the
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`ʼ250 patent, demonstrated that daily administration of 40 mg of GA was, in fact,
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`no better than daily administration of 20 mg formulation and that, as of the priority
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`date, the 20 mg daily dose “remain[ed] the optimal treatment dose.” (Ex. 2001.)
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`The results of the FORTE trial thus taught away from a 40 mg dose – particularly
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`when a 20 mg dose had been used safely and successfully by thousands of patients
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`for over ten years.
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`Similarly, Mylan ignores results from the prior art that would have
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`discouraged research into less frequent dosing. For example, the results from the
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`small Flechter study reflect reduced efficacy of 20 mg of GA dosed on an alternate
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`day schedule. Infra at 19-20. Patients dosed on an every other day schedule in the
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`Flechter study experienced more frequent relapses and a worsening of disability
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`compared to patients on daily administration. Once again, these findings would
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`have expressly deterred development of a three times a week dosing regimen, yet
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`Mylan’s petition blithely assumes a person of skill would have been motivated to
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`do so.
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`Given the insufficient disclosure of the prior art references, Mylan attempts
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`to bolster its argument by deploying a chart comparing the treatment regimen
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`claimed in the ’250 patent to several prior art regimens, presumably in an effort to
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`show that the claimed regimen falls somewhere between the prior art in terms of
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`frequency and amount of GA administered. (Pet. at 44.) But merely pointing out
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`that some different alternative dosing regimens had been experimented with does
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`not establish a motivation to pursue the specific regimen claimed in the ’250
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`patent. Mylan’s only solution for this problem is to resort to impermissible
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`hindsight, relying on the claimed regimen as the lens through which the skilled
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`person would have viewed the prior art. But the skilled person would not have
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`had the claimed invention available to use as a tool for sifting through the prior
`
`art; Mylan’s reliance on hindsight-driven argument is contrary to law and should
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`be rejected.
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`Even if the skilled person were motivated to pursue a 40 mg/three times a
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`week regimen, that person could not have reasonably expected, without resort to
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`full scale clinical testing, that the claimed regimen would work. First, the
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`pharmaceutical arts are, as a whole, unpredictable, and that is especially true in the
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`case of treating MS through the administration of GA, where neither its active
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`molecule nor its mechanism of action are known. Second, no relationship between
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`the dose of GA or its frequency of dosing and its safety and efficacy had been
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`established as of 2009. This uncertainty about both the drug and the disease it
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`treats would have rendered any prediction about the success or failure of the
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`claimed regimen impossible. Mylan ignores these well-known complexities, and
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`instead tries to draw unpersuasive comparisons to inapposite cases involving
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`extensively studied and better characterized small molecule compounds whose
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`dosing schedule and dose-response relationship were well established in the prior
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`art. Third, a skilled person would not have expected such a regimen to be better
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`than daily administration of 20 mg of GA. (See, e.g., Ex. 1001, Claim 15 (directed
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`to a “method of increasing the tolerability of GA treatment”).) As set forth above,
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`the prior art would not have even suggested that the claimed regimen would be
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`safe and effective, much less better than the daily 20 mg regimen that had been
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`used successfully by many patients for many years. Mylan therefore failed to
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`establish a reasonable expectation of success.
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`For these and the reasons discussed below, Mylan has not established a
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`reasonable likelihood that it will prevail in showing the unpatentability of any of
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`the challenged claims of the ʼ250 patent and, accordingly, its petition should be
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`denied in its entirety.
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`II. THE ʼ250 PATENT
`The ʼ250 patent to Klinger issued on July 31, 2012 from U.S. Appl. No.
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`13/308,299, which was filed on November 30, 2011 (claiming a priority date of
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`August 20, 2009). The patent includes 20 claims, 3 of which are independent.
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`Independent claims 1, 15, and 19 read as follows:
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`Case No. IPR2015-00643
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`1. A method of alleviating a symptom of relapsing-remitting multiple
`sclerosis in a human patient suffering from relapsing-remitting
`multiple sclerosis or a patient who has experienced a first clinical
`episode and is determined to be at high risk of developing clinically
`definite multiple sclerosis comprising administering to the human
`patient a therapeutically effective regimen of three subcutaneous
`injections of a 40 mg dose of glatiramer acetate over a period of seven
`days with at least one day between every subcutaneous injection, the
`regimen being sufficient to alleviate the symptom of the patient.
`
`15. A method of increasing the tolerability of GA treatment in a
`human patient suffering from relapsing-remitting multiple sclerosis or
`a patient who has experienced a first clinical episode and is
`determined to be at high risk of developing clinically definite multiple
`sclerosis which comprises reducing frequency of subcutaneous
`injections from daily subcutaneous injections of a pharmaceutical
`composition comprising a 20 mg dose of glatiramer acetate to a
`regimen of three subcutaneous injections of a 40 mg dose of
`glatiramer acetate over a period of seven days with at least one day
`between every injection, wherein the regimen is therapeutically
`effective, so as to thereby increase the tolerability of GA treatment in
`the patient.
`
`19. A method of reducing frequency of relapses in a human patient
`suffering from relapsing-remitting multiple sclerosis comprising
`administering to the human patient a therapeutically effective regimen
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`of three subcutaneous injections of a 40 mg dose of glatiramer acetate
`over a period of seven days with at least one day between every
`subcutaneous injection, the regimen being sufficient to reduce
`frequency of relapses in the human patient.
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`(Ex. 1001.) The dependent claims are directed to, inter alia, alleviating specific
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`symptoms associated with a form of disease known as relapsing remitting MS
`
`(“RRMS”).
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`The only treatment regimen disclosed in the ’250 patent involves the
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`administration of three, and no more than three, 40 mg GA injections in each
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`seven day period. There is absolutely no disclosure or suggestion of an alternate
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`day schedule, or any other schedule involving more than three injections in each
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`seven day period. (See, e.g., id. 4:14-16 (“In another embodiment, there are three
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`injections for every seven days and there must be at least one day between each
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`injection.”).) The protocol for a double-blind study disclosed in the specification
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`compares the “efficacy, safety and tolerability of [GA] injection 40 mg/ml
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`administered three times weekly” to a placebo treatment. (Id. at 9:18-20; see also
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`8:64-67 (“The study is designed to select three days a week for injection. Three
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`injections are administered for every seven days and there must be at least one day
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`between each injection,” (emphasis added).)
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`8
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`III. BACKGROUND FACTS
`A. Multiple Sclerosis
`MS is a neurological disease characterized by an autoimmune attack on the
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`central nervous system (“CNS”).1 The term “multiple sclerosis” refers to the scars
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`(scleroses or plaques) that characterize the white matter of the brain and spinal cord
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`of MS patients. (Id.) The autoimmune attack that drives MS is thought to produce
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`these scars. (Id.) The disease results in damage to the myelin sheaths (the
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`insulation surrounding nerve fibers) and injury to the axons (long arm-like
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`extensions) of the nerve cells. (Id.) This damage interferes with the neurons’
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`ability to conduct electrical signals, and it is believed that the clinical symptoms
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`seen in MS patients result from the blockade of electrical conduction that follows
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`the damage to the myelin sheaths and the loss of axons. (Id.)
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`A variety of symptoms characterize MS, among them are visual and motor
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`problems, changes in sensation in the arms and legs, and weakness. (Id.) Greater
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`than 80% of the patients present with RRMS, which is characterized by discrete
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`attacks of disability followed by periods of partial or total recovery. (Id.)
`
`
`1 Ex. 2002, Quintana, Franscisco J. et al., Systems Biology approaches for the
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`study of multiple sclerosis, 12 J. CELL. MOL. MED., 2008 at 1087.
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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.2 First,
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`the precise cause of MS is unknown. (Ex. 1007 at 133-134.) Lack of a complete
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`understanding of the causative entity (or entities), or the precise target associated
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`with instigation of the disease, undermines any expectation of success concerning
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`therapies proposed to interrupt the disease by focusing on its cause.
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`In addition, existing animal models differ from humans in terms of both the
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`pathology of the disease model and the animals’ immunologic responses. And
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`individual MS patients differ dramatically from one another in clinical
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`manifestation of the disease and response to therapies.3 Further, no reliable
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`biomarker exists that allows therapeutic efficacy to be assessed. (Ex. 2003, Virley
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`at 646.) For these reasons, predicting the efficacy of any particular MS drug or
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`treatment regimen de novo absent clinical testing is essentially impossible. (Id.)
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`
`
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`2 Ex. 2003, David J. Virley, Developing Therapeutics for the treatment of multiple
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`sclerosis, 2 J. AM. SOC. EXP. NEUROTHERAPEUTICS, October, 2005, at 638.
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`3 Ex. 2004, Manuel A. Friese, The value of animal models for drug development in
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`multiple sclerosis, 129 BRAIN, 2006, at 1940; see also id.
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`Case No. IPR2015-00643
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`B. COPAXONE® - Glatiramer Acetate
`GA is the active ingredient in Copaxone. In 1996, the FDA approved
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`Copaxone to treat RRMS at a dosage of 20 mg, administered daily by
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`subcutaneous injection. Importantly, that was the only approved dosage of
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`Copaxone for nearly twenty years until the FDA approved Teva’s 40 mg product in
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`January 2014. The prescribing information for the 40 mg product states that the
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`product should be administered “three times per week and at least 48 hours apart.”4
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`The Active Molecule In GA Is Unknown
`
`1.
`Unlike virtually all other active pharmaceutical ingredients, GA is not made
`
`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. The polypeptides are
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`chains of four naturally occurring amino acid building blocks: L-glutamic acid, L-
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`alanine, L-lysine, and L-tyrosine. The polypeptides in GA are synthesized by
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`polymerizing the amino acids such that they attach to one another in almost
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`random fashion. This polymerization process results in a complex mixture of
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`many different polypeptides that vary in their length (number of amino acids),
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`4 Ex. 2005, Copaxone Prescribing Information (Jan. 2014) at 1.
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`Case No. IPR2015-00643
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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.5
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`Even today, using the most sensitive analytical techniques available, it is
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`impossible to separate and fully characterize all of the molecules present in GA due
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`to their number and structural complexity. Because the molecules in GA cannot be
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`fully characterized, and because the target molecules in MS remain unidentified,
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`the specific molecules in the GA drug that are responsible for its activity remain
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`unknown. Further complicating this story, GA is, as discussed below, rapidly
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`degraded into smaller peptides after administration, and it is unknown whether it is
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`the smaller peptide degradation products or the polypeptides found in the GA drug
`
`product itself (or both) that are responsible for the clinical effect of the drug.6
`
`
`
`
`5 Ex. 2007, Jill Conner, Glatiramer acetate and therapeutic peptide vaccines for
`
`multiple sclerosis, 1 J. OF AUTOIMMUNITY AND CELL RESPONSES 3, 2014
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`at 2.
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`6 Ex. 2025, McKeage K., Glatiramer Acetate 40 mg/mL in Relapsing-Remitting
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`Multiple Sclerosis: A Review, CNS DRUGS (Apr. 24, 2015).
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`Case No. IPR2015-00643
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`2. GA’s Mechanism Of Action Is Unknown
`Not only is the active molecule(s) of GA unknown, but the mechanism by
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`which the drug works is also not fully understood, despite extensive research.7
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`Several different mechanisms appear to play a role in the drug’s activity, and
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`additional mechanisms continue to be discovered as research progresses.8 The
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`currently theorized mechanisms of action suggest that GA works through both
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`immunomodulatory (shifting the immune response from a pro-inflammatory
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`response to an anti-inflammatory response) and neuroprotective (causing a
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`response that protects nervous system tissues) processes.
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`The mechanism of action of GA, to the extent known, involves a local
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`immune response to the drug in the subcutaneous tissue that somehow brings about
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`an anti-inflammatory effect on the diseased brain tissue. A brief explanation of
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`what is understood about the pathology of MS will provide some backdrop for the
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`current thinking with respect to GA’s mechanism of action. MS occurs, at least in
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`part, due to immune cells from outside the CNS entering the brain and causing
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`damage to the nerve tissues. The precise chain of events leading to this outcome is
`
`
`7 Ex. 2008, Copaxone, Physicians’ Desk Reference 62ed. (2008).
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`8 See Ex. 2009, W. Schrempf and T. Ziemssen, Glatiramer acetate: Mechanisms of
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`action in multiple sclerosis, AUTOIMMUN. REV. Aug. 6, 2007, at 471.
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`still not completely known, but it is believed that so-called “antigen presenting
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`cells” (or “APCs”) present molecules from the brain tissue or from viral agents (or
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`something else) to T cells (a type of immune system cell) by displaying the
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`molecules on the surface of the APCs as part of the “major histocompatibility
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`complex” (or “MHC”). The T cells are then made reactive against the body’s own
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`nervous system tissue and acquire the ability to cross the “blood brain barrier” and
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`gain access to the CNS, where they cause damage.
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`Copaxone is believed to work through complicated and incompletely
`
`understood mechanisms at several stages in this process:
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`• Copaxone is thought to bind to MHC and alter the immune response
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`associated with MS;
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`• Copaxone is thought to compete with “self” molecules for binding to
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`MHC receptors, and thus to alter the autoimmune response;
`
`• Copaxone is thought to increase the formation and activation of
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`beneficial, anti-inflammatory “T-helper type 2” (“Th2”) cells and
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`decrease the formation of harmful, pro-inflammatory “T-helper
`
`type 1” (“Th1”) cells;
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`• Copaxone is thought to enhance the migration of anti-inflammatory
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`Th2 cells into the CNS where they cause a decrease in the
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`inflammation associated with MS; and
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`• Copaxone is thought to protect the neurons and axons in the CNS by
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`stimulating the release of protective anti-inflammatory chemicals
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`known as chemokines and cytokines.
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` (Ex. 2009, Schrempf at 471.9)
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`No PK/PD Correlation Exists For GA
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`3.
`While a non-skilled person might make the simplistic assumption that
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`doubling the dose of a medication would in turn double its efficacy, a skilled
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`artisan would know that one could not expect such a result with GA.10 Unlike
`
`most other pharmaceutical products, it is not possible to determine the
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`pharmacokinetics (“PK”) of GA, i.e., the speed with which the drug is taken up
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`into and eliminated from the body, and to correlate the pharmacokinetics with the
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`pharmacodynamic (“PD”) effects of the drug, i.e., its biochemical and physiologic
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`effects. This is because GA cannot be measured in the bloodstream after
`
`
`9 See also Ex. 2010, V.Wee Yong, Differential mechanisms of action of interferon-
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`β and GA in MS, 59 NEUROLOGY, 802-8 (2002); Ex. 2011, Suhayl Dhib-Jalbut,
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`Mechanisms of action of interferons and [GA] in MS, 58 NEUROLOGY (8 Suppl.
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`4), S3-S9 (2002).
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`10 Ex. 2001, Teva press release, Teva provides update on FORTE TRIAL (July
`
`7, 2008), http:www.tevapharm.com.
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`subcutaneous administration. Since GA cannot be measured once in the body, and
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`no biomarker exists to measure the effect of GA, clinical trials remain the sole way
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`to determine the efficacy of any particular GA dose or regimen and to make a
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`correlation between GA drug amount and GA drug effect. (Ex. 2009 at 473.)11
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`The scientific literature makes clear that GA is very quickly broken down to
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`small peptides and individual amino acids after subcutaneous injection. Only 10%
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`of the drug is present at