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`Filed: July 13, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC.
`Petitioner,
`
`v.
`
`BIOGEN MA, INC.
`Patent Owner.
`
`
`
`Patent No. 8,399,514
`
`
`
`
`Inter Partes Review IPR2018-01403
`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,399,514
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`

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`TABLE OF CONTENTS
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`Page
`
`
`INTRODUCTION .......................................................................................... 1
`I.
`II. MANDATORY NOTICES ............................................................................ 1
`A.
`Real Parties-In-Interest (37 C.F.R. § 42.8 (b)(1)) ................................ 1
`B.
`Related Matters (37 C.F.R. § 42.8(b)(2)) ............................................. 1
`C.
`Identification of Counsel (37 C.F.R. § 42.8(b)(3)) .............................. 3
`D.
`Service Information (37 C.F.R. § 42.8(b)(4)) ...................................... 4
`III. GROUNDS FOR STANDING (37 C.F.R. § 42.101 AND 42.104) .............. 4
`IV.
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED (37 C.F.R. § 42.22(a) and 37
`C.F.R. § 42.104(b)) ......................................................................................... 4
`THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW ............ 6
`V.
`VI. STATEMENT OF REASONS FOR RELIEF REQUESTED ....................... 6
`A.
`Summary of the Argument ................................................................... 6
`B.
`Level of Ordinary Skill in the Art ...................................................... 10
`C.
`The ’514 Patent and its Prosecution ................................................... 11
`1.
`The Treatment of Multiple Sclerosis ....................................... 11
`2.
`The ’514 Patent ........................................................................ 11
`3.
`Prosecution of the ’514 Patent ................................................. 13
`Claim Construction (37 C.F.R. §§ 42.100(b), 42.104(b)(3)) ............. 17
`Scope and Content of the Prior Art .................................................... 18
`1.
`January 2006 Biogen Press Release ......................................... 18
`2.
`Schimrigk 2004 Abstract ......................................................... 19
`3.
`Kappos 2006 ............................................................................ 20
`4. WO ’342 ................................................................................... 21
`5.
`Clinical Trials ........................................................................... 23
`6.
`Joshi ’999 ................................................................................. 24
`7.
`ICH ........................................................................................... 25
`
`D.
`E.
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`TABLE OF CONTENTS
`(continued)
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`Page
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`F.
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`8.
`
`3.
`
`Prior Art Informing the General Knowledge of
`Ordinarily-Skilled Artisans ...................................................... 25
`Summary of Petitioner’s Obviousness Positions ............................... 26
`1.
`Law of Obviousness ................................................................. 26
`2.
`The Use of DMF to Treat Autoimmune Diseases, Such
`As MS, Was Well Known in the Art ....................................... 27
`Skilled Artisans Would Have Been Motivated to Use 480
`mg/day of DMF to Treat MS with a Reasonable
`Expectation of Success ............................................................ 29
`G. Ground 1: Claims 1-20 Are Unpatentable As Obvious Over the
`January 2006 Biogen Press Release in View of the Schimrigk
`2004 Abstract ..................................................................................... 34
`1.
`Independent Claims 1, 11, 15, and 20 are Obvious Over
`the January 2006 Biogen Press Release in View of the
`Schimrigk 2004 Abstract ......................................................... 35
`The Dependent Claims of the ’514 Patent are Obvious
`Over the January 2006 Biogen Press Release in View of
`the Schimrigk 2004 Abstract ................................................... 39
`H. Ground 2: Claims 1-20 Are Unpatentable As Obvious over
`Kappos 2006 in view of the Schimrigk 2004 Abstract ...................... 44
`1.
`Independent Claims 1, 11, 15, and 20 are Obvious over
`Kappos 2006 in view of the Schimrigk 2004 Abstract ............ 44
`The Dependent Claims are Obvious over Kappos 2006
`Press Release in view of the Schimrigk 2004 Abstract ........... 48
`Ground 3: Claims 1-20 Are Unpatentable As Obvious over
`Kappos 2006 in View of WO ’342 .................................................... 48
`1.
`Independent Claims 1, 11, 15, and 20 are Obvious over
`Kappos 2006 in view of WO ’342 ........................................... 48
`The Dependent Claims are Obvious over Kappos 2006 in
`View of WO ’342 ..................................................................... 50
`
`2.
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`2.
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`2.
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`I.
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`-ii-
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`TABLE OF CONTENTS
`(continued)
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`Page
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`
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`J.
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`Ground 4: Claims 1-20 are Unpatentable as Obvious Over
`Kappos 2006, Clinical Trials, Joshi ’999, and ICH ........................... 50
`1.
`Independent Claims 1, 11, 15, and 20 are obvious over
`Kappos 2006, Clinical Trials, Joshi ’999, and ICH ................. 50
`The Dependent Claims are Obvious Over Kappos 2006,
`Clinical Trials, Joshi ’999, and ICH ........................................ 53
`K. Any Purported Secondary Considerations Fail to Overcome
`Prima Facie Obviousness ................................................................... 53
`1.
`The Methods Recited in the ’514 Patent Produced No
`Unexpected Results .................................................................. 54
`The ’514 Patent Satisfied No Long-Felt But Unmet Need ...... 60
`Industry Praise Does Not Overcome Prima Facie
`Obviousness ............................................................................. 60
`This Petition Should Not Be Denied Institution under § 325(d) ....... 61
`L.
`VII. CONCLUSION ............................................................................................. 66
`
`2.
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`2.
`3.
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`-iii-
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`TABLE OF AUTHORITIES
`
`
`Page
`
`
`CASES
`Becton, Dickinson and Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Decision, Paper No. 8 .............................................................. 63
`Becton, Dickson and Co.,
`IPR2017-01586, Paper 8 ..................................................................................... 63
`Boehringer Ingelheim Pharms., Inc. v. Genetech, Inc.,
`IPR2017-02031, 2018 WL 1605267 (PTAB Mar. 29, 2018) ............................. 65
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) ........................................................................................ 17
`Enova Tech. Corp. v. Seagate Tech. (US) Holdings Inc.,
`706 F. App’x 987 (Fed. Cir. 2017) ..................................................................... 61
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 60
`General Plastic Indus. Co. v. Canon Kabushiki Kaisha,
`IPR2016-01357, Paper 19 ..................................................................................... 6
`In re Am. Acad. of Sci. Tech. Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) .......................................................................... 17
`In re Boesch,
`617 F.2d 272 (C.C.P.A. 1980) ............................................................................ 27
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 27
`Merck Sharp & Dohme Corp. v. Pfizer Inc.,
`IPR2017-02138, 2018 WL 1475743 (PTAB Mar. 22, 2018) ............................. 64
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 53
`
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`- iv -
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`

`TABLE OF AUTHORITIES
`(continued)
`
`
`Pfizer, Inc. v. Biogen, Inc.,
`IPR2018-00285, Paper 10 ..................................................................................... 6
`Pfizer, Inc. v. Genentech, Inc.,
`IPR2017-01923, 2018 WL 1666694 (PTAB Apr. 4, 2018) ............................... 65
`Reckitt Benckiser Pharm. Inc. v. Watson Labs., Inc.,
`C.A. Nos. 13-1674-RGA, 14-422-RGA, 2016 WL 3186659 (D.
`Del. June 3, 2016) ............................................................................................... 27
`STATUTES
`35 U.S.C. § 102(a) ....................................................................................... 21, 23, 26
`35 U.S.C. § 102(b) ............................................................................................passim
`35 U.S.C. § 102(e) ............................................................................................. 23, 24
`35 U.S.C. § 103(a) ............................................................................................. 14, 26
`35 U.S.C. § 314(a) ..................................................................................................... 6
`35 U.S.C. § 325(d) ................................................................................................... 61
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`EXHIBIT
`NO.
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`1001
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`1002
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`1003
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`1004
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`1005
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`1006
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`1007
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`1008
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`1009
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`1010
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`LIST OF EXHIBITS
`
`
`DESCRIPTION
`
`U.S. Patent No. 8,399,514, Treatment for Multiple Sclerosis
`(filed Feb. 13, 2012) (issued Mar. 19, 2013)
`
`Declaration of John R. Corboy, M.D.
`
`Declaration of Leslie Benet, Ph.D.
`
`Declaration of Ian McKeague, Ph.D.
`
`Biogen News Release, Phase II Study of Oral Compound BG-
`12 Meets Primary Endpoint in Multiple Sclerosis (Jan. 9, 2006)
`
`S. Schimrigk et al., A Prospective, Open-Label, Phase II Study
`of Oral Fumarate Therapy for the Treatment of Relapsing-
`Remitting Multiple Sclerosis, 10 (Suppl. 2) MULTIPLE
`SCLEROSIS CLIN. & LAB. RES. S258, Abstract P642 (2004)
`
`L. Kappos et al., Efficacy of a Novel Oral Single-Agent
`Fumarate, BG00012, in Patients with Relapsing-Remitting
`Multiple Sclerosis: Results of a Phase 2 Study, 253 (Suppl. 2) J.
`NEUROL. II27, O108 (2006)
`
`International Publication No. WO 2006/0037342 A2 (published
`Apr. 13, 2006)
`
`U.S. Patent No. 7,320,999, Dimethyl Fumarate for the
`Treatment of Multiple Sclerosis (filed July 17, 2002) (issued
`Jan. 22, 2008)
`
`NCT00168701, CLINICALTRIALS.GOV, https://clinicaltrials.gov/
`archive/NCT00168701/2005_09_14
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`EXHIBIT
`NO.
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`1011
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`1012
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`1013
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`1014
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`1015
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`1016
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`LIST OF EXHIBITS
`(continued)
`
`DESCRIPTION
`
`ICH HARMONISED TRIPARTITE GUIDELINE - DOSE-RESPONSE
`INFORMATION TO SUPPORT DRUG REGISTRATION E4 (Mar. 10,
`1994)
`
`S. Schimrigk et al., A Prospective, Open-Label, Phase II Study
`of Oral Fumarate Therapy for the Treatment of Relapsing-
`Remitting Multiple Sclerosis (2004), available at
`http://web.archive.org/web/
`20041021033354/http://www.fumapharm.ch:80/pdf/BG-12_
`Schimrigk_Poster_Final.pdf (“Schimrigk 2004 Poster”)
`
`N. Brune et al., Oral Fumarate Therapy Alters Cytokine
`Production in Patients with Relapsing-Remitting Multiple
`Sclerosis, 10 (suppl. 2) MULTIPLE SCLEROSIS CLIN. & LAB. RES.
`S259, Abstract P643 (2004)
`
`S. Schimrigk et al., An Open-Label, Prospective Study of Oral
`Fumaric Acid Therapy for the Treatment Relapsing-Remitting
`Multiple Sclerosis (RRMS), 64(6)(Suppl. 1) NEUROLOGY A392,
`S46.003 (2005)
`
`L. Kappos et al., A Randomised, Placebo-controlled Phase II
`Trial of a Novel Oral Single-Agent Fumarate Therapy,
`BG00012, in Patients with Relapsing-Remitting Multiple
`Sclerosis, 252 (Suppl. 2) J. NEUROL. II/148, P574 (2005)
`
`Biogen News Release, Oral Compound BG-12 Achieves
`Primary Endpoint in Phase II Study of Relapsing-Remitting
`Multiple Sclerosis; Treatment with BG-12 Led to Statistically
`Significant Reductions in MRI Measures (May 30, 2006)
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`- vii -
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`EXHIBIT
`NO.
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`1017
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`1018
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`1019
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`1020
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`1021
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`1022
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`1023
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`1024
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`1025
`
`1026
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`LIST OF EXHIBITS
`(continued)
`
`DESCRIPTION
`
`C. Nieboer et al., Fumaric Acid Therapy in Psoriasis: A
`Double-Blind Comparison between Fumaric Acid Compound
`Therapy and Monotherapy with Dimethylfumaric Acid Ester,
`181 DERMATOLOGICA 33 (1990)
`
`S. Schimrigk et al., Oral Fumaric Acid Esters for the Treatment
`of Active Multiple Sclerosis: An Open-Label, Baseline-
`Controlled Pilot Study, 13 EUR. J. NEUOL. 604 (2006)
`
`U. Mrowietz et al., Dimethylfumarate for Psoriasis: More than
`a Dietary Curiosity, 11(1) TRENDS MOL. MED. 43 (2005)
`
`Fumaderm® prescribing information
`
`H.M. Ockenfels et al., The Antipsoriatic Agent
`Dimethylfumarate Immunomodulates T-Cell Cytokine Secretion
`and Inhibits Cytokines of the Psoriatic Cytokine Network, 139
`BR. J. DERM. 390 (1998)
`INTENTIONALLY LEFT BLANK
`R. de Jong et al., Selective Stimulation of T Helper 2 Cytokine
`Responses by the Anti-Psoriasis Agent Monomethylfumarate,
`26 EUR. J. IMMUNOL. 2067 (1996)
`
`P. Nibbering et al., Effects of Monomethylfumarate on Human
`Granulocytes, 101 J. INVEST. DERMATOL. 37 (1993)
`
`U.S. Patent No. 6,509,376, Utilization of Dialkyfumarates
`(filed Oct. 29, 1999) (issued Jan 21, 2003)
`
`Biogen News Release, BG-12 Psoriasis Study Meets Primary
`Endpoint; Oral Compound Also Being Studied for MS in Phase
`II Trial (Apr. 7, 2005)
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`EXHIBIT
`NO.
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`LIST OF EXHIBITS
`(continued)
`
`DESCRIPTION
`
`1027
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`1028
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`1029
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`1030
`
`1031
`
`1032
`
`A.D. Ormerod et al., Fumaric Acid Esters, Their Place in the
`Treatment of Psoriasis, 150 BR. J. DERMATOL. 630 (2004)
`
`U. Mrowietz et al., Treatment of Psoriasis with Fumaric Acid
`Esters: Results of a Prospective Multicentre Study, 138(3) BR.
`J. DERMATOL. 456 (1998)
`
`W. Nugteren-Huying et al., Fumaric Acid Therapy for
`Psoriasis: A Randomized, Double-Blind, Placebo-Controlled
`Study,” 22(2) J. AM. ACAD. DERMATOL. 311 (1990)
`
`P. Altmeyer et al., Antipsoriatic Effect of Fumaric Acid
`Derivatives: Results of a Multicenter Double-Blind Study in
`100 Patients, 30 J. AM. ACAD. DERMATOL. 977 (1994)
`
`C. Nieboer et al., Systemic Therapy with Fumaric Acid
`Derivatives: New Possibilities in the Treatment of Psoriasis, 20
`J. AM. ACAD. DERM. 601 (1989)
`
`N. Brune et al., Detection of Altered Intracellular TH1- and
`TH2-Type Cytokine Production of Peripheral Blood
`Mononuclear cells (PBMCs) in Patients with Relapsing-
`Remitting Multiple Sclerosis (RRMS) Undergoing an Oral
`Fumaric-Acid Ester Therapy, 4(4) MULTIPLE SCLEROSIS:
`CLINICAL AND LABORATORY RESEARCH P3038 (1998)
`(ECTRIMS 98:14th Congress of the European Committee for
`Treatment and Research in Multiple Sclerosis, Sept. 9-12,
`1998, Stockholm, Sweden)
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`EXHIBIT
`NO.
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`
`LIST OF EXHIBITS
`(continued)
`
`DESCRIPTION
`
`S. Schimrigk et al., Oral Fumaric Acid Ester (FAE) in
`Relapsing-Remitting Multiple Sclerosis (RRMS). A Short
`Term, Open, clinical, Immunological and Magnetic Resonance
`Imaging (MRI) Controlled Phase II Trial, 246 (Suppl. 1) J.
`NEUROL. I/36, 144 (1999) (Ninth Meeting of the European
`Neurological Society, June 5-9, 1999, Milan, Italy)
`
`L. Kappos et al., A Randomized, Placebo-Controlled Phase 2
`Trial of a Novel Oral Fumarate, BG00012, in Patients with
`Relapsing-Remitting Multiple Sclerosis (15th Meeting of the
`European Neurological Society, June 18-22, 2005), and
`Declaration of Gilmore O'Neill, M.D.
`
`A. Wierinckx et al., Detoxication Enzyme Inducers Modify
`Cytokine Production in Rat Mixed Glial Cells, 166 J.
`NEUROIMMUNOL. 132 (2005)
`
`R. Fox et al., Dimethyl Fumarate to Treat Multiple Sclerosis, in
`MULTIPLE SCLEROSIS THERAPEUTICS 387 (Jeffrey A. Cohen et
`al. eds., 4th ed. 2011)
`
`European Medicines Agency, Assessment Report, Tecfidera
`(Nov. 26, 2013)
`
`R. Gold et al., Placebo-Controlled Phase 3 Study of Oral BG-
`12 for Relapsing Multiple Sclerosis, 367 NEW ENG. J. MED.
`1098 (2012) (“Define Study”)
`
`R. Fox et al., Placebo-Controlled Phase 3 Study of Oral BG-12
`or Glatiramer in Multiple Sclerosis, 367 NEW ENG. J. MED.
`1087 (2012) (“Confirm Study”)
`
`E. Frohman et al., Multiple Sclerosis - The Plaque and its
`Pathogenesis, 354 NEW ENG. J. MED. 942 (2006)
`
`1033
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`1034
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`1035
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`1036
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`1037
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`1038
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`1039
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`1040
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`EXHIBIT
`NO.
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`LIST OF EXHIBITS
`(continued)
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`DESCRIPTION
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`1041
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`1042
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`1043
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`1044
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`1045
`
`J. Miller, The Importance of Early Diagnosis of Multiple
`Sclerosis, 10(3) J. MANAG. CARE PHARM. S4 (2004)
`
`MS Prevalence, NATIONALMSSOCIETY.ORG,
`https://www.nationalmssociety.org/About-the-Society/MS-
`Prevalence (last visited July 9, 2018)
`
`S. Rich et al., Stepped-Care Approach to Treating MS: A
`Managed Care Treatment Algorithm, 10(3) J. MANAG. CARE
`PHARM. S26 (2004)
`
`D. Meier et al., Monitoring Treatment Efficacy with Magnetic
`Resonance Imaging (MRI) in an Open Phase II Study with
`Fumaric-Acid Esters (Fumaderm®) in Patients with relapsing-
`Remitting MS (RRMS), 4(4) MULTIPLE SCLEROSIS: CLINICAL
`AND LABORATORY RESEARCH P3037 (1998) (ECTRIMS
`98:14th Congress of the European Committee for Treatment
`and Research in Multiple Sclerosis, Sept. 9-12, 1998,
`Stockholm, Sweden)
`
`N. Brune et al., Oral Fumaric-Acid Ester Therapy (FAE)
`Influence T-Helper Cell Apoptosis in Peripheral Blood
`Lymphocytes (PBLS) and Soluble Intercellular Adhesion
`Molecule-I (SICAM-1) in Serum of Patients with Relapsing-
`Remitting Multiple Sclerosis (RRMS), 246 (Suppl. 1) J.
`NEUROL. I/61, P272 (1999) (Ninth Meeting of the European
`Neurological Society, June 5-9, 1999, Milan, Italy)
`
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`
`
`EXHIBIT
`NO.
`
`
`LIST OF EXHIBITS
`(continued)
`
`DESCRIPTION
`
`L. Kappos et al., Efficacy of a Novel Oral Single-Agent
`Fumarate, BG00012, in Patients with Relapsing-Remitting
`Multiple Sclerosis: Results of a Phase II Study (16th Meeting
`of the European Neurological Society, May 30, 2006) attached
`as Exhibit C to the Declaration of Katherine T. Dawson in
`Biogen U.S. Patent App. No. 12/526,296 and marked as Ex.
`1018 in Biogen MA Inc. v. Forward Pharma A/S, Interference
`No. 106,023 (“Kappos 2006 Presentation”)
`
`Leon Shargel et al., APPLIED BIOPHARMACEUTICS &
`PHARMACOKINETICS 575-611 (5th ed. 2005)
`
`L. Kappos et al., Efficacy and Safety of Oral Fumarate in
`Patients with Relapsing-Remitting Multiple Sclerosis: A
`Multicentre, Randomised, Double-Blind, Placebo-Controlled
`Phase IIb Study, 372 LANCET 1463 (2008)
`
`FDA GUIDANCE FOR INDUSTRY - NON-INFERIORITY CLINICAL
`TRIALS TO ESTABLISH EFFECTIVENESS (Nov. 2016)
`
`E. de Klerk et al., Patient Compliance in Rheumatoid Arthritis,
`Polymyalgia Rheumatica, and Gout, 30 J. RHEUMATOLOGY 44
`(2003)
`
`A. Paes et al., Impact of Dosage Frequency on Patient
`Compliance, 20(10) DIABETES CARE 1512 (1997)
`
`S. Eisen et al., The Effect of Prescribed Daily Dose Frequency
`on Patient Medication Compliance, 150 ARCH. INTERN. MED.
`1881 (1990)
`
`Prosecution History Excerpts, U.S. Patent No. 8,399,514
`
`Declaration of Robert Mihail
`
`- xii -
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`1046
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`1047
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`1048
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`1049
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`1050
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`1051
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`1052
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`1053
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`1054
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`EXHIBIT
`NO.
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`1055
`
`LIST OF EXHIBITS
`(continued)
`
`DESCRIPTION
`
`Declaration of Jennifer Rock
`
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`
`
`
`
`I.
`
`
`
`INTRODUCTION
`Mylan Pharmaceuticals Inc. (“Petitioner”) petitions for Inter Partes Review
`
`of claims 1-20 of U.S. Patent No. 8,399,514 (“the ’514 patent”) (Ex. 1001), which
`
`is assigned to Biogen MA Inc. (“Patent Owner”), under 35 U.S.C. §§ 311-319 and
`
`37 C.F.R. § 42 and seeks a determination that all claims (1-20) of the ’514 patent
`
`be canceled as unpatentable.
`
`This Petition is filed in accordance with 37 C.F.R. § 42.106(a). Filed
`
`herewith is a power of attorney and exhibit list per § 42.10(b) and § 42.63(e).
`
`Pursuant to 37 C.F.R. § 42.103, the fee set forth in § 42.15(e) accompanies this
`
`Petition.
`
`II. MANDATORY NOTICES
`A. Real Parties-In-Interest (37 C.F.R. § 42.8 (b)(1))
`The real parties-in-interest for Petitioner are Mylan Pharmaceuticals Inc.,
`
`Mylan Laboratories Ltd., Mylan Inc., and Mylan N.V.
`
`B. Related Matters (37 C.F.R. § 42.8(b)(2))
`Petitioner is not aware of any reexamination certificates or pending
`
`prosecution concerning the ’514 patent. Petitioner is a defendant to the following
`
`litigation involving the ’514 patent:
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`
`
`Biogen Int’l GmbH v. Mylan Pharm. Inc., C.A. No. 17-cv-116-IMK
`
`(N.D.W. Va.).
`
`Other pending litigations involving the ’514 patent: Biogen Int’l GmbH v.
`
`Amneal Pharms LLC, C.A. No. 17-cv-00823-LPS (consolidated) (D. Del.); Biogen
`
`MA Inc. v. Caribe Holdings (Cayman) Co. Ltd., C.A. No. 18-cv-00121-LPS (D.
`
`Del.); Biogen Int’l GmbH v. Sandoz Inc., C.A. No. 17-cv-00874-LPS (D. Del.);
`
`Biogen Int’l GmbH v. Accord Healthcare Inc., C.A. No. 17-cv-00872-LPS (D.
`
`Del.); Biogen Int’l GmbH v. Sawai USA, Inc., C.A. No. 17-cv-00875 (D. Del.);
`
`Biogen MA Inc. v. Shipla Medicare Ltd., C.A. No. 17-cv-00847-LPS (D. Del.);
`
`Biogen MA Inc. v. Sun Pharma Global FZE, C.A. No. 17-cv-00848-LPS (D. Del.);
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`Biogen MA Inc. v. Windlas Healthcare, Pvt. Ltd., C.A. No. 17-cv-00849-LPS (D.
`
`Del.); Biogen Int’l GmbH v. Alkem Labs Ltd., , C.A. No. 17-cv-00850-LPS (D.
`
`Del.); Biogen Int’l GmbH v. Cipla Ltd., C.A. No. 17-cv-00851-LPS (D. Del.);
`
`Biogen Int’l GmbH v. Glenmark Pharm. Ltd., C.A. No. 17-cv-00852-LPS (D.
`
`Del.); Biogen Int’l GmbH v. Lupin Atlantis Holdings SA, C.A. No. 17-cv-00853-
`
`LPS (D. Del.); Biogen Int’l GmbH v. Torrent Pharm. Ltd., C.A. No. 17-cv-00854-
`
`LPS (D. Del.); Biogen Int’l GmbH v. Pharmathen S.A., C.A. No. 17-cv-00855-LPS
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`(D. Del.); Biogen Int’l GmbH v. Twi Pharms., Inc., C.A. No. 17-cv-00856-LPS (D.
`
`Del.); Biogen Int’l GmbH v. Macleods Pharm., Ltd., C.A. No. 17-cv-00857-LPS
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`(D. Del.); Biogen MA Inc. v. Graviti Pharms. Pvt. Ltd., 17-cv-00846-LPS (D.
`
`2
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`
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`Del.); Biogen Int’l GmbH v. MSN Labs. Pvt. Ltd., C.A. No. 17-cv-00845-LPS (D.
`
`Del.); Biogen Int’l GmbH v. Zydus Pharms. (USA) Inc., C.A. No. 17-cv-00954-
`
`LPS (D. Del.); Biogen Int’l GmbH v. Banner Life Sciences LLC, C.A. No. 18-cv-
`
`00582-LPS (D. Del.); Biogen Int’l GmbH v. Aurobindo Pharma U.S.A., Inc., C.A.
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`No. 17-cv-00824-LPS (D. Del.); Biogen Int’l GmbH v. Hetero USA Inc., C.A. No.
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`17-cv-00825-LPS (D. Del.); Biogen MA Inc. v. Impax Labs., Inc., C.A. No. 17-cv-
`
`00826-LPS (D. Del.); Biogen MA Inc. v. Prinston Pharm. Inc., C.A. No. 17-cv-
`
`00827-LPS (D. Del.); Biogen MA Inc. v. Slayback Pharma LLC, C.A. No. 17-cv-
`
`00828-LPS (D. Del.).
`
`Other proceedings in front of the Patent Trial and Appeal Board include:
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`Coalition for Affordable Drugs V LLC v. Biogen MA Inc., IPR2015-01993;
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`Coalition for Affordable Drugs V LLC v. Biogen MA Inc., IPR2015-01136; Biogen
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`MA Inc., v. Forward Pharma A/S, Patent Interference 106,023.
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`Patent applications in the same patent family are pending as U.S. Patent
`
`Application Nos. 15/959,651, 15/988,578, and 15/983,837.
`
`C.
`
`Identification of Counsel (37 C.F.R. § 42.8(b)(3))
`Lead Counsel
`Back-Up Counsel
`Brandon M. White (Reg. No. 52,354)
`Emily J. Greb (Reg. No. 68,244)
`Perkins Coie LLP
`Perkins Coie LLP
`1 East Main Street, Suite 201
`700 Thirteenth Street, N.W.
`Madison, WI 53703
`Suite 600
`Telephone: (608) 663-7494
`Washington, D.C. 20005
`Facsimile: (608) 283-4494
`Telephone: (202) 654-6206
`Facsimile: (202) 654-9681
`egreb@perkinscoie.com
`
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`bmwhite@perkinscoie.com
`D.
`Service Information (37 C.F.R. § 42.8(b)(4))
`Petitioner respectfully request that all correspondence be directed to lead
`
`
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`counsel and back-up counsel at the contact information provided above. Petitioner
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`consents to electronic service by e-mail at the following email addresses:
`
`bmwhite@perkinscoie.com;
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`egreb@perkinscoie.com; and
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`Tecfidera@perkinscoie.com.
`
`III. GROUNDS FOR STANDING (37 C.F.R. § 42.101 AND 42.104)
`Pursuant to 37 C.F.R. § 42.104(a), Petitioner certifies that the ’514 patent is
`
`available for inter partes review and that the Petitioner is not barred or estopped
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`from requesting inter partes review on the grounds identified herein.
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`IV.
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`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED (37 C.F.R. § 42.22(A) AND 37 C.F.R.
`§ 42.104(B))
`Petitioner respectfully requests inter partes review and cancellation of
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`claims 1-20 on the grounds set forth below.
`
`Ground 1: Claims 1-20 of the ’514 patent are obvious over the January
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`2006 Biogen Press Release in view of the Schimrigk 2004 Abstract.
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`Ground 2: Claims 1-20 of the ’514 patent are obvious over Kappos 2006 in
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`view of the Schimrigk 2004 Abstract.
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`Ground 3: Claims 1-20 of the ’514 patent are obvious over Kappos 2006 in
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`view of WO ’342.
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`Ground 4: Claims 1-20 of the ’514 patent are obvious over Kappos 2006,
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`Clinical Trials, Joshi ’999, and ICH.
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`Petitioner’s full statement of the reasons for the relief is set forth below. In
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`support of these grounds for unpatentability, Petitioner submits the expert
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`declarations of Dr. John Corboy (Ex. 1002 (“Corboy Decl.”)), Dr. Leslie Benet
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`(Ex. 1003 (“Benet Decl.”)), and Dr. Ian McKeague (Ex. 1004 (“McKeague
`
`Decl.”)), and also relies on other Exhibits set forth in the concurrently-filed Listing
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`of Exhibits
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`Statement of No Redundancy: This is the first petition for inter partes
`
`review of the ’514 patent by Petitioner. Grounds 1-3 presented in this Petition
`
`have not previously been before the Board. Ground 4 was previously decided by
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`the Board based on Patent Owner’s presentation of unexpected results, and a
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`complete failure on the part of the previous petitioner, the Coalition for Affordable
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`Drugs, to present rebuttal evidence on unexpected results. See IPR2015-01993,
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`Paper 63 at 25-27. This Petition provides such rebuttal evidence. Additional detail
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`is presented in this Petition infra at Section L detailing why the new evidence,
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`arguments, and art presented in this petition.
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`V. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
`A petition for inter partes review must demonstrate a “reasonable likelihood
`
`that the petitioner would prevail with respect to at least 1 of the claims challenged
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`in the petition.” 35 U.S.C. § 314(a). This Petition clears that threshold. There is a
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`reasonable likelihood that Petitioner will prevail with respect to at least one of the
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`challenged claims. Moreover, it would be an inappropriate exercise of the Board’s
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`discretion to deny institution here under § 314(a). First, Mylan Pharmaceuticals
`
`Inc. has not previously filed a petition for inter partes review of the ’514 patent.
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`Moreover, the timing of this Petition does not suggest any delay by Petitioner;
`
`Petitioner was not involved in the earlier petitions filed by the Coalition for
`
`Affordable Drugs. Petitioner has filed this Petition within the statutory time frame
`
`for filing its Petition asserting additional arguments and evidence. See General
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`Plastic Indus. Co. v. Canon Kabushiki Kaisha, IPR2016-01357, Paper 19; see also
`
`e.g., Pfizer, Inc. v. Biogen, Inc., IPR2018-00285, Paper 10 at 22-25.
`
`VI. STATEMENT OF THE REASONS FOR THE RELIEF REQUESTED
`Summary of the Argument
`A.
`The claims of the ’514 patent are directed towards treating multiple sclerosis
`
`(“MS”) with 480 mg/day of dimethyl fumarate (“DMF”). The treatment of MS
`
`with DMF is nothing new; skilled artisans had known for years prior to the earliest
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`priority date of the ’514 patent that DMF was an efficacious MS treatment. To
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`extend patent protection on DMF for the treatment of MS, Patent Owner simply
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`chose a dose—480 mg/day—that fell squarely within a predictable range of
`
`efficacious doses, and claimed that it “unexpectedly” achieved similar efficacy to
`
`the existing 720 mg/day DMF dose that was known to be efficacious. While
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`Patent Owner’s alleged unexpected results argument caused the Board to find the
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`’514 patent claims not unpatentable when the argument went unrebutted in a
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`petition by the Coalition for Affordable Drugs, this Petition provides new evidence
`
`that proves skilled artisans would have expected efficacy. As detailed below,
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`Biogen’s unexpected results argument rests on a faulty premise: that 360 mg/day
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`of DMF is not efficacious. This Petition demonstrates that is not so, and the wealth
`
`of data available to skilled artisans would have led them directly to dosing DMF at
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`480 mg/day.
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`DMF has been studied extensively and used since the 1990s. DMF was used
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`in combination with monoethyl fumarate (MEF) salts, a composition known as
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`Fumaderm®. Fumaderm® has been commercially available in Germany since the
`
`1990s, and is a well-known treatment for psoriasis. Like MS, psoriasis is an
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`autoimmune disease. Studies throughout the 1990s also demonstrated that DMF is
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`the most active component in Fumaderm®. Skilled artisans believed that MEF
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`salts (Fumaderm®’s other component) provided little efficacy. Prior art studies
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`also demonstrated that a 480 mg/day dose of DMF was effective to treat psoriasis.
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`During the early 2000s, skilled artisans investigated treating MS with
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`Fumaderm®, because of certain similarities between MS and psoriasis.
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`Unsurprisingly, Fumaderm® was found to be an MS effective treatment in a prior
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`art study by Schimrigk. Schimrigk found that Fumaderm® doses containing 360
`
`mg/day and 720 mg/day of DMF were effective to treat MS. Skilled artisans also
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`knew that DMF was associated with certain bothersome dose-dependent side
`
`effects, such as flushing and gastrointestinal issues.
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`In the mid-2000s, Biogen conducted a clinical trial to gain approval to
`
`market DMF to treat MS. This study (the “Kappos study” or the “phase II study”)
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`tested DMF at concentrations of 120 mg/day (once daily), 360 mg/day (three times
`
`daily) and 720 mg/day (three times daily). Given the wealth of knowledge skilled
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`artisans had before the Kappos study, it was not surprising that in January 2006
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`Biogen announced in a press release that its trial had successfully met its primary
`
`endpoint.
`
`In May 2006, Kappos published an abstract and presented his study results.
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`He reported that the 720 mg/day DMF dose demonstrated a “statistically
`
`significant response” and that the response was “dose-dependent.” Again, none of
`
`this was surprising given skilled artisans’ knowledge about the efficacy of DMF in
`
`treating MS. Taking this knowledge, together with DMF’s well-known side-effect
`
`profile, a skilled artisan would have had all she needed to optimize the DMF dose.
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`A dose of 480 mg/day was well within the predictably efficacious range of doses in
`
`MS; had been shown previously to be effective in treating psoriasis; would have
`
`been expected to improve the tolerability of DMF therapy; and was simple to
`
`administer twice a day, and thereby expected to improve compliance versus typical
`
`thrice daily dosing.
`
`Biogen argued extensively during examination and before this Board that it
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`was “unexpected” that 480 mg/day DMF exhibited similar efficacy to 720 mg/day
`
`DMF. In a May 2006 Press Release reporting on the Kappos study, Biogen stated
`
`that the 360 mg/day dose did not achieve “statistically significant” efficacy versus
`
`placebo. Based on that finding, Biogen argued that it is surprising that 480 mg/day
`
`is as efficacious as 720 mg/day because 480 is numerically closer to 360 than to
`
`720. That argument is legally and scientifically unsound, and ignores data
`
`suggesting 360 mg/day is an efficacious dose.
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`When Kappos presented his data at a conference in May 2006, he provided a
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`slide presentation showing the baseline disease activity for each of the study’s
`
`treatment groups (placebo, 120 mg/day, 360 mg/day and 720 mg/day). Skilled
`
`artisans would have immediately noticed that the baseline disease activity for the
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`360 mg/day group was markedly higher than the baseline disease activity for the
`
`other groups, and it did not appear Kappos had accounted for the difference.
`
`Several later publications—including one by the lead clinical investigators of
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`Biogen’s Phase III DMF trials—recognized this flaw and corrected for it, finding
`
`that the 360 mg/day dose likely was, in fact, efficacious. This is powerful new
`
`evidence rebutting unexpected results not previously before the Patent Office or
`
`Board.
`
`In short, before the priority date, skilled artisans knew that DMF was an
`
`effective MS treatment; expected that doses between 360 mg/day and 720 mg/day
`
`would be effective; and would have looked to optimize the dose to reduce side
`
`effects and enhance p