Case No. IPR2015-00644
`
`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 PRELIMINARY PATENT OWNER RESPONSE
`
`
`
`
`
`
`
`
`
`
`
`
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 1/67
`
`

`
`Table of Contents
`
`Case No. IPR2015-00644
`
`Page
`
`INTRODUCTION ........................................................................................... 1
`I.
`THE ʼ413 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 1-6 And 8-20
` ............................................................................................................. 32
`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
` ............................................................................................................. 34
`1. Mylan’s Definition Of The Person Of Ordinary Skill
`Should Be Rejected ........................................................ 34
`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 .................................................... 35
`
`C.
`
`B.
`
`2.
`
`i
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 2/67
`
`

`
`Case No. IPR2015-00503
`Yeda’s Preliminary Response
`
`3.
`
`A Skilled Artisan Would Not Have Been Motivated To
`Dose GA Three Times Weekly ...................................... 38
`It Would Not Have Been Obvious To Use A 40 mg Dose
` ........................................................................................ 45
`The Person of Skill Would Not Have Been Motivated to
`Combine Pinchasi with the SBOA And/Or Flechter. ..... 46
`6. Mylan Has Failed To Prove That The SBOA Document
`Is Available As Prior Art ................................................ 48
`VIII. IF IPR IS INSTITUTED, IT SHOULD NOT BE INSTITUTED FOR ALL
`CLAIMS ........................................................................................................ 50
`A.
`The Board Should Not Institute Review Of Dependent Claims 6-7
`And 14-18 Where Mylan’s Only Argument Is An Insufficiently
`Supported Assertion That The Claim Limitations Are “Inherent” In
`The Prior Art ....................................................................................... 51
`The Board Should Not Institute Review Of Claim 7 .......................... 53
`B.
`IX. UNEXPECTED RESULTS AND OBJECTIVE INDICIA SUPPORT THE
`PATENTABILITY OF THE ’413 PATENT CLAIMS ................................ 54
`A. Unexpected Results Support The Patentability Of The ’413 Patent’s
`Claims .................................................................................................. 54
`Commercial Success Supports The Patentability Of The ’413 Patent’s
`Claims .................................................................................................. 55
`The Claimed Invention Met A Long Felt But Unmet Need ............... 56
`C.
`CONCLUSION .............................................................................................. 58
`
`B.
`
`4.
`
`5.
`
`X.
`
`
`ii
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 3/67
`
`

`
`Case No. IPR2015-00644
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Cedarapids, Inc. v. Nordberg, Inc.,
`No. 95-1529, 1997 WL 452801 (Fed. Cir. Aug. 11, 1997) ................................ 35
`
`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) .......................................................................... 32
`
`In re Fritch,
`972 F.2d 1260 (Fed. Cir. 1992) .......................................................................... 40
`
`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) .................................................................... 37, 38
`
`Interconnect Planning Corp. v. Feil,
`774 F.2d 1132 (Fed. Cir. 1985) .................................................................... 46, 47
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 37
`
`Mass. Inst. of Tech. v. Harman Int’l Indus.,
`584 F. Supp. 2d 297 (D. Mass. 2008) ................................................................. 48
`
`In re McLaughlin,
`443 F.2d 1392 (C.C.P.A. 1971) .......................................................................... 56
`
`In re Robertson,
`169 F.3d 743 (Fed. Cir. 1999) ............................................................................ 33
`
`iii
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 4/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
`Spectrum Int’l, Inc. v. Sterilite Corp.,
`164 F.3d 1372 (Fed. Cir. 1998) .......................................................................... 29
`
`SRI Int’l Inc. v. Internet Sec. Sys., Inc. et al.,
`511 F.3d 1186 (Fed. Cir. 2008) .................................................................... 49, 50
`
`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) .................. 56
`
`U.S. v. Telectronics, Inc.,
`857 F.2d 778 (Fed. Cir. 1988) ............................................................................ 35
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) .......................................................................... 36
`
`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) .......................................................................... 40
`
`Warner Chilcott Co., LLC v. Teva Pharms. USA, Inc.,
`594 Fed. Appx. 630 (Fed. Cir. Nov. 18, 2014) ............................................. 37, 38
`
`Zhejiang Med. Co. v. Kaneka Corp.,
`No. H-11-1052, 2012 WL 4795623 (S.D. Tex. Aug. 23, 2012) ......................... 29
`
`Statutes
`35 U.S.C. §102 ..................................................................................................passim
`
`35 U.S.C. §312(a)(3) ................................................................................................ 50
`
`Other Authorities
`
`M.P.E.P. §2141.03(I) ............................................................................................... 35
`
`
`
`iv
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 5/67
`
`

`
`Case No. IPR2015-00644
`
`I.
`
`INTRODUCTION
`
`In 1996, Yeda’s commercial partner Teva obtained approval from the FDA
`
`for Copaxone®, a multiple sclerosis (“MS”) treatment administered by injection at
`
`a dose of 20 mg every day. After more than a decade of additional research,
`
`including many failed attempts at alternate dosing regimens, Teva discovered that
`
`Copaxone® could be administered on the very specific regimen of 40 mg/three
`
`times per week. Upon the launch of this new dose and schedule last year, doctors
`
`and patients quickly adopted it. Mylan’s argument that U.S. Pat. No. 8,399,413
`
`(“the ’413 patent”), which covers Teva’s blockbuster 40 mg/three times per week
`
`MS treatment, is anticipated or obvious should be rejected. No prior art reference
`
`disclosed the claimed treatment regimen, and Mylan’s obviousness argument is
`
`tainted by hindsight and ignores the teaching of the entire prior art.
`
`Mylan focuses on a handful of prior art references it deems “close” to the
`
`claimed invention and simplistically suggests it would have been obvious to arrive
`
`at a method of treating MS using a regimen of glatiramer acetate three times per
`
`week. But nothing about treating MS with glatiramer acetate is simple or obvious.
`
`At the relevant time, no one fully understood what causes the onset of MS and no
`
`one fully understood why or how glatiramer acetate (“GA”) works to treat the
`
`disease. This remains true today.
`
`
`
`1
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 6/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
`GA is fundamentally different from typical “small molecule” drugs. Unlike
`
`most drugs, GA is not a single type of molecule; it is a complex mixture of many
`
`millions of different peptide chains of varying lengths and amino acid sequences.
`
`It is unknown which of those millions of molecules is active in the body or
`
`whether the active molecule is created by degradation of GA in the body after
`
`administration. Also unknown is the mechanism by which GA works to treat MS;
`
`scientists have not fully elucidated the various means by which the drug exerts its
`
`therapeutic effect. GA molecules cannot be detected in the bloodstream after it is
`
`administered and there is no known dose-response relationship for the drug.
`
`With no certainty on any of these issues, a person of ordinary skill could not
`
`have predicted in advance whether dosing 40 mg of GA three times per week
`
`would prove safe, effective and more tolerable than daily treatment with 20 mg
`
`GA. A full scale clinical trial—like the one commissioned and successfully
`
`completed by Teva in 2013—was necessary to determine whether such a regimen
`
`would work. Mylan’s suggestion to the contrary overlooks the complexity of the
`
`relevant art and the teachings of references cited in its own petition that would
`
`have discouraged a skilled artisan from even attempting a 40 mg/three times a
`
`week regimen.
`
`Mylan first posits that some, but not all, of the inventions claimed in the
`
`’413 patent were already disclosed in the prior art. But Mylan has not identified a
`
`2
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 7/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
`single prior art reference disclosing three times per week dosing of GA. And
`
`Mylan’s attempt to conceal this fundamental flaw in its argument by improperly
`
`altering the scope of the claim under the guise of claim construction should be
`
`rejected. As the patent makes clear, the claims cover a very specific dosing
`
`regimen of three, and only three, administrations per week—a regimen that was
`
`proven by clinical trial to be safe and effective. Contrary to Mylan’s assertions,
`
`the claim term “comprising” cannot be used to change the scope of this specific
`
`claimed regimen from three times per week to four times per week. Significantly,
`
`during prosecution, Yeda expressly amended its claims in order to disclaim any
`
`dosing regimen that was not limited to three and only three administrations per
`
`week in order to overcome a rejection under 35 U.S.C. §102. Mylan’s proposed
`
`construction, which is the lynchpin of its anticipation argument, is not reasonable
`
`and should be rejected.
`
`Mylan’s obviousness arguments, like its anticipation arguments, raise issues
`
`that were already considered and rejected by the Examiner during prosecution.
`
`For example, Mylan relies on reports of some small studies that had experimented
`
`with either a 40 mg daily dose or alternate day dosing of 20 mg GA to argue that a
`
`person of skill would have pursued a 40 mg/three times a week regimen. But
`
`these studies were all before the Examiner during prosecution, and Mylan ignores
`
`3
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 8/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
`teachings from the prior art that would have expressly discouraged pursuit of a 40
`
`mg/three times a week regimen.
`
`For example, the Phase III FORTE clinical trial, which is prior art to the
`
`ʼ413 patent, demonstrated that daily administration of 40 mg of GA was, in fact,
`
`no better than daily administration of the 20 mg formulation and that, as of the
`
`priority date, the 20 mg daily dose “remain[ed] the optimal treatment dose.” (Ex.
`
`2001.) The results of the FORTE trial thus taught away from a 40 mg dose –
`
`particularly when a 20 mg dose had been used safely and successfully by
`
`thousands of patients for over ten years.
`
`Similarly, Mylan ignores results from the prior art that would have
`
`discouraged research into less frequent dosing. For example, the results from the
`
`small Flechter study reflect reduced efficacy of 20 mg of GA dosed on an alternate
`
`day schedule. Infra at 38-39. Patients dosed on an every other day schedule in the
`
`Flechter study experienced more frequent relapses and a worsening of disability
`
`compared to patients on daily administration. Once again, these findings would
`
`have expressly deterred development of a three times a week dosing regimen, yet
`
`Mylan’s petition blithely assumes a person of skill would have been motivated to
`
`do so.
`
`Given the insufficient disclosure of the prior art references, Mylan attempts
`
`to bolster its argument by deploying a chart comparing the treatment regimen
`
`4
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 9/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
`claimed in the ’413 patent to several prior art regimen, presumably in an effort to
`
`show that the claimed regimen falls somewhere between the prior art in terms of
`
`frequency and amount of GA administered. (Pet. at 44.) But merely pointing out
`
`that some different alternative dosing regimens had been experimented with does
`
`not establish a motivation to pursue the specific regimen claimed in the ’413
`
`patent. Mylan’s only solution for this problem is to resort to impermissible
`
`hindsight, relying on the claimed regimen as the lens through which the skilled
`
`person would have viewed the prior art. But the skilled person would not have
`
`had the claimed invention available to use as a tool for sifting through the prior
`
`art; Mylan’s hindsight-driven argument is contrary to law and should be rejected.
`
`Even if the skilled person were motivated to pursue a 40 mg/three times a
`
`week regimen, that person could not have reasonably expected, without resort to
`
`full scale clinical testing, that the claimed regimen would work. First, the
`
`pharmaceutical arts are, as a whole, unpredictable, and that is especially true in the
`
`case of treating MS through the administration of GA, where neither its active
`
`molecule nor its mechanism of action are known. Second, no relationship between
`
`the dose of GA or its frequency of dosing and its safety and efficacy had been
`
`established as of 2009. This uncertainty about both the drug and the disease it
`
`treats would have rendered any prediction about the success or failure of the
`
`claimed regimen impossible. Mylan ignores these well-known complexities, and
`
`5
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 10/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
`instead tries to draw unpersuasive comparisons to inapposite cases involving
`
`extensively studied and better characterized small molecule compounds, whose
`
`dosing schedule and dose-response relationship were well established in the prior
`
`art. Third, a skilled person would not have expected such a regimen to be
`
`beneficial over daily administration of 20 mg of GA. (See, e.g., Ex. 1001, Claim 7
`
`(directed to “reducing the frequency of immediate post injection reaction or the
`
`frequency of an injection site reaction relative to daily subcutaneous
`
`administration of 2 mg GA”).) As set forth above, the prior art would not have
`
`even suggested that the claimed regimen would be safe and effective, much less
`
`better than the daily 20 mg regimen that had been used successfully by many
`
`patients for many years. Mylan therefore failed to establish a reasonable
`
`expectation of success.
`
`For these and the reasons discussed below, Mylan has not established a
`
`reasonable likelihood that it will prevail in showing the unpatentability of any of
`
`the challenged claims of the ʼ413 patent and, accordingly, its petition should be
`
`denied in its entirety.
`
`II. THE ʼ413 PATENT
`The ʼ413 patent to Klinger issued on March 19, 2013 from U.S. Appl. No.
`
`12/806,684, which was filed on August 19, 2010 (claiming a priority date of
`
`6
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 11/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
`August 20, 2009). The patent includes 20 claims, 3 of which are independent.
`
`Independent claims 1, 19, and 20 read as follows:
`
`1. A method of reducing the frequency of relapses in a human patient
`suffering from relapsing-remitting multiple sclerosis or a patient who
`has experienced a first clinical episode and has MRI features
`consistent with multiple sclerosis comprising administering to the
`human patient a therapeutically effective dosage regimen of three
`subcutaneous injections of 1 ml of a pharmaceutical composition
`comprising 40 mg of glatiramer acetate over a period of seven days
`with at least one day between every subcutaneous injection, the
`regimen being sufficient to reduce the frequency of relapses in the
`patient.
`19. A method of reducing the frequency of relapses in a human patient
`suffering from relapsing-remitting multiple sclerosis comprising
`administering to the human patient a therapeutically effective dosage
`regimen of three subcutaneous injections of 1 ml of a pharmaceutical
`composition comprising 40 mg of glatiramer acetate over a period of
`seven days with at least one day between every subcutaneous
`injection, wherein the pharmaceutical composition is in a prefilled
`syringe for self administration by
`the patient, wherein
`the
`pharmaceutical composition further comprises mannitol, and wherein
`the pharmaceutical composition has a pH in the range of 5.5 to 7.0,
`the regimen being sufficient to reduce the frequency of relapses in the
`patient
`20. A method of reducing the frequency of relapses in a human patient
`who has experienced a first clinical episode and has MRI features
`
`7
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 12/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
`consistent with multiple sclerosis comprising administering to the
`human patient a therapeutically effective dosage regimen of three
`subcutaneous injections of 1 ml of a pharmaceutical composition
`comprising 40 mg of glatiramer acetate over a period of seven days
`with at least one day between every subcutaneous injection, wherein
`the pharmaceutical composition is in a prefilled syringe for self
`administration by the patient, wherein the pharmaceutical composition
`further comprises mannitol, and wherein
`the pharmaceutical
`composition has a pH in the range of 5.5 to 7.0, the regimen being
`sufficient to reduce the frequency of relapses in the patient.
`
`(Ex. 1001.) The dependent claims are directed to, inter alia, alleviating specific
`
`symptoms associated with a form of disease known as relapsing remitting MS
`
`(“RRMS”). (See e.g., Ex. 1001 at Claims 2-4, 8-11.)
`
`The only treatment regimen disclosed in the ’413 patent involves the
`
`administration of three, and no more than three, 40 mg GA injections in each
`
`seven day period. There is absolutely no disclosure or suggestion of an alternate
`
`day schedule, or any other schedule involving more than three injections in each
`
`seven day period. (See, e.g., id. 4:9-11 (“In another embodiment, there are three
`
`injections for every seven days and there must be at least one day between each
`
`injection.”).) The protocol for a double-blind study disclosed in the specification
`
`compares the “efficacy, safety and tolerability of [GA] injection 40 mg/ml
`
`administered three times weekly” to a placebo treatment. (Id. at 9:11-14; see also
`
`8
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 13/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
`8:59-62 (“The study is designed to select three days a week for injection. Three
`
`injections are administered for every seven days and there must be at least one day
`
`between each injection,” emphasis added).)
`
`III. BACKGROUND FACTS
`A. Multiple Sclerosis
`MS is a neurological disease characterized by an autoimmune attack on the
`
`central nervous system (“CNS”).1 The term “multiple sclerosis” refers to the scars
`
`(scleroses or plaques) that characterize the white matter of the brain and spinal cord
`
`of MS patients. (Id.) The autoimmune attack that drives MS is thought to produce
`
`these scars. (Id.) The disease results in damage to the myelin sheaths (the
`
`insulation surrounding nerve fibers) and injury to the axons (long arm-like
`
`extensions) of the nerve cells. (Id.) This damage interferes with the neurons’
`
`ability to conduct electrical signals, and it is believed that the clinical symptoms
`
`seen in MS patients result from the blockade of electrical conduction that follows
`
`the damage to the myelin sheaths and the loss of axons. (Id.)
`
`A variety of symptoms characterize MS, among them are visual and motor
`
`problems, changes in sensation in the arms and legs, and weakness. (Id.) Greater
`
`
`1 Ex. 2002, Franscisco J. Quintana et al., Systems Biology approaches for the study
`
`of multiple sclerosis, 12 J. CELL. MOL. MED., 2008, at 1087.
`
`9
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 14/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
`than 80% of the patients present with RRMS, which is characterized by discrete
`
`attacks of disability followed by periods of partial or total recovery. (Id.)
`
`Because of the complex and chronic nature of MS, there are significant
`
`obstacles to developing safe and effective therapies for treating the disease.2 First,
`
`the precise cause of MS is unknown. (Ex. 1007 at 133-134.) Lack of a complete
`
`understanding of the causative entity (or entities), or the precise target associated
`
`with instigation of the disease, undermines any expectation of success concerning
`
`therapies proposed to interrupt the disease by focusing on its cause.
`
`In addition, existing animal models differ from humans in terms of both the
`
`pathology of the disease model and the animals’ immunologic responses. And
`
`individual MS patients differ dramatically from one another in clinical
`
`manifestation of the disease and response to therapies.3 Further, no reliable
`
`biomarker exists that allows therapeutic efficacy to be assessed. (Ex. 2003, Virley
`
`
`2 Ex. 2003, David J. Virley, Developing Therapeutics for the treatment of multiple
`
`sclerosis, 2 J. AM. SOC. FOR EXP. NEUROTHERAPEUTICS, October, 2005, at
`
`638.
`
`3 Ex. 2004, Manuel A. Friese, The value of animal models for drug development in
`
`multiple sclerosis, 129 BRAIN, 2006, at 1940; see also id.
`
`10
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 15/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
`at 646.) For these reasons, predicting the efficacy of any particular MS drug or
`
`treatment regimen de novo absent clinical testing is essentially impossible. (Id.)
`
`B. COPAXONE® - Glatiramer Acetate
`GA is the active ingredient in Copaxone. In 1996, the FDA approved
`
`Copaxone to treat RRMS at a dosage of 20 mg, administered daily by
`
`subcutaneous injection. Importantly, that was the only approved dosage of
`
`Copaxone for nearly twenty years until the FDA approved Teva’s 40 mg product in
`
`January 2014. The prescribing information for the 40 mg product states that the
`
`product should be administered “three times per week and at least 48 hours apart.”4
`
`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
`
`synthetic polypeptides of varying length and sequence. The polypeptides are
`
`chains of four naturally occurring amino acid building blocks: L-glutamic acid, L-
`
`alanine, L-lysine, and L-tyrosine. The polypeptides in GA are synthesized by
`
`polymerizing the amino acids such that they attach to one another in almost
`
`random fashion. This polymerization process results in a complex mixture of
`
`many different polypeptides that vary in their length (number of amino acids),
`
`
`4 Ex. 2005, Copaxone Prescribing Information (Jan. 2014) at 1.
`
`11
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 16/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`sequence, and molecular weight. It has been estimated that any of >1030 different
`
`potential polypeptide sequences could be found in Copaxone.5
`
`Even today, using the most sensitive analytical techniques available, it is
`
`impossible to separate and fully characterize all of the molecules present in GA due
`
`to their number and structural complexity. Because the molecules in GA cannot be
`
`fully characterized, and because the target molecules in MS remain unidentified,
`
`the specific molecules in the GA drug that are responsible for its activity remain
`
`unknown. Further complicating this story, GA is, as discussed below, rapidly
`
`degraded into smaller peptides after administration, and it is unknown whether it is
`
`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
`
`at 2.
`
`6 Ex. 2025, McKeage K., Glatiramer Acetate 40 mg/mL in Relapsing-Remitting
`
`Multiple Sclerosis: A Review, CNS DRUGS (Apr. 24, 2015).
`
`12
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 17/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`2. GA’s Mechanism Of Action Is Unknown
`Not only is the active molecule(s) of GA unknown, but the mechanism by
`
`which the drug works is also not fully understood, despite extensive research.7
`
`Several different mechanisms appear to play a role in the drug’s activity, and
`
`additional mechanisms continue to be discovered as research progresses.8 The
`
`currently theorized mechanisms of action suggest that GA works through both
`
`immunomodulatory (shifting the immune response from a pro-inflammatory
`
`response to an anti-inflammatory response) and neuroprotective (causing a
`
`response that protects nervous system tissues) processes.
`
`The mechanism of action of GA, to the extent known, involves a local
`
`immune response to the drug in the subcutaneous tissue that somehow brings about
`
`an anti-inflammatory effect on the diseased brain tissue. A brief explanation of
`
`what is understood about the pathology of MS will provide some backdrop for the
`
`current thinking with respect to GA’s mechanism of action. MS occurs, at least in
`
`part, due to immune cells from outside the CNS entering the brain and causing
`
`damage to the nerve tissues. The precise chain of events leading to this outcome is
`
`
`7 Ex. 2008, Copaxone, Physicians’ Desk Reference 62ed. (2008).
`
`8 See Ex. 2009, W. Schrempf and T. Ziemssen, Glatiramer acetate: Mechanisms of
`
`action in multiple sclerosis, AUTOIMMUN. REV. Aug. 6, 2007, at 471.
`
`13
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 18/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
`still not completely known, but it is believed that so-called “antigen presenting
`
`cells” (or “APCs”) present molecules from the brain tissue or from viral agents (or
`
`something else) to T cells (a type of immune system cell) by displaying the
`
`molecules on the surface of the APCs as part of the “major histocompatibility
`
`complex” (or “MHC”). The T cells are then made reactive against the body’s own
`
`nervous system tissue and acquire the ability to cross the “blood brain barrier” and
`
`gain access to the CNS, where they cause damage.
`
`Copaxone is believed to work through complicated and incompletely
`
`understood mechanisms at several stages in this process:
`
` Copaxone is thought to bind to MHC and alter the immune response
`
`associated with MS;
`
` Copaxone is thought to compete with “self” molecules for binding to
`
`MHC receptors, and thus to alter the autoimmune response;
`
` Copaxone is thought to increase the formation and activation of
`
`beneficial, anti-inflammatory “T-helper type 2” (“Th2”) cells and
`
`decrease the formation of harmful, pro-inflammatory “T-helper
`
`type 1” (“Th1”) cells;
`
` Copaxone is thought to enhance the migration of anti-inflammatory
`
`Th2 cells into the CNS where they cause a decrease in the
`
`inflammation associated with MS; and
`
`14
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 19/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
` Copaxone is thought to protect the neurons and axons in the CNS by
`
`stimulating the release of protective anti-inflammatory chemicals
`
`known as chemokines and cytokines.
`
` (Ex. 2009, Schrempf at 471.9)
`
`No PK/PD Correlation Exists For GA
`
`3.
`While a non-skilled person might make the simplistic assumption that
`
`doubling the dose of a medication would in turn double its efficacy, a skilled
`
`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 pharmacokinetics
`
`(“PK”) of GA, i.e., the speed with which the drug is taken up into and eliminated
`
`from the body, and to correlate the pharmacokinetics with the pharmacodynamic
`
`(“PD”) effects of the drug, i.e., its biochemical and physiologic effects. This is
`
`
`9 See also Ex. 2010, V.Wee Yong, Differential mechanisms of action of interferon-
`
`β and GA in MS, 59 NEUROLOGY, 802-8 (2002); Ex. 2011, Suhayl Dhib-Jalbut,
`
`Mechanisms of action of interferons and [GA] in multiple sclerosis, 58
`
`NEUROLOGY (8 Suppl. 4), S3-S9 (2002).
`
`10 Ex. 2001, Teva press release, Teva provides update on FORTE TRIAL (July
`
`7, 2008), http:www.tevapharm.com (showing that doubling the then-accepted
`
`dosage of GA did not result in any increase in clinical efficacy).
`
`15
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2019 - 20/67
`
`

`
`Case No. IPR2015-00644
`Yeda’s Preliminary Response
`
`because GA cannot be measured in t