Filed: October 31, 2019
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`MYLAN PHARMACEUTICALS INC.,
`SAWAI USA, INC., AND
`SAWAI PHARMACEUTICAL CO., LTD.,
`Petitioner,
`
`
`v.
`
`
`BIOGEN MA INC.,
`Patent Owner.
`____________________________________________
`
`IPR2018-014031
`Patent No. 8,399,514
`____________________________________________
`
`
`PATENT OWNER’S SUR-REPLY
`
`
`
`
`
`
`
`
`
`
`
`
`
`1 Case IPR2019-00789 has been joined with this proceeding.
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`MYLAN PHARMACEUTICALS INC.,
`SAWAI USA, INC., AND
`SAWAI PHARMACEUTICAL CO., LTD.,
`Petitioner,
`
`
`v.
`
`
`BIOGEN MA INC.,
`Patent Owner.
`____________________________________________
`
`IPR2018-014031
`Patent No. 8,399,514
`____________________________________________
`
`
`PATENT OWNER’S SUR-REPLY
`
`
`
`
`
`
`
`
`
`
`
`
`
`1 Case IPR2019-00789 has been joined with this proceeding.
`
`
`
`TABLE OF CONTENTS
`
`U.S. Patent No. 8,399,514
`IPR2018-01403
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`Page(s)
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`
`
`
`
`2.
`
`Introduction ...................................................................................................... 1
`The Challenged Claims Are Not Obvious ....................................................... 4
`A.
`The Prior Art Does Not Teach an Effective Dose Range ..................... 4
`1.
`Schimrigk 2004 and January 2006 Press Release Do Not
`Show That 360 mg/day Was Effective to Treat MS
`(Ground 1) ................................................................................... 5
`Kappos 2006 Does Not Teach a Range of Effective DMF
`Doses (Grounds 2-4) ................................................................... 8
`B. A POSA Would Not Have Been Motivated to Target a DMF
`Dose of 480 mg/day With a Reasonable Expectation of Success
`(Grounds 1-4) ........................................................................................ 9
`1.
`Side Effects and Convenience Considerations Would Not
`Have Motivated a POSA to Select 480 mg/day .......................... 9
`Biogen’s Phase II Data Indicated That a Dose Lower
`Than 720 mg/day Would Not Be Effective (Grounds 2-4) ...... 11
`Alleged “Obscured” Treatment Effect Does Not Support
`a Reasonable Expectation of Success (Grounds 2-4) ............... 12
`C. None of Petitioner’s Additional Arguments Support Its
`Obviousness Challenge ....................................................................... 15
`1.
`Psoriasis Dosing Does Not Provide a Reasonable
`Expectation of Success for MS (Grounds 1-4) ......................... 15
`2. WO ’342 Adds Nothing to Kappos 2006 in Ground 3 ............. 16
`3.
`Additional Ground 4 References Do Not Support
`Unpatentability .......................................................................... 17
`
`2.
`
`3.
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`i
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`U.S. Patent No. 8,399,514
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` Biogen’s Claimed Method Exhibited a Significant Unexpected
`Benefit in Phase III Studies ........................................................................... 17
` Biogen’s Other Objective Evidence Demonstrates Patentability .................. 19
`The Claims Cannot Be Obvious Over Dr. O’Neill’s Own Work
`(Exhibits 1007, 1016, and 1046) ................................................................... 21
` Conclusion ..................................................................................................... 25
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`ii
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`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Coal. for Affordable Drugs LLC v. Acorda Therapeutics, Inc.,
`IPR2015-01850, Paper 72 (PTAB Mar. 9, 2017) ......................................... 22, 24
`Argentum Pharm., LLC v. Alcon Research, Ltd.,
`IPR2017-01053, Paper 52 (PTAB Sept. 20, 2018) ............................................. 21
`Arthrex, Inc. v. Smith & Nephew, Inc.,
`No. 2018-2140 (Fed. Cir. Oct. 31, 2019)............................................................ 25
`FWP IP ApS v. Biogen MA Inc.,
`749 F. App’x 969 (Fed. Cir. 2018) ..................................................................... 16
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Pat.
`Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 18
`In re Katz,
`687 F.2d 450 (CCPA 1982) .........................................................................passim
`In re Soni,
`54 F.3d 746 (Fed. Cir. 1995) .............................................................................. 18
`In re Spormann,
`363 F.2d 444 (CCPA 1966) ................................................................................ 11
`Return Mail, Inc. v. U.S. Postal Serv.,
`139 S. Ct. 1853 (2019) ........................................................................................ 20
`Sanofi v. Watson Labs. Inc.,
`875 F.3d 636 (Fed. Cir. 2017) ............................................................................ 14
`Star Sci., Inc. v. R.J. Reynolds Tobacco Co.,
`655 F.3d 1364 (Fed. Cir. 2011) ............................................................................ 2
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) .......................................................................... 18
`
`iii
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`U.S. Patent No. 8,399,514
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`Varian Med. Sys., Inc. v. William Beaumont Hosp.,
`IPR2016-00160, Paper 82 (PTAB May 4, 2017) ............................................... 24
`Federal Statutes
`35 U.S.C. § 102(a) ..................................................................................................... 2
`
`
`iv
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`U.S. Patent No. 8,399,514
`IPR2018-01403
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`TABLE OF ABBREVIATIONS
`
`DESCRIPTION
`U.S. Patent No. 8,399,514
`Biogen MA Inc
`
`Emphasis added unless otherwise noted
`Coal. for Affordable Drugs V LLC v. Biogen MA Inc.,
`IPR2015-01993
`Dimethyl fumarate
`Disease-modifying therapy
`Gastrointestinal
`Multiple sclerosis
`Biogen’s Patent Owner Response (Paper 38)
`Person of Ordinary Skill in the Art
`Relapsing-remitting multiple sclerosis
`
`ABBREVIATION
`’514 patent
`Biogen or Patent
`Owner
`Italics
`Coalition II
`DMF
`DMT
`GI
`MS
`POR
`POSA
`RRMS
`
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`v
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`U.S. Patent No. 8,399,514
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`
`
`Introduction
`Biogen’s ’514 patent, embodied in Tecfidera®, claims a method of treating
`
`MS by orally administering 480 mg/day of DMF. Biogen’s Phase III trials
`
`demonstrated that this claimed treatment regimen showed “stunning” efficacy. As
`
`Biogen’s experts Drs. Duddy, Wynn, Brundage, and Thisted testified, the
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`480 mg/day DMF dose exhibited an unexpected magnitude of benefit and similar
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`efficacy for every endpoint compared to a higher 720 mg/day DMF dose. Multiple
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`regulatory authorities approved Tecfidera® based on this data. Once launched,
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`Tecfidera® shattered commercial expectations, becoming a $4 billion/year drug that
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`is now the most prescribed oral MS treatment.
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`The Board previously upheld the patentability of the ’514 patent claims,
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`finding that “the degree of efficacy of the 480 mg/day dose of DMF would have
`
`been unexpected.” Coalition II, Paper 63, 25-27. Petitioner argued that another
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`inter partes review was nevertheless warranted because Petitioner purportedly had
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`evidence rebutting unexpected results. Petitioner’s only “evidence,” however, is a
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`hindsight allegation of a “flaw” in Biogen’s Phase II data that Petitioner “corrects”
`
`based solely on documents prepared after Biogen’s priority date and after the
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`surprising results from the Phase III trials were unveiled. Petitioner has failed to
`
`present any evidence that anyone before Biogen’s 2007 priority date recognized a
`
`flaw that needed correction. Petitioner’s post-hoc (i.e., hindsight) analysis is
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`scientifically invalid and unsupported in the prior art, thus violating the cardinal rule
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`that obviousness must be analyzed “without any hint of hindsight.” Star Sci., Inc. v.
`
`R.J. Reynolds Tobacco Co., 655 F.3d 1364, 1375 (Fed. Cir. 2011).
`
`In addition to establishing unexpected results, Biogen has proven commercial
`
`success and other objective evidence of nonobviousness. Petitioner’s own rebuttal
`
`witness, Dr. Hay, conducted an analysis in 2015 before his retention in this matter
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`and concluded that Tecfidera®’s “actual efficacy and reduction of side effects is
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`better than any other drug” of the four MS drugs he analyzed. Ex. 2230, 66:3-67:13.
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`Petitioner has failed to prove its own theory of obviousness that the prior art
`
`established that both 360 mg/day DMF and 720 mg/day DMF were effective for
`
`treating MS and provided sufficient motivation for a POSA to use doses in that
`
`range, and that a POSA would have selected 480 mg/day DMF with a reasonable
`
`expectation of success in treating MS.
`
`First, the prior art did not establish that a 360 mg/day DMF dose was effective
`
`for treating MS. That dose did not show statistical significance compared to placebo
`
`in Biogen’s Phase II trial, as reported in the Kappos slide presentation (Ex. 1046)
`
`and a press release (Ex. 1016).2 The Schimrigk six-person study administered
`
`
`2 None of these references, including Kappos 2006 (Ex. 1007), are prior art because
`
`they are the inventor’s own work. 35 U.S.C. §102(a). Infra §V.
`
`2
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`Fumaderm®, a mixture of four active agents and not DMF monotherapy. Ex. 1006,
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`5; Ex. 1018, 3. As Petitioner’s own Dr. Benet admitted, the only way to understand
`
`the contribution of individual active agents is to study them individually, which
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`Schimrigk did not do. Ex. 2062, 33:1-25. Petitioner has failed to prove that
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`Schimrigk 2004 or Kappos 2006 teach that a 360 mg/day DMF dose treats MS.
`
`Second, there was no known effective dose range of DMF for treating MS.
`
`Petitioner’s attempts to suggest that a POSA would have understood that the
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`360 mg/day DMF dose demonstrated efficacy are based on post-filing date hindsight
`
`contradicted by the contemporaneous evidence. Kappos 2006 says nothing about
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`baseline lesions—the sole basis for Petitioner’s theory that a POSA would have
`
`challenged the reported conclusion that the 360 mg/day DMF dose was not effective.
`
`The only contemporaneous document with baseline lesion data is Exhibit 1046,
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`which Petitioner does not assert as a reference in any of its Grounds, which does not
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`disclose any flaw in the Phase II study, and which is not prior art.
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`Third, based on Phase II results, a POSA would not have been motivated to
`
`pursue a DMF dose below 720 mg/day. Although it showed impressive efficacy in
`
`large Phase III trials, the 720 mg/day dose showed less impressive efficacy in Phase
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`II. Ex. 2058 ¶95. A POSA would not have sacrificed any of that efficacy—the most
`
`important consideration for both parties’ clinical experts—especially when the 720
`
`mg/day DMF dose was described as “well-tolerated.”
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`Fourth, a POSA would not have had a reasonable expectation of success in
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`treating MS with a DMF dose of 480 mg/day. 480 mg/day is substantially lower
`
`than the 720 mg/day dose and would have been expected to have a response similar
`
`to the 360 mg/day dose that failed to exhibit a statistically significant effect on Gd+
`
`lesions. In addition, references regarding treatment of psoriasis, a different disease
`
`with different pathology, would not have directed a POSA to 480 mg/day of DMF
`
`to treat MS.
`
`Lastly, Petitioner has not met its burden of proof to overcome Biogen’s
`
`evidence not only of unexpected results, but also of commercial success and other
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`secondary considerations, and the strong evidence that Kappos 2006 and other
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`references related to Biogen’s Phase II studies are not prior art because they are the
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`work of the inventor.
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`As set forth below, the full record shows that Petitioner’s obviousness
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`arguments fail for every Ground.
`
` The Challenged Claims Are Not Obvious
`A. The Prior Art Does Not Teach an Effective Dose Range
`Central to each of Petitioner’s Grounds is its allegation that Schimrigk 2004
`
`(Ex. 1006) and/or Kappos 2006 (Ex. 1007) disclose that 360 mg/day and 720 mg/day
`
`of DMF are both effective to treat MS, that it would have been obvious to optimize
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`the dose in that range, and that a POSA would have selected 480 mg/day DMF with
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`4
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`a reasonable expectation of success. E.g., Pet., 6-10; Reply, 2-3. Biogen has
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`demonstrated that there was no range to optimize. POR, 21-23, 25-26. Public
`
`information taught that 360 mg/day was ineffective. Only 720 mg/day showed any
`
`efficacy in Biogen’s Phase II trial.
`
`1.
`
`Schimrigk 2004 and January 2006 Press Release Do Not
`Show That 360 mg/day Was Effective to Treat MS
`(Ground 1)
`Schimrigk 2004 is a brief abstract providing certain results from an
`
`exploratory, open-label, six-patient, non-placebo-controlled study of Fumaderm® in
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`RRMS patients. POR, 18-19; Ex. 1006, 5; Ex. 1018, 3. Fumaderm® is not “akin to
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`DMF monotherapy.” Reply, 5. It is a mixture of four active agents: DMF; Calcium
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`Monoethyl Fumarate; Magnesium Monoethyl Fumarate; and Zinc Monoethyl
`
`Fumarate. Ex. 1020, 2; POR, 18-21; Ex. 1018, 2; Ex. 1037, 109-120; Ex. 1125,
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`93:5-14; Ex. 1126, 123:7-124:12; Ex. 1131, 32:8-33:14, 35:2-36:6. The therapeutic
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`moieties in DMF monotherapy and Fumaderm® are different, as Petitioner’s own
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`evidence from scientific experts at the European Medicines Agency demonstrates.
`
`Ex. 1037, 120. Petitioner asks this Board to ignore three of Fumaderm®’s four active
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`agents even though Petitioner’s expert admitted that the only way to understand the
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`contribution of individual active agents is to study them individually. Ex. 2062,
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`33:1-25. Schimrigk 2004 did not study DMF individually, and Petitioner’s own
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`evidence shows that the other components are active. POR, 18-21; Ex. 1131, 41:6-
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`5
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`42:3, 52:9-53:3, 55:5-11; Ex. 1037, 109-120. It is erroneous to state that Schimrigk
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`2004 discloses the activity of DMF monotherapy to treat MS, let alone any type of
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`dose range for DMF monotherapy.
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` POR, 18-21.
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` Petitioner’s repeated
`
`mischaracterization of Schimrigk 2004 as disclosing “DMF dosed as Fumaderm®”
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`is misleading and scientifically incorrect.
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`Moreover, Schimrigk 2004 did not—and could not—identify its 3-tablet dose
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`of Fumaderm® as an effective dose for treating MS, let alone a range of effective
`
`doses. POR, 21-23. The Schimrigk study started patients on a six-tablet dose of
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`Fumaderm® and later reduced the dose by half, to a three-tablet dose. Ex. 1006, 5.
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`Biogen’s Dr. Duddy testified that it is “impossible to determine the contribution, if
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`any, of the 3-tablet dose” because “[t]he trial design … does not lend itself to
`
`determining whether [that dose] is effective to treat MS.” POR, 21-23; Ex. 2058
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`¶52; see also Ex. 2057 ¶¶39-40; Ex. 2061 ¶77; Ex. 1125, 109:9-114:11, 117:5-
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`119:16, 120:21-123:19. Furthermore, Schimrigk 2004 did not find a reduction in
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`Gd+ lesions “over the course of each treatment.” Reply, 4-5. Petitioner’s expert Dr.
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`Benet admitted that the 3-tablet dose provided no further improvement for Gd+
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`lesions or any clinical measure during the 3-tablet phase—both remained constant
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`or numerically worsened. Ex. 2062, 135:22-136:9, 136:22-137:1, 137:12-138:2;
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`POR, 21-22.
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`6
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`Further, Schimrigk 2004 is not a “commonly used phase I study design” that
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`“provides useful teachings to optimize the dose.” Reply, 6. Petitioner’s Dr. Benet
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`admitted that starting with a much higher dose, as was done, “would not be a normal
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`way to carry out a dose-response study” and “you just don’t do those kinds of
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`studies” to assess dose-response information. Ex. 2062, 58:9-59:7; see also Ex. 2057
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`¶39; Ex. 2058 ¶52. Dr. Benet also admitted that the effects of the initial 6-tablet
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`phase can carry over and interfere with the later phases, making it impossible to
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`attribute any effect to the 3-tablet dose. Ex. 2062, 53:13-54:25, 57:1-58:7, 58:9-
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`59:7; POR, 21-22; Ex. 2231, 202:5-203:19 (Dr. Greenberg admitting that drug
`
`effects can persist for months). Accordingly, no POSA would have concluded that
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`Schimrigk 2004 reported a treatment effect for its lower, 3-tablet dose, let alone any
`
`treatment effect of DMF alone.
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`The Schimrigk 2004 study was also too small (6 of 10 subjects completed it
`
`(Ex. 1018, 3)) to yield results upon which a POSA would rely. Ex. 2057 ¶21; POR,
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`22. It was conducted without placebo control and confounded by the use of anti-
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`inflammatory steroid treatments, which Petitioner’s Dr. Corboy admits “will alter
`
`the gadolinium enhancement,” precluding attributing an effect to the three-tablet
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`dose. Ex. 2063, 61:9-17; Ex. 2058 ¶54; Ex. 2061 ¶78; POR, 22-23.
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`The January 2006 Press Release (Ex. 1005) does not remedy any of Schimrigk
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`2004’s deficiencies. See Ex. 1125, 37:7-38:4. The Board already acknowledged
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`7
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`that the press release says nothing about which dose met its endpoint. Paper 12, 11;
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`Ex. 1125, 82:6-87:4, 89:21-92:15. Petitioner’s expert Dr. Hay agrees: “in terms of
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`clinical safety and efficacy, there’s nothing” in the press release. Ex. 2230, 33:6-11.
`
`2. Kappos 2006 Does Not Teach a Range of Effective DMF
`Doses (Grounds 2-4)
`Kappos 2006 is a short abstract providing limited information about Biogen’s
`
`Phase II study. POR, 25-26. It is also not prior art because it is the work of the
`
`inventor. Infra §V.
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`Kappos 2006 reports that “BG00012 (720 mg/day [of DMF]) significantly
`
`reduced the mean number of new Gd+ lesions (the primary end point) compared
`
`with placebo.” It says nothing about the 360 mg/day dose. Ex. 1007, 27; POR, 26.
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`Had the study investigators interpreted the results to demonstrate or suggest
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`effectiveness for the 360 mg/day dose, they would have said so. Other public
`
`information confirmed that the “360 mg BG-12-treated group [was] not statistically
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`significant versus placebo.” Ex. 1016, 1; Ex. 1046, 19-22; POR, 26.
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`Further, the use of the words “dose-dependent” does not provide motivation
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`or a reasonable expectation that 480 mg/day, let alone 360 mg/day “could likely
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`achieve statistical significance in achieving an MS endpoint.” See Ex. 1121 ¶185.
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`“Dose-dependent” means what the data showed: 720 mg/day had a statistically
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`significant effect and the other two doses did not. Ex. 1133, 80:16-19. As Dr.
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`Brundage explained, “[y]ou gave one dose, you saw no effect; you gave a different
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`dose, and you saw efficacy. So that means the efficacy depends on the dose you
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`give, by definition.” Ex. 1131, 18:9-19. A POSA would have understood that “dose-
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`dependent” does not mean that efficacy was found at multiple doses. Ex. 2057 ¶¶
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`67-75, 77; Ex. 1131, 12:13-21:4; Ex. 1125, 236:12-237:7, 239:3-22; Ex. 1133,
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`103:7-11. Petitioner’s Dr. Benet agrees with Biogen’s experts: “[A] dose response
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`doesn’t imply that all doses have efficacy.” Ex. 2062, 32:10-23.
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`B. A POSA Would Not Have Been Motivated to Target a DMF Dose
`of 480 mg/day With a Reasonable Expectation of Success
`(Grounds 1-4)
`1.
`Side Effects and Convenience Considerations Would Not
`Have Motivated a POSA to Select 480 mg/day
`Even though the asserted references do not establish a range of effective doses
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`(supra §II.A), Petitioner asserts that “general drug development principles”
`
`including reduction of side effects and convenience considerations would have led
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`a POSA to 480 mg/day of DMF (Reply, 2).
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`MS is a chronic, debilitating, and notoriously hard-to-treat disease, and GI
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`disturbance and convenience would not have driven a POSA to reduce the only dose
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`(720 mg/day) shown to have a potential effect in a clinical trial. POR, 23-25, 39.
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`As Dr. Brundage testified, “[w]hen you’re facing the consequences of MS, you may
`
`be quite willing to tolerate a higher frequency of some side effects for the ability to
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`keep walking and stay out of wheelchairs.” Ex. 1131, 95:8-17. Disease modification
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`is the “key treatment objective,” where maximizing efficacy to prevent disability
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`and maintain independence is demanded by physicians and patients alike. Ex. 2058
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`¶19; Ex. 2061 ¶23; Ex. 1125, 18:2-18; Ex. 1131, 94:7-95:1; Ex. 2053, 8; Ex. 2055,
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`1; Ex. 2230, 213:19-214:16, 90:19-91:4; Ex. 2231, 172:1-16 (efficacy goal is zero
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`relapses and zero MRI events). Indeed, “[e]fficacy” and “[e]fficacy” are the top two
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`considerations for Petitioner’s Dr. Corboy, who “treat[s] aggressively from the
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`outset, so as to maximize reduction in inflammatory disease activity.” Ex. 2055, 1-
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`2.
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`Undertreatment of MS, leading to relapses or disease progression, cannot be
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`corrected. Ex. 2061 ¶¶54, 83. As Petitioner’s Dr. Hay testified, “a poor decision
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`means a lifetime of bad outcomes.” Ex. 2230, 89:15-90:18. “[Y]ou can never go
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`backwards.” Id., 82:12-83:7. Unwilling to risk the grave consequences of
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`undertreatment, MS clinicians would switch a drug-intolerant patient to another drug
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`rather than use an unproven lower dose. Ex. 2058 ¶¶43-44; Ex. 2061 ¶¶55, 65, 121;
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`Ex. 2055, 1; Ex. 2053, 8; Ex. 2230, 88:8-20 (“you will probably regret wrong
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`decisions much more profoundly because you can’t reverse them”), 95:19-97:10.
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`A POSA would not have risked losing efficacy with a DMF dose below
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`720 mg/day where, as here, there were no dose-related side effect concerns. The
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`720 mg/day dose was “well tolerated.” Ex. 1046, 24-26; Ex. 1016, 1; Ex. 2058 ¶¶96-
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`10
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`99; Ex. 2061 ¶89; Ex. 1116, 5; see also POR, 24; Ex. 2062, 38:13-22. GI side effects
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`and flushing were not meaningfully dose-related and would not have been expected
`
`to be meaningfully lower at doses below 720 mg/day. Ex. 1046, 18, 24-26; Ex. 2058
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`¶¶96-99; Ex. 2061 ¶89; Ex. 1126, 66:6-25, 69:20-70:4; Ex. 1131, 78:1-11; Ex. 2063,
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`120:4-123:15. Petitioner’s unsupported speculation about undisclosed “incidence of
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`events or severity of side effects” (Reply, 3) would not have been of particular
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`interest or relevance to a POSA. Ex. 1126, 66:6-25; In re Spormann, 363 F.2d 444,
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`448 (CCPA 1966) (“Obviousness cannot be predicated on what is unknown.”). A
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`POSA would not have been motivated to sacrifice any efficacy of the 720 mg/day
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`dose when there was no expectation that lowering the dose would lead to
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`meaningfully reduced side effects. POR, 23-25, 39. If anything, a POSA would
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`have been motivated to target even higher doses, seeking even greater efficacy. Ex.
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`2057 ¶¶44-45; Ex. 2058 ¶¶94-95; Ex. 2061 ¶68; Ex. 1131, 93:4-18; see also Ex.
`
`1121 ¶188.
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`2.
`
`Biogen’s Phase II Data Indicated That a Dose Lower Than
`720 mg/day Would Not Be Effective (Grounds 2-4)
`Biogen’s reported Phase II results provided no expectation that a clinical
`
`effect would occur below 720 mg/day. POR, 25-40; Ex. 1007, 27; Ex. 1046, 19, 27;
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`Ex. 1016, 1; Ex. 1125, 38:12-44:14. At that time, researchers were looking for
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`“drugs that were going to do better than the interferons,” e.g., Rebif®. Ex. 1125,
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`184:14-189:5; Ex. 1046, 9; see also Ex. 2053, 12 (citing ref. 60, 2002 paper). As
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`Dr. Duddy commented, Biogen’s 720 mg/day dose performed worse than Rebif® in
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`MRI outcomes but “Rebif like” for preliminary annualized relapse rates. Ex. 1125,
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`187:9-13, 189:1-5. After Biogen released its Phase II results, he positioned DMF as
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`a low-risk, low-efficacy drug. Ex. 2124, 30; Ex. 2058 ¶¶175-176. In light of the
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`Phase II data, a POSA would not have expected lower DMF doses, including 480
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`mg/day, to be effective to treat MS, especially when 360 mg/day showed no efficacy.
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`POR, 38-39; Ex. 2058 ¶¶116-148; Ex. 2061 ¶¶59-66; Ex. 1131, 81:14-82:19, 85:13-
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`86:1, 87:13-88:12; Ex. 1125, 237:9-238:6, 239:3-243:10. This lack of any
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`reasonable expectation of success is compounded by a history of failed MS drugs,
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`including many that showed promising signals in early studies. Ex. 2058 ¶¶150-
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`164; Ex. 1126, 115:16-116:1, 153:5-12, 154:3-23.
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`3.
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`Alleged “Obscured” Treatment Effect Does Not Support a
`Reasonable Expectation of Success (Grounds 2-4)
`Petitioner’s hindsight-driven attempt to argue that Kappos 2006 teaches a
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`range of effective doses is not supported in the prior art. Reply, 8-10. No one,
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`including Petitioner’s own experts, contemporaneously identified any alleged “flaw”
`
`in the baseline characteristics of Biogen’s Phase II studies or “corrected” for it.
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`POR, 28-31; Ex. 2231, 136:15-143:4, 219:9-221:9.
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`First, Petitioner’s arguments regarding an alleged baseline imbalance are not
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`based on anything described in Kappos 2006 itself. Instead, Petitioner turns to
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`another document, Exhibit 1046, which it does not assert in its Grounds and which
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`is not prior art. Infra §V; POR, 4-13.
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`Furthermore, Biogen’s evidence shows that no POSA identified any “flaw” in
`
`Biogen’s Phase II baseline Gd+ lesion characteristics. POR, 32-33. Dr. Duddy
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`testified that the baseline Gd+ lesion values were “unremarkable” and “typical,” and
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`Petitioner’s Dr. Benet agreed that the baseline Gd+ lesion characteristics were not
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`statistically different. Ex. 2058 ¶¶119-123; Ex. 2062, 150:2-3; Ex. 1126, 196:12-
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`197:12. Dr. Greenberg, petitioner’s new expert, also admitted that in his own prior
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`publications discussing the Biogen Phase II results he did not identify any baseline
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`imbalances. Ex. 2231, 136:15-143:4, 219:9-221:9.
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`Nor has Petitioner established that a POSA would have “corrected” for the
`
`purported baseline imbalance. The only people ever to have conducted such
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`calculations, including Petitioner’s experts, did so only after Biogen obtained
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`surprising results with the 480 mg/day dose in Phase III studies in 2011. POR, 28-
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`31. Biogen’s experts have consistently shown these analyses are not valid and, at
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`most, represent a long-after-the-fact effort to understand the surprising results
`
`observed in Phase III. Ex. 2058 ¶¶116-148; Ex. 2061 ¶¶59-66; Ex. 1125, 138:16-
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`139:7; Ex. 1133, 58:21-59:5. While Petitioner’s Dr. Greenberg relies on a new
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`reference from 2013 (Ex. 1066), this even later speculation does not reflect the
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`perspective of a POSA in 2007.3 Such after-the-fact speculation cannot establish a
`
`reasonable expectation of success. Sanofi v. Watson Labs. Inc., 875 F.3d 636, 648
`
`(Fed. Cir. 2017) (recognizing mere “potential” for beneficial results in after-the-fact
`
`publications does not establish obviousness).
`
`Biogen thoroughly discredited Petitioner’s post-hoc calculations. POR, 31-
`
`37. Dr. Benet—the only expert to support such calculations with the Petition—
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`admitted that the clinical import of Gd+ lesions was “[o]utside of [his] area of
`
`expertise” and that measurements not linked to a validated clinical outcome, which
`
`is the case with the post-hoc analyses of record, “do[]n’t tell you anything.” Ex.
`
`2062, 12:14-18, 80:2-11; Ex. 2064, 69:18-70:2. Petitioner seeks to rehabilitate its
`
`case with rebuttal expert Dr. Greenberg, but he copied Dr. Benet’s baseless
`
`calculations and did not address Dr. Benet’s admissions. Ex. 1121 ¶¶155-157.
`
`Further, Dr. Greenberg’s testimony does not support Petitioner’s contention
`
`that a POSA “would have anticipated the heightened disease activity obscured a
`
`treatment effect in the 360 mg/day group.” Reply, 8. Dr. Greenberg takes an
`
`unsupported leap from stating that unequal randomization in Biogen’s Phase II trials
`
`“could potentially skew” the results for the 360 mg/day group to proclaiming that a
`
`
`3 Petitioner does not cite Ex. 1066 in its Reply. As such, it should be given no weight.
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`14
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`POSA “would … expect that the 480 mg/day dose of DMF,” which had never been
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`studied, “would be statistically significantly effective in treating MS.” Compare Ex.
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`1121 ¶¶141, 153 with id. ¶175. This assertion contradicts the admissions of
`
`Petitioner’s other experts that none of the post-hoc calculations included any
`
`statistical analysis and ignores the “important” difference between statistical and
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`clinical significance admitted by Petitioner’s Dr. McKeague. Ex. 2063, 130:7-
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`132:12; Ex. 2064, 53:20-54:5.
`
`C. None of Petitioner’s Additional Arguments Support Its
`Obviousness Challenge
`1.
`Psoriasis Dosing Does Not Provide a Reasonable
`Expectation of Success for MS (Grounds 1-4)
`Petitioner asserts that a POSA would have reasonably expected a dose of
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`480 mg/day of DMF would treat MS because it had been shown to work in a small-
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`scale study in psoriasis. Pet., 32; Reply, 7. Petitioner’s argument is unfounded. Ex.
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`1131, 98:2-101:14; Ex. 1125, 74:7-76:17. In 2007, MS clinicians viewed psoriasis
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`and MS as very different diseases, and even today, there is no scientific consensus
`
`on the cause of MS. Ex. 2057 ¶¶58-64; Ex. 2058 ¶¶72-91; Ex. 1125, 203:9-204:4;
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`POR, 40-43. Thus, a POSA would not have extrapolated dosing information from a
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`skin disease like psoriasis, where treatment effects are plainly visible, to MS, the
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`course of which is unpredictable and often silently progressive, and for which
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`15
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`positive treatment effects can only be determined over the long-term. Ex. 2057
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`¶¶58-64; Ex. 2058 ¶¶72-91; Ex. 1125, 201:19-204:4; Ex. 2231, 160:3-161:3.
`
`2. WO ’342 Adds Nothing to Kappos 2006 in Ground 3
`Petitioner asserts that Kappos 2006 in combination with WO ’342 renders the
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`challenged claims obvious. WO ’342 does not remedy the failures of Kappos 2006
`
`to provide any motivation for selecting a therapeutically effective dose of 480
`
`mg/day of DMF for treating MS, much less any reasonable expectation of success.
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`WO ’342 “does not indicate 480 mg/day is a therapeutically effective dose with
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`respect to any condition or disease.” Ex. 2030, 22; FWP IP ApS v. Biogen MA Inc.,
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`749 F. App’x 969, 973 (Fed. Cir. 2018). WO ’342 thus cannot provide the missing
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`motivation. As Dr. Duddy testified:
`
`With [the knowledge that DMF monotherapy effectively
`treated MS from Biogen’s Phase II studies] in my head, I
`come to ’342, and I find a long list of diseases with nothing
`pointing me towards multiple sclerosis. I find a long list
`of fumarates, none of which is specifically linked to
`multiple sclerosis, and I find a massive dose range, none
`of which is linked to any fumarate or multiple sclerosis.
`So no, I could not take that and find in this a way of
`treating multiple sclerosis.
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`Ex. 1125, 174:14-175:12; see also id. 171:17-182:7.
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`3.
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`Additional Ground 4 References Do Not Support
`Unpatentability
`Beyond citing selected Coalition II panel statements about Joshi ’999, ICH
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`Guidelines, and ClinicalTrials, Petitioner has failed to address Biogen’s evidence
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`showing that none of these references compensate for the deficiencies of Kappos
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`2006. POR, 44-48; Reply, 12. The Board here, however, is not bound by statements
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`in the prior panel’s decision. None support obviousness:
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` Joshi ’999 does not disclose an effective range of daily doses and does
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`not teach that GI and flushing side effects are dose-related. POR, 48.
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` ICH Guidelines is not specific to MS or its treatment; and, if anything,
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`further demonstrates that a POSA would not have been motivated to
`
`select a dose lower than 720 mg/day. Ex. 1011, 10 (to recommend a
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`lower dose, it must have statistical significance and a clinically
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`meaningful effect); POR, 45-47.
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` ClinicalTrials relates to a prospective study and provides no
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`information regarding any efficacious dose of DMF to treat MS. POR,
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`47-48.
`
` Biogen’s Claimed Method Exhibited a Significant Unexpected Benefit in
`Phase III Studies
`Biogen demonstrated that administering 480 mg/day of DMF to treat MS
`
`achieved an unexpected and “stunning” magnitude of effect. Ex. 2060 ¶100; POR,
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`49-53; Coalition II, Paper 63, 23-25. Evidence from two pivotal Phase III clinical
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`studies established that the 480 mg/day dose had an unexpected magnitude of
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`efficacy, similar to the higher 720 mg/day dose for almost every endpoint measured.
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`POR, 49-51. As Biogen’s experts explained, the magnitude of clinical efficacy
`
`exhibited by the 480 mg/day dose in view of Biogen’s Phase II trials was entirely
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`unexpected. Id., 51-53.
`
`The Board must consider this objective evidence as part of the obviousness
`
`analysis to safeguard against even a hint of hindsight, especially becaus
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