UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`COALITION FOR AFFORDABLE DRUGS V LLC,
`Petitioner,
`
`v.
`
`BIOGEN MA INC.,
`Patent Owner.
`__________
`
`Case IPR2015-01136
`Patent 8,399,514 B2
`__________
`
`
`
`BIOGEN’S PRELIMINARY RESPONSE
`
`
`
`
`
`

`
`Case No. IPR2015-01136
`Patent 8,399,514
`
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`Introduction ...................................................................................................... 1
`
`The ’514 Patent Properly Claims Priority to Its Provisional
`Application ...................................................................................................... 4
`
`III. The Petition Fails to Construe the Term “Therapeutically Effective
`Amount” or Present Any Evidence Addressing That Claim Element ............ 5
`
`IV. The Petition Fails to Address Reasonable Expectation of Success ................. 8
`
`V.
`
`Claims 1-20 Would Not Have Been Obvious Over Kappos 2005 in
`View of ICH Guideline E4 ............................................................................ 12
`
`A.
`
`The Petition Does Not Prove That BG00012 in Kappos 2005
`Refers to DMF ..................................................................................... 12
`
`B. One Would Not Have Added a Fifth Dose to the Proposed
`Study of Kappos 2005 ......................................................................... 14
`
`C. One Would Not Have Reasonably Expected from Kappos 2005
`in View of ICH Guideline E4 That a Dose of About 480
`mg/day Would Be Therapeutically Effective or Useful ...................... 16
`
`1.
`
`Kappos 2005 and ICH Guideline E4 Disclose No Results ....... 16
`
`VI. Claims 1-20 Would Not Have Been Obvious Over ClinicalTrials
`NCT00168701 in View of ICH Guideline E4 ............................................... 20
`
`A.
`
`The Petition Fails to Prove That the ClinicalTrials Document Is
`Prior Art ............................................................................................... 20
`
`B. One Would Not Have Added a Fifth Dose to the Proposed
`Study of ClinicalTrials NCT00168701 ............................................... 22
`
`C. One Would Not Have Reasonably Expected from ClinicalTrials
`NCT00168701 in View of ICH Guideline E4 That a Dose of
`About 480 mg/day Would Be Therapeutically Effective or
`Useful .................................................................................................. 23
`
`VII. Claims 1-20 Would Not Have Been Obvious Over Alleged Admitted
`Prior Art in View of ICH Guideline E4 ......................................................... 25
`
`i
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`

`
`Case No. IPR2015-01136
`Patent 8,399,514
`
`A. An Alleged Admission Is Not a Patent or Printed Publication ........... 25
`
`B.
`
`C.
`
`The Alleged ’514 Patent Admission and ICH Guideline E4 Fail
`to Disclose or Suggest Each Claim Element ....................................... 28
`
`The Petition Identifies No Reason to Modify the Alleged ’514
`Patent Admission in View of ICH Guideline E4 ................................ 29
`
`D. One Would Not Have Reasonably Expected from the Alleged
`’514 Patent Admission in View of ICH Guideline E4 That a
`Dose of About 480 mg/day Would Be Therapeutically Effective
`or Useful .............................................................................................. 30
`
`VIII. The Petition Fails to Rebut the Record Evidence of Unexpected
`Results ............................................................................................................ 31
`
`A.
`
`B.
`
`The Claimed Invention Exhibits Unexpected Results ........................ 31
`
`The Petition Disregards the Claimed Invention’s Unexpected
`Efficacy................................................................................................ 36
`
`IX. The Board Should Exercise Its Discretion to Deny Institution ..................... 39
`
`X.
`
`The Petition Fails to Name All Real Parties-in-Interest ................................ 41
`
`XI. Conclusion ..................................................................................................... 43
`
`
`
`
`
`ii
`
`

`
`Case No. IPR2015-01136
`Patent 8,399,514
`
`
`TABLE OF AUTHORITIES
`
`Cases
`
`Page(s)
`
`Actavis, Inc. v. Research Corp. Techs., Inc.,
`IPR2014-01126, Paper 22 (PTAB Jan. 9, 2015) ................................................ 22
`
`Amgen Inc. v. F. Hoffmann-La Roche Ltd.,
`580 F.3d 1340 (Fed. Cir. 2009) ............................................................................ 9
`
`In re Baird,
`16 F.3d 380 (Fed. Cir. 1994) .............................................................................. 12
`
`Berk-Tek, LLC v. Belden Inc.,
`IPR2013-00057, Paper 46 (PTAB Mar. 18, 2014) ............................................. 28
`
`BioGatekeeper, Inc. v. Kyoto Univ.,
`IPR2014-01286, Paper 12 (PTAB Feb. 11, 2015) ........................................ 11, 20
`
`Biomune Co. v. Merial,
`IPR2015-00254, Paper 11 (PTAB May 21, 2015) ....................................... 17, 24
`
`Broadcom Corp. v. Emulex Corp.,
`732 F.3d 1325 (Fed. Cir. 2013) ................................................................ 9, 11, 20
`
`Bulk Lift Int’l Inc. v. Flexcon & Sys., Inc.,
`122 F.R.D. 493 (W.D. La. 1988) ........................................................................ 26
`
`CCS Fitness, Inc. v. Brunswick Corp.,
`288 F.3d 1359 (Fed. Cir. 2002) ............................................................................ 6
`
`Cisco Sys., Inc. v. Constellation Techs. L.L.C.,
`IPR2014-01085, Paper 11 (PTAB Jan. 9, 2015) ................................................ 20
`
`Coalition for Affordable Drugs II LLC v. NPS Pharm., Inc.,
`IPR2015-00990, Paper 14 and IPR2015-01093, Paper 13
`(PTAB July 2, 2015) ........................................................................................... 41
`
`Creative Compounds, LLC v. Starmark Labs.,
`651 F.3d 1303 (Fed. Cir. 2011) .......................................................................... 38
`
`In re Cuozzo Speed Techs., LLC,
`No. 2014-1301, 2015 WL 4097949 (Fed. Cir. July 8, 2015) ............................... 6
`
`iii
`
`

`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) ...................................................................passim
`
`Case No. IPR2015-01136
`Patent 8,399,514
`
`
`Google Inc. v. B.E. Tech., L.L.C.,
`IPR2014-00038, Paper 9 (PTAB Apr. 9, 2014) ................................................. 27
`
`Graham v. John Deere Co. of Kansas City,
`383 U.S. 1 (1966) ............................................................................................ 5, 13
`
`Hybritech Inc. v. Monoclonal Antibodies, Inc.,
`802 F.2d 1367 (Fed. Cir. 1986) .................................................................... 36, 37
`
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`IPR2013-00324, Paper 19 (PTAB Nov. 21, 2013) ............................................. 40
`
`Intri-Plex Techs., Inc. v. Saint-Gobain Performance Plastics Rencol Ltd.,
`IPR2014-00309, Paper 15 (PTAB June 10, 2014) ............................................. 27
`
`Intri-Plex Techs., Inc. v. Saint-Gobain Performance Plastics Rencol Ltd.,
`IPR2014-00309, Paper 83 (PTAB Mar. 23, 2015) ............................................. 26
`
`Johnston v. IVAC Corp.,
`885 F.2d 1574 (Fed. Cir. 1989) .......................................................................... 38
`
`Kinetic Techs., Inc. v. Skywork Solutions, Inc.,
`IPR 2014-00529, Paper 8 (PTAB Sept. 23, 2014) .............................................. 10
`
`Knoll Pharm. Co. v. Teva Pharm. USA, Inc.,
`367 F.3d 1381 (Fed. Cir. 2004) .......................................................................... 36
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .................................................................................. 9, 15, 29
`
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) .......................................................................... 19
`
`LG Elecs., Inc. v. Advanced Micro Devices, Inc.,
`IPR2015-00329, Paper 13 (PTAB July 10, 2015) .............................................. 21
`
`Liberty Mutual Ins. Co. v. Progressive Casual Ins. Co.,
`CBM2012-00003, Paper 8 (PTAB Oct. 25, 2012) ....................................... 29, 30
`
`iv
`
`

`
`In re Lister,
`583 F.3d 1307 (Fed. Cir. 2009) .......................................................................... 20
`
`Case No. IPR2015-01136
`Patent 8,399,514
`
`
`Ex parte McGaughey,
`6 U.S.P.Q.2d 1334 (BPAI Mar. 4, 1988) ...................................................... 25, 26
`
`Microsoft Corp. v. Proxyconn, Inc.,
`IPR2012-00026, Paper 17 (PTAB Dec. 21, 2012) ............................................... 6
`
`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1372 (Fed. Cir. 2012) .......................................................................... 10
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) ............................................................ 6
`
`Pride Solutions, LLC v. Not Dead Yet Mfg., Inc.,
`IPR2013-00627, Paper 14 (PTAB Mar. 17, 2014) ............................................. 27
`
`Ex parte Raychem Corp.,
`25 U.S.P.Q.2d 1265 (BPAI June 30,1992) ......................................................... 26
`
`Smiths Indus. Med. Sys., Inc. v. Vital Signs, Inc.,
`183 F.3d 1347 (Fed. Cir. 1999) ........................................................................ 5, 8
`
`In re Soni,
`54 F.3d 746 (Fed. Cir. 1995) .............................................................................. 37
`
`SRI Int’l Inc. v. Internet Sec. Sys., Inc.,
`511 F.3d 1186 (Fed. Cir. 2008) .......................................................................... 22
`
`Tasco, Inc. v. Pagnani,
`IPR2013-00103, Paper 6 (PTAB May 23, 2013) ......................................... 27, 28
`
`TRW Auto. US LLC v. Magna Elecs., Inc.,
`IPR2014-00258, Paper 18 (PTAB Aug. 27, 2014) ............................................. 10
`
`Zetec, Inc. v. Westinghouse Elec. Co.,
`IPR2014-00384, Paper 10 (PTAB July 23, 2014) .......................................... 5, 30
`
`
`
`v
`
`

`
`Federal Statutes
`
`Case No. IPR2015-01136
`Patent 8,399,514
`
`
`35 U.S.C. § 102 .............................................................................................. 4, 20, 22
`
`35 U.S.C. § 119 .......................................................................................................... 5
`
`35 U.S.C. § 301 .................................................................................................. 25, 26
`
`35 U.S.C. § 302 ........................................................................................................ 26
`
`35 U.S.C. § 305 ........................................................................................................ 26
`
`35 U.S.C. § 311 ...................................................................................... 20, 25, 26, 40
`
`35 U.S.C. § 312 ........................................................................................................ 29
`
`35 U.S.C. § 314 ............................................................................................ 22, 40, 41
`
`35 U.S.C. § 316 .................................................................................................. 40, 41
`
`Regulations
`
`37 C.F.R. § 1.41 ......................................................................................................... 4
`
`37 C.F.R. § 1.132 ..................................................................................................... 32
`
`37 C.F.R. § 42.12 ..................................................................................................... 40
`
`37 C.F.R. § 42.104 ............................................................................................passim
`
`37 C.F.R. § 42.107 ..................................................................................................... 1
`
`37 C.F.R. § 42.108 ....................................................................................... 17, 24, 40
`
`Other Authorities
`
`H.R. REP. NO. 112-98, pt. 1 (2011) .......................................................................... 25
`
`
`
`
`
`vi
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`

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`Case No. IPR2015-01136
`Patent 8,399,514
`
`
`TABLE OF ABBREVIATIONS
`
`Definition
`
`dimethyl fumarate
`
`monomethyl fumarate
`
`multiple sclerosis
`
`
`
`
`
`vii
`
`Abbreviation
`
`DMF
`
`MMF
`
`MS
`
`

`
`I.
`
`Introduction
`
`Case No. IPR2015-01136
`Patent 8,399,514
`
`
`Patent Owner Biogen MA Inc. respectfully submits this preliminary
`
`response under 37 C.F.R. § 42.107 to the Petition for Inter Partes Review of U.S.
`
`Patent No. 8,399,514 (“the ’514 patent”).
`
`The ’514 patent claims a method of treating a subject in need of treatment
`
`for multiple sclerosis (“MS”) by orally administering a therapeutically effective
`
`amount of about 480 mg/day of dimethyl fumarate (“DMF”), monomethyl
`
`fumarate (“MMF”), or a combination thereof. The Petition asserts that claims 1-20
`
`are unpatentable as obvious over Kappos 2005 or ClinicalTrials NCT00168701 or
`
`alleged ’514 patent admissions in view of ICH Guideline E4. (See Am. Pet. at 6.)
`
`The Guideline provides general guidance on dose-ranging clinical studies.
`
`Petitioner contends that, based on the Guideline, it would have been obvious to
`
`modify the planned dose-ranging studies of Kappos 2005 or ClinicalTrials
`
`NCT00168701 to arrive at the claimed dose of DMF of about 480 mg/day. The
`
`proposed grounds of unpatentability, however, lack merit for several reasons,
`
`including:
`
`1.
`
`The Petition fails to construe the claim term “therapeutically effective
`
`amount” or to present any evidence addressing this claim element. Thus, the
`
`Petition does not present a proper Graham obviousness analysis, which requires
`
`comparing each claim as a whole (with all of its properly construed elements) to
`
`1
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`Case No. IPR2015-01136
`Patent 8,399,514
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`the prior art. For the same reason, the Petition does not comply with the Board’s
`
`requirement for a detailed comparison between each claim element and the prior
`
`art. See 37 C.F.R. § 42.104(b)(4).
`
`2.
`
`The Petition never even alleges, much less proves, any reasonable
`
`expectation of success. Indeed, it is silent as to why one of ordinary skill would
`
`have had a reasonable expectation of success in combining the teachings of the
`
`cited references to achieve the claimed invention. Because the Petition never
`
`addresses this legal requirement for obviousness, it cannot establish a reasonable
`
`likelihood that any claim is unpatentable.
`
`3.
`
`The Petition fails to address the unexpected results evidenced by the
`
`claimed invention. During prosecution of the ’514 patent, the applicant proved that
`
`it was unexpected that a dose of about 480 mg/day of DMF was similarly effective
`
`for treating a patient with MS as a dose of 720 mg/day. The Petition and
`
`supporting declaration of Dr. Linberg never mention (much less rebut) these
`
`unexpected results. This unrebutted evidence of unexpected results precludes any
`
`reasonable likelihood that any claim is unpatentable for obviousness.
`
`4.
`
`The Petition asserts that, based on ICH Guideline E4, one of ordinary
`
`skill would have added a fifth dose to the planned dose-ranging studies of Kappos
`
`2005 or ClinicalTrials NCT00168701. But the Petition disregards the most relevant
`
`portion of the Guideline, which states that a “widely used, successful and
`
`2
`
`

`
`acceptable design” for a dose-ranging study is a parallel, randomized dose-
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`Case No. IPR2015-01136
`Patent 8,399,514
`
`
`response study “with three or more dosage levels, one of which may be zero
`
`(placebo).” (Ex. 1004A at 9 (emphasis added).) The Kappos 2005 and
`
`ClinicalTrials references, cited by Petitioner, describe planned dose-ranging
`
`studies with four proposed doses, fully satisfying the Guideline. Nothing in the
`
`Guideline requires testing five or more doses or any particular spacing between
`
`doses. Thus, the Guideline itself refutes Petitioner’s obviousness theory.
`
`5.
`
`Because the Kappos 2005 and ClinicalTrials references only describe
`
`planned clinical studies, they disclose no results for any planned dose of DMF,
`
`making it impossible to predict based on these disclosures whether any particular
`
`dose (including about 480 mg/day) would be therapeutically effective or useful for
`
`treating a patient with MS. Petitioner’s obviousness theory is thus based solely on
`
`improper hindsight reasoning rather than any suggestion in the prior art to select
`
`the claimed dose.
`
`6.
`
`Petitioner fails to meet its burden to prove that “BG00012” in Kappos
`
`2005 refers to DMF. It relies on the ClinicalTrials document to link the designation
`
`“BG00012” to DMF. But the Petition only presents evidence that the ClinicalTrials
`
`document was downloaded in April 2015, not that it was publicly available before
`
`the February 2007 priority date of the ’514 patent. Petitioner has therefore not met
`
`its burden to prove that the ClinicalTrials document is a prior art printed
`
`3
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`Case No. IPR2015-01136
`Patent 8,399,514
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`publication under 35 U.S.C. § 102(b) (pre-AIA). This failure of proof precludes
`
`reliance on the ClinicalTrials document for any purpose, including to link
`
`“BG00012” to DMF.
`
`Accordingly, for these and other reasons developed below, Petitioner has not
`
`shown that it is likely to prove that any claim of the ’514 patent is unpatentable.
`
`The Board should therefore deny institution of an inter partes review.
`
`II. The ’514 Patent Properly Claims Priority to Its Provisional Application
`The Petition asserts that the ’514 patent is not entitled to the benefit of the
`
`February 8, 2007 filing date of U.S. Provisional Application No. 60/888,921
`
`because no inventor was named on the provisional’s cover sheet. (Am. Pet. at 10-
`
`11.) This is incorrect. Although no inventor was named on the original cover sheet,
`
`a revised cover sheet listing Matvey E. Lukashev as inventor was filed on April 20,
`
`2007, in response to a notice of missing parts. See pre-AIA 37 C.F.R. § 1.41(a)(2)
`
`(Ex. 2008 at 55.) The Office then issued an updated filing receipt listing Lukashev
`
`as inventor and confirming the filing date of February 8, 2007. (Id. at 61-66.)
`
`Thus, the publicly available prosecution history shows that an inventor was
`
`named, and Petitioner’s assertion to the contrary is incorrect. (See Am. Pet. at 11
`
`(acknowledging that inventors may be named during pendency of a provisional
`
`application under 37 C.F.R. § 1.41(a)(2)).)
`
`4
`
`

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`Case No. IPR2015-01136
`Patent 8,399,514
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`Lukashev was subsequently named as an inventor for PCT/US/2008/001602,
`
`in parent Application No. 12/526,296, and in Application No. 13/372,426, which
`
`led to the ’514 patent. (Ex. 1014A at 8; Ex. 2010 at 1, 5; Ex. 2011 at 1, 3.)
`
`Accordingly, continuity of inventorship exists under 35 U.S.C. § 119(e), and the
`
`’514 patent is entitled to the ’921 provisional’s February 2007 filing date. Further,
`
`the Petition does not rely on any intervening prior art that would benefit from a
`
`lack of priority. Thus, Petitioner’s assertion concerning alleged lack of priority is
`
`factually incorrect and irrelevant to the asserted grounds of obviousness.
`
`III. The Petition Fails to Construe the Term “Therapeutically Effective
`Amount” or Present Any Evidence Addressing That Claim Element
`
`The Petition asserts that claims 1-20 are obvious over Kappos 2005 or
`
`ClinicalTrials NCT00168701 or alleged ’514 patent admissions in view of ICH
`
`Guideline E4. (See, e.g., Am. Pet. at 6, 16.) Thus, although the Petition purports to
`
`raise one “Ground” of obviousness, in fact it advances three distinct grounds
`
`(addressed individually in Sections V-VII below). See Zetec, Inc. v. Westinghouse
`
`Elec. Co., IPR2014-00384, Paper 10 at 7 (PTAB July 23, 2014).
`
`A proper obviousness analysis requires construing the terms of the claims
`
`and comparing them to the scope and content of the prior art. Smiths Indus. Med.
`
`Sys., Inc. v. Vital Signs, Inc., 183 F.3d 1347, 1353-54 (Fed. Cir. 1999); Graham v.
`
`John Deere Co. of Kansas City, 383 U.S. 1, 17-18 (1966). The Petition, however,
`
`5
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`Case No. IPR2015-01136
`Patent 8,399,514
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`fails to construe the term “therapeutically effective amount.” Consequently, the
`
`Petition fails to present any evidence comparing the scope and content of the prior
`
`art to this claim term. This incomplete analysis thus fails to establish obviousness
`
`or satisfy the requirements for a proper Petition. See 37 C.F.R. § 42.104(b)(4), (5)
`
`(Petition must explain where each element of each challenged claim is found in the
`
`prior art and the relevance of the evidence to the challenge raised).
`
`Claim terms are given their broadest reasonable interpretation in inter partes
`
`review proceedings. In re Cuozzo Speed Techs., LLC, No. 2014-1301, 2015 WL
`
`4097949, at *7-8 (Fed. Cir. July 8, 2015). A patentee may act as its own
`
`lexicographer by defining a claim term in the specification or prosecution history.
`
`Phillips v. AWH Corp., 415 F.3d 1303, 1316 (Fed. Cir. 2005) (en banc); CCS
`
`Fitness, Inc. v. Brunswick Corp., 288 F.3d 1359, 1366 (Fed. Cir. 2002); Microsoft
`
`Corp. v. Proxyconn, Inc., IPR2012-00026, Paper 17 at 12 (PTAB Dec. 21, 2012).
`
`The claim term “therapeutically effective amount” in claims 1-10, 15-17,
`
`and 19-20 should be construed according to its definition in the specification:
`
`and
`effective dose”
`“therapeutically
`terms
`The
`“therapeutically effective amount” refer to that amount of
`a compound which results in at least one of prevention or
`delay of onset or amelioration of symptoms of a
`neurological disorder in a subject or an attainment of a
`desired
`biological
`outcome,
`such
`as
`reduced
`
`6
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`Case No. IPR2015-01136
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`
`neurodegeneration (e.g., demyelination, axonal loss, and
`neuronal death) or reduced inflammation of the cells of
`the CNS.
`
`(Ex. 1001A at 5:52-59.)
`
`This construction is consistent with the term’s use in the prosecution history.
`
`During prosecution, the applicant argued that the therapeutically effective amount
`
`of 480 mg/day of DMF demonstrated unexpected therapeutic efficacy in two large-
`
`scale Phase III MS clinical studies. (See, e.g., Ex. 1007A at 9-11; Ex. 1008A at 6-
`
`7, 12-18; Ex. 2012 at 6, 10-16.) These results were especially unexpected in view
`
`of a Phase II clinical study demonstrating that doses of 120 mg/day and 360
`
`mg/day did not show any significant efficacy compared to placebo. (Id.) This
`
`discussion of
`
`therapeutic efficacy during prosecution comports with
`
`the
`
`specification’s definition. The claim term “therapeutically effective amount”
`
`should therefore be construed based on this definition.
`
`Petitioner’s expert, Dr. Linberg, never addresses the term “therapeutically
`
`effective” or “therapeutically effective amount” anywhere in his declaration. (See
`
`generally Ex. 1005A.) Instead, he states only that the prior art suggested that DMF
`
`was “therapeutically active” for treating MS. (See, e.g., id. at ¶¶ 23, 24, 27, 28, 30,
`
`35, 41 (emphasis added).) He never defines this amorphous “therapeutically
`
`active” term or explains how it compares to the requirement of claims 1-10, 15-17,
`
`7
`
`

`
`Case No. IPR2015-01136
`Patent 8,399,514
`
`and 19-20 for administering a “therapeutically effective” amount of DMF, MMF,
`
`or a combination thereof to an MS patient in need of therapy. (See id.) This
`
`omission undercuts the probative value of his declaration and highlights the
`
`Petition’s failure to present a legally complete obviousness analysis. Smiths Indus.
`
`Med. Sys., Inc., 183 F.3d at 1353-54; see also 37 C.F.R. § 42.104(b)(4), (5)
`
`(requiring element-by-element comparison of each challenged claim to the prior
`
`art).
`
`IV. The Petition Fails to Address Reasonable Expectation of Success
`Another overarching legal deficiency cuts across all three grounds:
`
`Petitioner never even alleges—much less proves—that one of ordinary skill would
`
`have had a reasonable expectation of success in combining the teachings of the
`
`cited references to achieve the claimed invention. Therefore, on its face, the
`
`Petition cannot establish a reasonable likelihood that any challenged claim is
`
`unpatentable.
`
`Claims 1-10, 15-17, and 19-20 require treating an MS patient by orally
`
`administering a “therapeutically effective amount” of about 480 mg/day of a
`
`specified active ingredient or ingredients (DMF, MMF, or a combination thereof).
`
`(Ex. 1001A at 27:59-29:19, 30:1-28.) Claims 11-14 and 18 require treating an MS
`
`patient by orally administering about 480 mg/day of DMF, MMF, or a combination
`
`thereof. (Id. at 29:20-29.)
`
`8
`
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`Case No. IPR2015-01136
`Patent 8,399,514
`
`The Petition asserts that a person of ordinary skill would have been
`
`motivated to conduct routine testing of DMF at 480 mg/day, but not that such
`
`person would have reasonably expected that such dose would be therapeutically
`
`effective or useful in treating an MS patient. (See, e.g., Am. Pet. at 17-22, 46-51.)
`
`An alleged motivation to combine references is not enough. See Broadcom Corp.
`
`v. Emulex Corp., 732 F.3d 1325, 1335 (Fed. Cir. 2013). Obviousness requires that
`
`one of ordinary skill would have had a reasonable expectation of success in making
`
`the invention. Id; Amgen Inc. v. F. Hoffmann-La Roche Ltd., 580 F.3d 1340, 1362-
`
`63 (Fed. Cir. 2009). It also must be based on some articulated reasoning. KSR Int’l
`
`Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007).
`
`Here, the Petition fails to address, much less prove, that one of ordinary skill
`
`would have had a reasonable expectation of success. At most, it asserts that routine
`
`experiments would reveal that 480 mg/day of DMF is therapeutically effective for
`
`treating a patient with MS. (Am. Pet. at 36; Ex. 1005A at ¶ 64.) This conclusory
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`statement, however, lacks evidentiary support because, for example, Dr. Linberg
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`never addresses therapeutic effectiveness as required by claims 1-10, 15-17, and
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`19-20. (See generally Ex. 1005A.) Moreover, as discussed below, Kappos 2005
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`and the other cited references do not disclose any results at any dose of DMF. (See
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`infra at Sections V.C, VI.C, VII.D.) Thus, it would not have been possible to
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`predict from these references whether any particular dose (including about 480
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`mg/day) would be therapeutically effective or useful in treating an MS patient. The
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`Petition’s assertion that it would have been obvious to select a dose of about 480
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`mg/day must be based on the ’514 patent’s disclosure or (non-prior art) Phase III
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`clinical trial results, reflecting improper hindsight reasoning. Mintz v. Dietz &
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`Watson, Inc., 679 F.3d 1372, 1377 (Fed. Cir. 2012).
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`Dr. Linberg’s declaration is silent as to reasonable expectation of success. It
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`simply repeats the Petition’s arguments. Kinetic Techs., Inc. v. Skyworks Solutions,
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`Inc., IPR2014-00529, Paper 8 at 15 (PTAB Sept. 23, 2014) (“Merely repeating an
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`argument from the Petition in the declaration . . . does not give that argument
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`enhanced probative value.”). Accordingly, the Board should give little weight to
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`this conclusory and unsupported expert testimony. TRW Auto. US LLC v. Magna
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`Elecs., Inc., IPR2014-00258, Paper 18 at 10-11 (PTAB Aug. 27, 2014) (finding
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`Petitioner’s obvious-to-try rationale unsupported and giving little weight to expert
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`declaration that simply repeated TRW’s conclusory statements verbatim).
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`This failure to address (much less prove) a reasonable expectation of success
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`is fatal to Petitioner’s burden to show a reasonable likelihood that at least one
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`claim is unpatentable. The Federal Circuit has consistently held claims nonobvious
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`where the challenger did not prove an expectation of success in making the
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`invention. See, e.g., In re Cyclobenzaprine Hydrochloride Extended-Release
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`Capsule Patent Litig., 676 F.3d 1063, 1069 (Fed. Cir. 2012). In In re
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`Cyclobenzaprine, for example, the Court concluded that no evidence established
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`that one of ordinary skill would have had a reasonable expectation that routine
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`experiments with a drug’s PK profile would produce a therapeutically effective
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`extended-release formulation. Id. at 1069-71. Similarly, in Broadcom, the Court
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`held that even if one of ordinary skill had some motivation to modify the cited
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`reference to add a data path, the record showed no reasonable expectation that this
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`modification would succeed. 732 F.3d at 1335. As a result, the Court held the
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`claims nonobvious. Id.
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`This case is analogous to In re Cyclobenzaprine and Broadcom. The Petition
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`fails to even allege a reasonable expectation of success, much less prove it.
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`Consequently, it fails as a matter of law to establish any reasonable likelihood that
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`the invention of claims 1-20 would have been obvious. In re Cyclobenzaprine, 676
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`F.3d at 1069-71; Broadcom, 732 F.3d at 1335; see also BioGatekeeper, Inc. v.
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`Kyoto Univ., IPR2014-01286, Paper 12 at 6-8 (PTAB Feb. 11, 2015) (denying
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`institution because the petition failed to establish that one of ordinary skill would
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`have had a reasonable expectation of success in achieving the claimed
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`combination).
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`V. Claims 1-20 Would Not Have Been Obvious Over Kappos 2005 in View
`of ICH Guideline E4
`A. The Petition Does Not Prove That BG00012 in Kappos 2005
`Refers to DMF
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`Petitioner has the burden to establish that each element of a challenged claim
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`is found in the cited prior art. 37 C.F.R. § 42.104(b)(4). Independent claims 1, 11,
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`and 20 require an active ingredient of DMF, MMF, or a combination thereof. (Ex.
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`1001A at 27:58-67, 29:20-23, 30:22-28.) Independent claim 15 requires DMF. (Id.
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`at 30:1-7.) The Petition asserts that Kappos 2005 discloses that BG00012 contains
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`DMF as the sole active ingredient. (Am. Pet. at 6, 18.) Kappos 2005, however,
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`does not state that BG00012 is DMF or use the terms “dimethyl fumarate” or
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`“DMF.” (Ex. 1003A at 2 (P574).) Nor does Kappos 2005 refer to MMF or a
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`combination of DMF and MMF. (Id.; Am. Pet. at 6.) ICH Guideline E4 similarly
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`does not disclose DMF, MMF, or a combination thereof. (See Ex. 1004A.)
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`The Petition quotes Kappos 2005’s statement that BG00012 is “a novel
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`single-agent oral fumarate therapy.” (Am. Pet. at 18.) But the description of a
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`genus (“fumarate”) does not necessarily disclose all species (such as DMF) within
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`the genus. In re Baird, 16 F.3d 380, 382 (Fed. Cir. 1994) (“The fact that a claimed
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`compound may be encompassed by a disclosed generic formula does not itself
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`render that compound obvious.”).
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`Petitioner’s expert, Dr. Linberg, does not appear to support Petitioner’s
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`position that Kappos 2005 discloses DMF. Paragraph 28 of his declaration is
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`essentially identical to a corresponding paragraph in the Petition with one key
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`distinction: He states only that Kappos 2005 “discloses BG00012 contains a sole
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`active ingredient” whereas the Petition asserts that Kappos 2005 “discloses
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`BG00012 contains DMF as the sole active ingredient.” (Compare Ex. 1005A at
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`¶ 28 with Am. Pet. at 18-19 (emphasis added).)
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`Dr. Linberg relies on ClinicalTrials NCT00168701, which identifies
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`BG00012 as DMF. (See, e.g., Ex. 1005A at ¶¶ 24, 27, 30, 32, 34, 35, 36, 37.) In
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`relying on ClinicalTrials NCT00168701, he simply asserts (with no record citation)
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`that it was “disclosed in 2005.” (Id. at ¶ 24.) But his reliance on this document is
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`misplaced because the Petition does not prove that this document (a 2015 web page
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`printout) is prior art. (See infra at Section VI.A.)
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`Accordingly, the Petition fails to present a proper Graham analysis or
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`establish a prima facie case of obviousness based on the combination of Kappos
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`2005 and ICH Guideline E4. Graham, 383 U.S. at 17-18 (requiring analysis of all
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`differences between the claims and prior art); see also 37 C.F.R. § 42.104(b)(4).
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`B. One Would Not Have Added a Fifth Dose to the Proposed Study
`of Kappos 2005
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`The Petition states that ICH Guideline E4 would have instructed one of
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`ordinary skill to perform dosing studies and to modify the clinical trial design of
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`Kappos 2005 by adding a fifth tested dose of 480 mg/day. (Am. Pet. at 20-21.) But
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`this overlooks that Kappos 2005 was already a well-designed dosing study in full
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`compliance with the Guideline. Petitioner’s theory of obviousness is unsupported.
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`ICH Guideline E4