Filed: May 31, 2019
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`
`v.
`
`
`BIOGEN MA INC.,
`Patent Owner.
`____________________________________________
`
`IPR2018-01403
`Patent No. 8,399,514
`____________________________________________
`
`
`PATENT OWNER’S RESPONSE
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`
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`
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`

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`TABLE OF CONTENTS
`
`U.S. Patent No. 8,399,514
`IPR2018-01403
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`Page(s)
`
`I.
`Introduction ...................................................................................................... 1
`II. All of Petitioner’s Grounds Fail Because They Rely On Non-Prior Art
`References ........................................................................................................ 4
`A.
`Exhibits 1007, 1046, and 1016 Describe Dr. O’Neill’s Work .............. 6
`B. Dr. O’Neill’s Own Work Is Not Prior Art to Claims 1-16, 20 ........... 10
`C. Dr. O’Neill’s Own Work Is Not Prior Art to Claims 17-19 ............... 10
`D.
`The ’514 Patent Is Entitled to Its Provisional Filing Date .................. 11
`III. Level of Ordinary Skill in the Art ................................................................. 14
`IV. Petitioner Has Failed to Establish Obviousness ............................................ 14
`A. Ground 1: Schimrigk 2004 in View of January 2006 Press
`Release ................................................................................................. 15
`1.
`Schimrigk’s Fumaderm® Treatment Is Different Than
`DMF Monotherapy ................................................................... 18
`Schimrigk Does Not Show Efficacy at the Three-Tablet
`Dose of Fumaderm® or Disclose a Range of Effective
`Doses ......................................................................................... 21
`Ground 1 Provides No Motivation or Reasonable
`Expectation of Success to Treat MS with 480 mg/day of
`DMF .......................................................................................... 23
`B. Ground 2: Kappos 2006 in View of Schimrigk 2004 ........................ 25
`1.
`Kappos 2006 and Schimrigk 2004 Do Not Establish an
`Effective DMF Dose Range ...................................................... 25
`Petitioner’s Hindsight-Based Post-Hoc Analyses Are
`Irrelevant to Obviousness ......................................................... 27
`
`2.
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`3.
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`2.
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`3.
`
`4.
`
`A POSA Would Have Been Directed Towards DMF
`Doses Greater Than 720 mg/day .............................................. 37
`Petitioner’s Psoriasis References Do Not Support
`Obviousness .............................................................................. 40
`C. Ground 3: Kappos 2006 in View of WO ’342 ................................... 43
`D. Ground 4: Kappos 2006, ICH Guidelines, Clinical Trials, and
`Joshi ’999 ............................................................................................ 44
`The Claims Are Patentable Based on Compelling Objective Evidence ........ 49
`A.
`480 mg/day DMF Achieved Unexpected Results ............................... 49
`1.
`480 mg/day DMF’s Magnitude of Clinical Efficacy Was
`Unexpectedly High and Unexpectedly Similar to 720
`mg/day ....................................................................................... 49
`Petitioner Fails to Rebut Unexpected Results .......................... 53
`2.
`Tecfidera® Embodies the ’514 Patent Claims ..................................... 55
`B.
`The Claimed DMF Dosing Regimen Satisfied a Long-Felt Need ...... 56
`C.
`Tecfidera® Has Been a Blockbuster Commercial Success ................. 59
`D.
`The Claimed Dosing Regimen Has Been Extensively Praised ........... 61
`E.
`VI. Conclusion ..................................................................................................... 62
`
`
`V.
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`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Abbott Labs. v. Sandoz, Inc.,
`544 F.3d 1341 (Fed. Cir. 2008) .......................................................................... 45
`Acceleration Bay, LLC v. Activision Blizzard Inc.,
`908 F.3d 765 (Fed. Cir. 2018) ............................................................................ 17
`Alcon Research, Ltd. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012) .......................................................................... 59
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) ............................................................................ 11
`Ariad Pharm., Inc. v. Eli Lilly & Co.,
`598 F.3d 1336 (Fed. Cir. 2010) (en banc) .......................................................... 12
`Ariosa Diagnostics v. Verinata Health, Inc.,
`IPR2013-00276, Paper 64 (PTAB Aug. 15, 2016) ............................................. 17
`Bone Care Int’l LLC v. Pentech Pharm., Inc.,
`No. 08-cv-1083, 2010 WL 3928598 (N.D. Ill. Oct. 1, 2010) ............................. 29
`In re Brana,
`51 F.3d 1560 (Fed. Cir. 1995) ............................................................................ 12
`Braun v. Lorillard Inc.,
`84 F.3d 230 (7th Cir. 1996) ................................................................................ 30
`
`Coal. for Affordable Drugs (ADROCA) LLC v. Acorda Therapeutics,
`Inc.,
`IPR2015-01850, Paper 72 (PTAB Mar. 9, 2017) ........................................... 6, 10
`Coal. for Affordable Drugs VIII, LLC v. Trs. of Univ. Penn.,
`IPR2015-01835, Paper 56 (PTAB Mar. 6, 2017) ............................................... 55
`In re Cronyn,
`890 F.2d 1158 (Fed. Cir. 1989) .......................................................................... 16
`
`iii
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`U.S. Patent No. 8,399,514
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`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .................................................................... 28, 56
`FWP IP ApS v. Biogen MA Inc.,
`749 Fed. Appx. 969 (Fed. Cir. 2018) .................................................................. 43
`Haliburton Energy Servs., Inc. v. Dynamic 3D Geosolutions LLC,
`IPR2014-01186, Paper 18 (PTAB Feb. 18, 2015) .............................................. 16
`Hospira, Inc. v. Genentech, Inc.,
`IPR2017-00804, Paper 83 (PTAB Oct. 3, 2018) ................................................ 35
`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .......................................................................... 61
`In re Katz,
`687 F.2d 450 (CCPA 1982) ........................................................................ 5, 9, 10
`KSR Int’l Co. v. Teleflex,
`550 U.S. 398 (2007) ............................................................................................ 28
`Lupin Ltd. v. Senju Pharm. Co.,
`IPR2015-01099, Paper 69 (PTAB Sept. 12, 2016) ....................................... 59, 61
`Neptune Generics, LLC v. Eli Lilly & Co.,
`921 F.3d 1372 (Fed. Cir. 2019) .................................................................... 28, 31
`Okajima v. Bourdeau,
`261 F.3d 1350 (Fed. Cir. 2001) .......................................................................... 14
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`No. 07-01000, 2010 WL 11636594 (D.N.J. Dec. 15, 2010) .............................. 58
`Pro-Mold & Tool Co. v. Great Lakes Plastics, Inc.,
`75 F.3d 1568 (Fed. Cir. 1996) ............................................................................ 49
`Procter & Gamble Co. v. Teva Pharms. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ............................................................................ 56
`Sanofi v. Watson Laboratories Inc.,
`875 F.3d 636 (Fed. Cir. 2017) ...................................................................... 27, 37
`
`iv
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`U.S. Patent No. 8,399,514
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`Securus Techs., Inc. v. Global Tel*Link Corp.,
`IPR2016-00996, Paper 32 (PTAB Oct. 30, 2017) .............................................. 11
`SRI Int’l, Inc. v. Internet Sec. Sys., Inc.,
`511 F.3d 1186 (Fed. Cir. 2008) .......................................................................... 16
`Varian Med. Sys., Inc. v. William Beaumont Hosp.,
`IPR2016-00160, Paper 82 (PTAB May 4, 2017) ................................................. 5
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) .......................................................................... 55
`Federal Statutes
`35 U.S.C. § 102(a) ....................................................................................... 2, 4, 5, 11
`35 U.S.C. § 112 ........................................................................................................ 12
`35 U.S.C. § 119(e)(1) ............................................................................................... 12
`35 U.S.C. § 120 ........................................................................................................ 12
`35 U.S.C. § 311(b) ................................................................................................... 17
`35 U.S.C. § 312(a)(3) ................................................................................................. 4
`Rules
`Fed. R. Evid. 702 ..................................................................................................... 35
`Regulations
`37 C.F.R. § 1.41(a)(2) .............................................................................................. 12
`37 C.F.R. § 42.65(a) ........................................................................................... 32, 35
`Other Authorities
`MPEP § 2132.01 .................................................................................................. 5, 11
`Trial Practice Guide Update (Aug. 2018) ................................................................ 17
`
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`TABLE OF ABBREVIATIONS
`
`ABBREVIATION
`
`’514tatent
`
`US. Patent No. 8,399,514
`
`Biogen or Patent Biogen MA Inc
`Owner
`
`Bolded Italics
`
`Emthasis added unless otherwise noted
`
`CNS
`
`Central nervous s stem
`
`Clinical Trials
`
`Ex. 1010
`
`EMA
`
`Euro u can Medicines A _enc
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`DNEF
`Dimeth l fumarate
`
`DMT
`Disease-modifying therapy
`GI
`Gastrointestinal
`
`
`
`
`
`ICH Guidelines
`
`Ex. 1011
`
`January 2006 Press Ex. 1005
`Release
`
`Joshi ’999
`
`US. Patent No. 7,320,999, Ex. 1009
`
`Ka. .05 2006
`
`Ex. 1007
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`MEF
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`MMF
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`MS
`
`Monoeth l fumarate
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`Monometh l flimarate
`
`Multi .le sclerosis
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`M lan or Petitioner M lan Pharmaceuticals Inc.
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`POSA
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`RRMS
`
`Person of Ordin
`
`Skill in the Art
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`Relao_sin-remittin; multi .le sclerosis
`
`Schimri; 2004
`
`Ex. 1006
`
`W0 ’342
`
`WO 2006/037342, Ex. 1008
`
`vi
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`I.
`
`Introduction
`Biogen’s ’514 patent is directed to a method of treating multiple sclerosis by
`
`orally administering about 480 mg/day of DMF and/or its active metabolite, MMF.
`
`Tecfidera®, Biogen’s oral 480 mg/day DMF regimen for treating MS, is a
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`commercial embodiment of this invention.
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`MS is a unique and complex disease that targets the central nervous system,
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`often leading to severe disability. It is a silently progressive disease—once there are
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`clinical manifestations, damage has already been done. Its relapsing and remitting
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`nature make it difficult to determine whether a drug is working or the patient is
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`simply in remission. Because of this and the grave consequences of undertreatment,
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`MS clinicians rely on large, well-designed clinical trials with placebo controls to
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`guide the treatment of MS and do not dose-titrate individual patients for
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`effectiveness.
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`Biogen’s Phase III clinical trials, involving over 2,000 MS patients and
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`spanning more than 2 years, demonstrated unexpected and significant efficacy for
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`the claimed 480 mg/day oral dose of DMF for treating MS. This generated
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`excitement in the MS community given the long-felt need for a safe and effective
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`oral MS treatment. Indeed, the results were so significant that many patients delayed
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`initiating MS therapy until Tecfidera® launched, foregoing available drugs that were
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`either burdensome injectables or subject to risks of serious side effects. Reflecting
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`1
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`U.S. Patent No. 8,399,514
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`its life-changing impact and low treatment burden, demand for Tecfidera® far
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`exceeded expectations. Within six months of being launched, Tecfidera® became
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`the most-prescribed oral MS medication in the United States.
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`Against the backdrop of this compelling objective evidence, Petitioner
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`advances obviousness theories that have no basis in the prior art.
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`First, Petitioner’s challenges rely either directly (Grounds 2-4) or indirectly
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`via its experts (Ground 1) on Kappos 2006 (Ex. 1007) and other references that
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`reflect the work of inventor Dr. O’Neill, and thus are not prior art under 35 U.S.C.
`
`§ 102(a). Because those references are not prior art, the Petition fails for this
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`fundamental reason.
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`Second, the Petition is premised on the alleged obviousness of optimizing
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`within a purportedly known range of effective doses. Petitioner has not, however,
`
`established any such range in the prior art. This failure is a fundamental flaw in all
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`grounds. The Petition further fails on this basis.
`
`Third, the Board should reject Petitioner’s hindsight arguments claiming that
`
`Kappos 2006 showed “likely efficacy” (Pet. 55) for the 360 mg/day DMF dose based
`
`on post-hoc discussions informed by knowledge of the surprising efficacy of
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`480 mg/day DMF monotherapy and published years after the patent’s priority date.
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`In addition, Petitioner’s own post-hoc analysis is scientifically invalid and not shown
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`2
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`to be correlated to any clinical outcome. Because Petitioner’s post-hoc theories are
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`incorrect, unreliable, and based on improper hindsight, all of its grounds fail.
`
`Fourth, the claims of the ’514 patent are nonobvious based on Biogen’s strong
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`objective evidence, including unexpected results. Biogen’s clinical experts Drs.
`
`Duddy (Ex. 2058 ¶¶2-7, 165-187) and Wynn (Ex. 2061 ¶¶3-8, 124-136); its expert
`
`pharmacologist Dr. Brundage (Ex. 2057 ¶¶2-16, 66, 88, 103); and its expert
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`statistician Dr. Thisted (Ex. 2060 ¶¶1-14, 89-113) testify that the magnitude of
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`clinical efficacy exhibited by the claimed 480 mg/day dose of DMF was surprising—
`
`“stunning” according to Dr. Thisted and a “game-changer” as explained by Dr.
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`Duddy (id. ¶100; Ex. 2058 ¶195)—as it proved to have similar efficacy in MS
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`patients as the much higher 720 mg/day dose for almost every endpoint measured.
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`These results defied expectations, and Tecfidera® satisfied a long-felt need in the
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`marketplace for a safe and effective oral disease-modifying MS therapy. The
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`remarkable success of Tecfidera®, including its strong market success over other oral
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`treatments, as explained by Petitioner’s economic expert Mr. Jarosz (Ex. 2022 ¶¶5-
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`10), confirms the strong benefits it provides to patients and the nonobviousness of
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`the claimed invention.
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`For these and other reasons discussed below, Biogen respectfully requests that
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`the Board find that Petitioner has not met its burden and confirm the patentability of
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`all claims of the ’514 patent.
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`3
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`II. All of Petitioner’s Grounds Fail Because They Rely On Non-Prior Art
`References
`Petitioner relies on three purported § 102(a) references that are not prior art
`
`against the ’514 patent claims because they describe inventor Dr. O’Neill’s work.
`
`The first is Kappos 2006 (Ex. 1007), an abstract relating to Biogen’s Phase II MS
`
`clinical trial. Pet. 20-21. The other two are a slide presentation (Ex. 1046) and a
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`press release (Ex. 1016), which likewise describe aspects of Biogen’s Phase II
`
`clinical trial.1
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`These three references are central to Petitioner’s Grounds 2-4; indeed, Kappos
`
`2006 is the lead reference for those grounds. These three references are also
`
`inexorably and inseparably part of Ground 1 as well: Petitioner’s Ground 1
`
`arguments repeatedly invoke purported “background” knowledge and the “state of
`
`
`1 Petitioner’s reliance on Exhibits 1016 and 1046 is further improper because
`
`Petitioner is not be permitted to back-fill gaps in its asserted grounds by relying,
`
`such as via expert declarations, on references that it did not identify as part of its
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`invalidity grounds. 35 U.S.C. § 312(a)(3) (requiring petitioner to identify “with
`
`particularity” its grounds and the evidence supporting each challenge).
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`4
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`the art”2 built upon these three references.3 Indeed, in the very footnote purportedly
`
`disavowing reliance on these references for Ground 1, Petitioner cites evidence that
`
`expressly depends upon Kappos 2006. See Pet. 37 n.8 (citing Ex. 1002 ¶153 (relying
`
`on Ex. 1007)).
`
`Because “one’s own work is not prior art under [§] 102(a),” these three
`
`references are not and cannot be prior art and Petition Grounds 1-4 fail. In re Katz,
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`687 F.2d 450, 454 (CCPA 1982); see also, e.g., Varian Med. Sys., Inc. v. William
`
`Beaumont Hosp., IPR2016-00160, Paper 82 at 22 (PTAB May 4, 2017) (finding
`
`petitioner failed to meet its burden of proving that the “portions of [the references]
`
`on which it relies are the work [of] ‘others’”); MPEP § 2132.01. Indeed, a recent
`
`decision addressed nearly identical facts, finding that an alleged § 102(a) reference
`
`describing the clinical trial work of the inventors, and those working under their
`
`
`2 E.g., Pet. 36 (“[c]onsidering the state of the art”); Pet. 37 (“taking into account its
`
`known side-effect profile”), Pet. 39, citing Ex. 1002 ¶150 (referring generally to the
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`“state of the art, and a skilled artisan’s general knowledge”).
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`3 E.g., Pet. 27-29 (state-of-the-art section citing Ex. 1003 ¶¶43, 46, 47 (relying on
`
`Exs. 1007, 1016, and 1046)); id. 29-34 (background section citing Ex. 1007 and Ex.
`
`1002 ¶153 (relying on Ex. 1007), ¶¶167-69 (relying on Ex. 1007), ¶176 (relying on
`
`Exs. 1007 and 1016)).
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`5
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`direction and supervision, was not prior art. Coal. for Affordable Drugs (ADROCA)
`
`LLC v. Acorda Therapeutics, Inc., IPR2015-01850, Paper 72 at 37-43 (PTAB Mar.
`
`9, 2017). As explained below, the same is true here.
`
`A. Exhibits 1007, 1046, and 1016 Describe Dr. O’Neill’s Work
`Petitioner relies on Kappos 2006 for its disclosure of certain results from
`
`Biogen’s Phase II study. E.g., Pet. 21. Petitioner relies on Exhibits 1016 and 1046
`
`for similar points, as well as Exhibit 1046 for the disclosure of Gd+ baseline lesions.
`
`Id., 46.
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`These disclosures, however, are the not “work of others” but rather are the
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`work of inventor Dr. O’Neill—the Medical Director of Biogen’s MS BG-12
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`(Tecfidera®) program—and those working at his direction and under his supervision.
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`See Exs. 2097, 2098, 2099, 2100. Indeed, the disclosures relied on by Petitioner are
`
`directly traceable to Dr. O’Neill’s own confidential and non-public presentation
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`from months earlier. Ex. 2091, 9, 14 (reporting on efficacy at 720 mg/day); id. 8
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`(reporting baseline lesion data); Ex. 2097 ¶13.4
`
`
`4 Exhibits 2088-2093 were confidential and non-public until the filing of this paper.
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`See Ex. 2097 ¶12 and Ex. 2099 ¶5 (information related to Biogen’s Phase II trial that
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`was shared among those involved in the trial was confidential and non-public).
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`As Biogen’s Medical Director for the Phase II clinical trial, Dr. O’Neill was
`
`responsible for all aspects of the trial, including its execution, analysis, and reporting
`
`of results. Ex. 2097 ¶¶7-18; Ex. 2098 ¶¶5-9; Ex. 2099 ¶¶5-11. Dr. O’Neill presented
`
`the initial dosing concepts to Biogen’s Clinical Trial Review Board, and Biogen
`
`proceeded in Phase II with the third of his four options. Ex. 2088; Ex. 2097 ¶8; Ex.
`
`2098 ¶6. He also supervised and directed the people, both within and outside
`
`Biogen, involved in carrying out the clinical trial. Ex. 2097 ¶¶9-12; Ex. 2098 ¶¶5-
`
`9; Ex. 2099 ¶¶6-11.
`
`Within Biogen, Dr. O’Neill held regular meetings of the Clinical
`
`Development Team and the Study Management Team for the clinical trial. Ex. 2097
`
`¶11; Ex. 2098 ¶¶5, 7; Ex. 2092. Dr. O’Neill and those working at his direction
`
`worked to set up over 40 investigation sites across 10 countries and undertook the
`
`numerous other activities required for a clinical trial. Ex. 2097 ¶9; Ex. 2098 ¶6; Ex.
`
`2089. Each trial site had a designated investigator responsible for overseeing the
`
`site, executing the approved study protocol, and receiving monitors who regularly
`
`visited to collect data and ensure adherence to the protocol. Ex. 2098 ¶7; Ex. 2097
`
`¶10; Ex. 2099 ¶9.
`
`Dr. O’Neill and those working at his direction arranged an initial meeting
`
`gathering the clinical investigators for training in preparation for executing Biogen’s
`
`Phase II protocol. Ex. 2098 ¶6; Ex. 2097 ¶9; Ex. 2099 ¶8; Ex. 2089. Dr. O’Neill
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`7
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`and those assisting him at Biogen also assembled a Scientific Advisory Committee
`
`for Biogen’s Phase II clinical trial. Ex. 2097 ¶10; Ex. 2098 ¶7. He held regular
`
`meetings of the Scientific Advisory Committee to obtain input on various aspects of
`
`the study, oversee the administrative process of the study, and address any issues as
`
`they arose. Ex. 2097 ¶¶10-11; Ex. 2099 ¶6. The Scientific Advisory Committee
`
`included several of the clinical investigators, a member of the MRI Reading Centre
`
`team, and a consultant. Ex. 2097 ¶10. All of these individuals—Biogen’s
`
`employees, the members of the Scientific Advisory Committee, the clinical
`
`investigators, the MRI Reading Centre team, and the various consultants and
`
`experts—worked on the Phase II trial under Dr. O’Neill’s direction and supervision.
`
`Id. ¶11; Ex. 2098 ¶7; Ex. 2099 ¶6.
`
`Dr. O’Neill was also responsible for the analysis of the Phase II study data
`
`and conclusions drawn therefrom. Ex. 2097 ¶¶11-12; Ex. 2099 ¶9. The clinical
`
`investigators were required to carry out the trial according to Biogen’s protocol and
`
`provide Biogen with the data collected from their individual sites. Id. All
`
`investigators were blinded to the individual and overall trial data throughout the
`
`course of the study; they did not see the collected data or results until after the data
`
`was unlocked, analyzed, and presented to them by Biogen. Id.; Ex. 2090. That
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`analysis was Dr. O’Neill’s responsibility and was carried out by Dr. O’Neill with
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`8
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`the assistance of Biogen’s designated statistician, Minhua Yang, and others working
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`under Dr. O’Neill’s direction and supervision. Ex. 2097 ¶¶11-12; Ex. 2099 ¶9.
`
`That Exhibits 1007 and 1046 list authors in addition to Dr. O’Neill does not
`
`make them prior art. Katz, 687 F.2d at 455. The members of the Scientific Advisory
`
`Committee jointly predetermined, before the trial, that publications of the Phase II
`
`study would include the following authors: the Coordinating Investigator, the
`
`Scientific Advisory Committee, the MRI Reading Centre team, the top-recruiting
`
`clinical investigators, Biogen’s Medical Director, and Biogen’s Lead Statistician.
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`Ex. 2097 ¶¶14-16; Ex. 2098 ¶9; Ex. 2099 ¶11; Ex. 2092. This authorship
`
`determination was made to acknowledge each person’s role in carrying out Biogen’s
`
`study. Id. Indeed, it is typical to include clinical investigators on such publications,
`
`and it is also typical to list first the person designated “Coordinating Investigator”
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`(Dr. Kappos). Ex. 2098 ¶9. But as the declarants who worked on the clinical trial
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`attest, Kappos 2006, as well as Exhibits 1046 and 1016, disclose the results of the
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`clinical trial led by Dr. O’Neill. Ex. 2097 ¶¶13-18; Ex. 2098 ¶¶8-9; Ex. 2099 ¶¶10-
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`11. The cited exhibits are thus the work of Dr. O’Neill, as further corroborated by
`
`(1) emails between Drs. O’Neill and Kappos showing that Dr. O’Neill was
`
`responsible for the content of Exhibit 1007 and received no substantive edits from
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`Dr. Kappos (Ex. 2097 ¶16; Ex. 2093) and (2) Dr. O’Neill’s own slides from months
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`9
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`earlier presenting the trial results and his analysis of the results (Ex. 2097 ¶13; Ex.
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`2091).
`
`B. Dr. O’Neill’s Own Work Is Not Prior Art to Claims 1-16, 20
`The ’514 patent names two inventors, Dr. O’Neill and Dr. Lukashev. As
`
`described in their declarations, each inventor had different roles in and contributions
`
`to the claimed inventions. Ex. 2097 ¶¶19-20; Ex. 2100 ¶¶5-7. As a clinician, Dr.
`
`O’Neill was responsible for the subject matter relating to treatment of MS patients
`
`with about 480 mg/day of DMF, MMF, or a combination thereof. Id. He is thus the
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`sole inventor of claims 1-16 and 20. Id. Because Dr. O’Neill is the sole inventor of
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`those claims, and the work described in Exhibits 1007, 1046, and 1016 is his own
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`work, those exhibits are not prior art against at least claims 1-16 and 20. Katz, 687
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`F.2d at 454; Acorda, IPR2015-01850, Paper 72 at 37-43.
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`C. Dr. O’Neill’s Own Work Is Not Prior Art to Claims 17-19
`Claims 17-19 depend from the claims 1, 11, and 15, respectively, and further
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`relate to the contributions of Dr. Lukashev (a translational research scientist)
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`regarding elevated expression levels of NQO1 after administering DMF, MMF, or a
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`combination thereof. Ex. 1001, 30:10-21. As Drs. Lukashev and O’Neill both attest,
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`they are coinventors of claims 17-19. Ex. 2097 ¶¶19-20; Ex. 2100 ¶¶5-7.
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`The work of Dr. O’Neill described in Exhibits 1007, 1046, and 1016 is also
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`not prior art to claims 17-19. The work of a subset of patent inventors cannot be
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`10
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`U.S. Patent No. 8,399,514
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`used to invalidate patent claims to a larger group under § 102(a). See MPEP
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`2132.01(II) (“An inventor’s or at least one joint inventor’s disclosure of his or her
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`own work within the year before the application filing date cannot be used against
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`the application as prior art under pre-AIA 35 U.S.C. 102(a).”); Allergan, Inc. v.
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`Apotex Inc., 754 F.3d 952, 968-69 (Fed. Cir. 2014) (considering whether reference
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`was shown to be the work of one of the inventors and therefore not prior art).
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`D. The ’514 Patent Is Entitled to Its Provisional Filing Date
`There is no dispute that the ’514 patent is entitled to the filing date of its
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`provisional application. Petitioner identifies § 102(a) as the only prior art basis for
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`Kappos 2006 and—despite submitting three expert declarations— Petitioner does
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`not contest that the ’514 patent is entitled to the February 8, 2007, priority date. See
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`Pet. 21. Any belated attempt by Petitioner to dispute priority would constitute an
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`improper reply. See, e.g., Securus Techs., Inc. v. Global Tel*Link Corp., IPR2016-
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`00996, Paper 32 at 17-19 (PTAB Oct. 30, 2017) (declining to consider petitioner’s
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`belated challenge to priority date).
`
`It is clear that the patent is entitled to the filing date of its provisional
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`application. Biogen filed Provisional Application No. 60/888,921 on February 8,
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`2007 (Ex. 2101), followed by a PCT application on February 7, 2008 (Ex. 2102),
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`which entered the U.S. national stage as U.S. Application No. 12/526,296 (Ex.
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`2203), followed by continuation Application No. 13/372,426 on February 13, 2012
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`11
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`U.S. Patent No. 8,399,514
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`(Ex. 2204), which issued as the ’514 patent. Ex. 1001, 1:6-11. The requirements of
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`§ 119(e)(1) are met: the PCT leading to the 12/526,296 application was filed within
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`twelve months of the filing of the provisional application, and contains a specific
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`reference to the provisional application. Ex. 2102, 1; Ex. 2103, 1-2, 22; Ex. 2110.
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`The requirements of § 120 are likewise met: non-provisional application 13/372,426
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`was filed during pendency of non-provisional application 12/526,296, and contains
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`a specific reference to both prior applications. Ex. 2204, 150; Ex. 1001, 1:6-11. And
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`throughout all the applications, Dr. Lukashev was named as an inventor, satisfying
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`the requirement for continuity of inventorship.5
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`Furthermore, the provisional application is substantively identical to the
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`specification of the ’514 patent and provides § 112 written description and
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`enablement for the ’514 patent claims. See Ariad Pharm., Inc. v. Eli Lilly & Co.,
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`598 F.3d 1336, 1351-52 (Fed. Cir. 2010) (en banc); In re Brana, 51 F.3d 1560, 1564
`
`
`5 Dr. Lukashev was properly added as inventor during the pendency of the
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`provisional application, see 37 C.F.R. § 1.41(a)(2), and was named as an inventor
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`on each of the remaining applications that led to the ’514 patent. Ex. 2104, 55; Ex.
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`2102, 1; Ex. 1001, 1. Dr. O’Neill was added as an inventor with the addition of
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`claims directed to methods of treating MS patients. See Ex. 2097 ¶¶19-20; Exs.
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`2105-2107, 2094-2096.
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`12
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`U.S. Patent No. 8,399,514
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`(Fed. Cir. 1995). As detailed in the declaration by Dr. Daniel Wynn, an MS
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`specialist with nearly thirty years of experience treating MS patients, the provisional
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`application fully supports these method-of-treatment claims. Ex. 2061 ¶¶137-161.
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`It repeatedly singles out MS as a chronic, progressive, and severely disabling
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`neurological disease for treatment with DMF and/or MMF. Id., ¶¶139-143; Ex. 2101
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`¶¶[0001]-[0004], [0011], [0066]. It describes methods for screening, evaluating, and
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`comparing neuroprotective properties of compounds based on Nrf2 pathway
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`upregulation with the specific goal of treating MS. Ex. 2061 ¶¶142, 159; Ex. 2101
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`¶¶[0006], [0010], [0041]-[0062], [0122]-[0124]. It describes pharmaceutical
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`formulations of DMF,
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`the frequency of administration,
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`the duration of
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`administration, and methods of treating neurological diseases, including MS. Ex.
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`2061 ¶¶143, 149-152, 158; Ex. 2101 ¶¶[0011], [0116]-[0120]. And it specifically
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`describes a dose of DMF or MMF of “about 480 mg” per day as therapeutically
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`effective for treating MS. Ex. 2061 ¶¶144-148, 158; Ex. 2101 ¶¶[0040], [0066],
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`[0112]-[0116].
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`Based on its express disclosures, a POSA would have readily understood that
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`the inventors possessed the claimed subject matter when the provisional application
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`was filed—including the expressly disclosed 480 mg/day dose of DMF and/or
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`MMF—and would have been able to make and use the invention without undue
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`experimentation. Ex. 2061 ¶¶137-161.
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`13
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`U.S. Patent No. 8,399,514
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`III. Level of Ordinary Skill in the Art
`The ’514 patent is directed to a method of treating MS, “a unique and complex
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`neurological autoimmune disease targeting the” CNS. Ex. 2058 ¶¶11-24; Ex. 2061
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`¶¶28-29, 32-33. Petitioner’s proposed definition omits any requirement that a
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`clinician—much less an MS clinician—be included. Pet. 10-11. Petitioner’s
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`proposed level of ordinary skill should be rejected as inconsistent with the subject
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`matter of the claimed invention.
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` Instead, the Board should adopt Biogen’s more relevant level of ordinary
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`skill: a person with a medical degree with at least three years of training in neurology
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`and at least three years of clinical experience treating MS. Ex. 2061 ¶¶35-36. This
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`definition is closely tied to the ’514 patent and the credentials of those involved in
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`the references Petitioner relies upon (e.g., Ex. 1007). Ex. 2097 ¶2; Ex. 2099 ¶1;
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`Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001).
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`IV. Petitioner Has Failed to Establish Obviousness
`The Petition was instituted based on an obviousness theory of dose
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`optimization within an established range. Institution Decision, Paper 12, 14 (“The
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`legal question before us, in each of Petitioner’s Grounds, is whether discovery of
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`the 480 mg/day dose of DMF in a method of treating multiple sclerosis was the result
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`of DMF dose optimization within an established effective range.”); Pet. 45. But the
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`evidence shows that only one dose (720 mg/day of DMF) was potentially effective
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`14
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`U.S. Patent No. 8,399,514
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`and that lower doses (120 and 360 mg/day) were ineffective. Ex. 1007, 27; Ex. 1016.
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`Petitioner’s obviousness challenges fail because there was no known “establ