Filed: November 8, 2018
`
`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 PRELIMINARY RESPONSE
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`TABLE OF CONTENTS
`
`U.S. Patent No. 8,399,514
`IPR2018-01403
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`Page(s)
`
`I.
`II.
`
`V.
`
`Introduction ...................................................................................................... 1
`Background ...................................................................................................... 4
`A.
`The Challenge of Multiple Sclerosis ..................................................... 4
`B.
`Biogen’s Phase II Clinical Trial ............................................................ 5
`C.
`Biogen’s Phase III Clinical Trials ......................................................... 7
`D.
`The FDA Approves Tecfidera® ............................................................. 8
`E.
`Biogen Launches Tecfidera®—Embodied by the ’514 Patent
`Claims—to Great Success ..................................................................... 9
`III. The Prosecution and Issuance of the ’514 Patent ............................................ 9
`IV. The Serial Challenges to the ’514 Patent Before the PTAB ......................... 11
`A.
`Coalition for Affordable Drugs V LLC v. Biogen MA Inc.,
`IPR2015-01136 (“Coalition I”) ........................................................... 13
`Biogen MA Inc. v. Forward Pharma A/S, Intf. 106,023
`(“FP Interference”) ............................................................................. 14
`Coalition for Affordable Drugs V LLC v. Biogen MA Inc.,
`IPR2015-01993 (“Coalition II”) ......................................................... 16
`The Petition Should Be Denied Because Mylan Fails to Rebut the
`Office’s Repeated Findings of Unexpected Results ...................................... 19
`A. Mylan’s Reliance on Post-Filing Date References to Challenge
`the Phase II Trial Results is Legally Deficient .................................... 20
`1.
`The Board Previously Considered Mylan’s Proposed
`Post Hoc Change to the Phase II Results .................................. 21
`2. Mylan Improperly Relies on Later-Dated References
`That Do Not Qualify as Prior Art ............................................. 22
`
`B.
`
`C.
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`U.S. Patent No. 8,399,514
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`3. Mylan’s Arguments Regarding the Phase II Trial Results
`Contradict the Asserted References and Do Not Address
`the Unexpected Magnitude of Efficacy of the Claimed
`480 mg/day Dose ...................................................................... 25
`B. Mylan Fails to Meaningfully Address the Phase III Trial
`Results Establishing Unexpected Results ........................................... 29
`VI. The Petition Should Be Denied Under § 325(d) Because the Office
`Considered Substantially the Same Disclosures and Arguments
`During Prosecution and Multiple PTAB Proceedings .................................. 32
`A.
`Summary of the Argument .................................................................. 32
`B.
`Legal Standards ................................................................................... 35
`C.
`The Office Allowed the Claims and the Board Upheld Their
`Patentability over the Combination of Schimrigk’s Small Study
`with Biogen’s Phase II Trial Results ................................................... 37
`1.
`Grounds 1 and 2 Allege Combinations of Schimrigk’s
`Study with Biogen’s Phase II Trial ........................................... 37
`These Grounds Were Considered and Rejected During
`Prosecution ................................................................................ 38
`The Board Also Considered the Schimrigk Study and
`Biogen’s Phase II Trial ............................................................. 40
`The Additional References That Mylan Cites—But Does
`Not Assert—in Grounds 1 and 2 Were Similarly
`Considered ................................................................................ 42
`D. Ground 4 Is the Very Same Ground Presented in Coalition II ........... 43
`E.
`Ground 3 Contradicts the Board’s and Federal Circuit’s
`Decisions in the FP Interference ......................................................... 45
`F. Mylan Fails to Challenge Biogen’s Extensive Antedating
`Evidence .............................................................................................. 47
`
`2.
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`3.
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`4.
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`U.S. Patent No. 8,399,514
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`VII. Mylan’s Concurrent Litigation Involving the Same Issues Strongly
`Favors Denial Under § 314(a) ....................................................................... 49
`VIII. Conclusion ..................................................................................................... 52
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`U.S. Patent No. 8,399,514
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`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) .......................................................................... 23
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8 (PTAB Dec. 15, 2017) ............................................... 34
`Cheese Sys., Inc. v. Tetra Pak Cheese & Powder Sys., Inc.,
`725 F.3d 1341 (Fed. Cir. 2013) .................................................................... 22, 26
`Coalition for Affordable Drugs V LLC v. Hoffman-LaRoche Inc.,
`IPR2015-01792, Paper 14 (PTAB Mar. 11, 2016) ............................................. 20
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .................................................................... 23, 24
`FWP IP ApS v. Biogen MA Inc.,
`No. 2017-2109, slip op. (Fed. Cir. Oct. 24, 2018) .......................................passim
`Gen. Plastic Indus. Co. v. Canon Kabushiki Kaisha,
`IPR2016-01357, Paper 19 (PTAB Sept. 6, 2017) ............................................... 48
`Graco Children’s Prods. Inc. v. Kolcraft Enters., Inc.,
`IPR2016-00810, Paper 8 (PTAB Sept. 28, 2016) ......................................... 47, 48
`In re Hedges,
`783 F.2d 1038 (Fed. Cir. 1986) .......................................................................... 26
`Hologic, Inc. v. bioMérieux, Inc.,
`IPR2018-00568, Paper 9 (PTAB Aug. 7, 2018) ..................................... 35, 36, 49
`Hospira, Inc. v. Genentech, Inc.,
`IPR2017-00739, Paper 16 (PTAB July 27, 2017) .............................................. 35
`Hulu, LLC v. Intertainer, Inc.,
`IPR2014-01456, Paper 8 (PTAB Mar. 6, 2015) ........................................... 47, 48
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`U.S. Patent No. 8,399,514
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`Kayak Software Corp. v. Int’l Bus. Machs. Corp.,
`CBM2016-00075, Paper 16 (PTAB Dec. 15, 2016) ........................................... 35
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 21, 24
`Lower Drug Prices for Consumers, LLC v. Forest Labs. Holdings Ltd.,
`IPR2016-00379, Paper 14 (PTAB July 1, 2016) .................................... 20, 31, 36
`In re Lunsford,
`357 F.2d 380 (CCPA 1966) ................................................................................ 23
`Mylan Labs. Ltd. v. Aventis Pharma S.A.,
`IPR2016-00627, Paper 10 (PTAB Aug. 23, 2016) ............................................. 25
`Neil Ziegmann, N.P.Z., Inc. v. Stephens,
`IPR2015-01860, Paper 13 (PTAB Sept. 6, 2017) ............................. 31-32, 43, 47
`Neptune Generics, LLC v. Eli Lilly & Co.,
`IPR2016-00240, Paper 82 (PTAB Oct. 5, 2017) .......................................... 21, 24
`NetApp Inc. v. Realtime Data LLC,
`IPR2017-01195, Paper 9 (PTAB Oct. 12, 2017) .......................................... 49, 50
`NHK Spring Co. v. Intri-Plex Techs., Inc.,
`IPR2018-00752, Paper 8 (PTAB Sept. 12, 2018) ............................................... 50
`Pfizer, Inc. v. Genentech, Inc.,
`IPR2018-00373, Paper 12 (PTAB Aug. 2, 2018) ......................................... 32, 41
`Samsung Elecs. Co. v. Elm 3DS Innovations, LLC,
`IPR2017-01305, Paper 11 (PTAB Oct. 17, 2017) .............................................. 49
`Sandoz, Inc. v. Genentech, Inc.,
`IPR2017-02042, Paper 11 (PTAB Mar. 4, 2018) ......................................... 34, 36
`Shenzhen Silver Star Intelligent Tech. Co. v. iRobot Corp.,
`IPR2018-00761, Paper 15 (PTAB Sept. 5, 2018) ......................................... 48, 50
`Siemens Healthcare Diagnostics, Inc. v. Radiometer Med. APS,
`IPR2018-00311, Paper 6 (PTAB June 25, 2018) ............................................... 35
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`Unified Patents Inc. v. Berman,
`IPR2016-01571, Paper 10 (PTAB Dec. 14, 2016) ....................................... 35, 43
`Unified Patents, Inc. v. PersonalWeb Techs., LLC,
`IPR2014-00702, Paper 13 (PTAB July 24, 2014) .............................................. 34
`W.L. Gore & Assocs., Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) .......................................................................... 44
`Statutes
`35 U.S.C. § 102(a) ................................................................................................... 46
`35 U.S.C. § 102(b) ................................................................................................... 46
`35 U.S.C. § 103 .................................................................................................passim
`35 U.S.C. § 314(a) ............................................................................................passim
`35 U.S.C. § 316(b) ................................................................................................... 50
`35 U.S.C. § 325(d) ............................................................................................passim
`Regulations
`37 C.F.R. § 42.65(a) ............................................................................... 27, 29, 30, 31
`Other Authorities
`H.R. Rep. No. 112-98 (2001) ................................................................................... 47
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`U.S. Patent No. 8,399,514
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`TABLE OF ABBREVIATIONS
`
`DESCRIPTION
`U.S. Patent Application No. 13/372,426
`U.S. Patent No. 8,399,514
`Abbreviated New Drug Application
`Twice-daily dosing
`Biogen MA Inc.
`
`ABBREVIATION
`’426 application
`’514 patent
`ANDA
`BID
`Biogen or Patent
`Owner
`Coalition I
`
`Coalition for Affordable Drugs V LLC v. Biogen MA Inc.,
`IPR2015-01136
`Coalition for Affordable Drugs V LLC v. Biogen MA Inc.,
`Coalition II
`IPR2015-01993
`Dimethyl fumarate
`DMF
`European Medicines Agency
`EMA
`U.S. Food and Drug Administration
`FDA
`Forward Pharma A/S
`FP
`Biogen MA Inc. v. Forward Pharma A/S, Intf. No. 106,023
`FP Interference
`Inter Partes Review
`IPR
`Emphases are added with italics unless otherwise stated
`Italics
`U.S. Patent Publication No. 2003/0018072
`Joshi ’072
`U.S. Patent No. 6,436,992
`Joshi 2002
`Monoethyl fumarate
`MEF
`Monomethyl fumarate
`MMF
`Multiple sclerosis
`MS
`Petitioner Mylan Pharmaceuticals Inc.
`Mylan
`New Drug Application
`NDA
`Office or USPTO U.S. Patent and Trademark Office
`POSA
`Person of ordinary skill in the art
`RRMS
`Relapsing-remitting multiple sclerosis
`TID
`Three times daily dosing
`Trial Practice
`Trial Practice Guide Update (Aug. 2018)
`Guide
`
`
`
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`U.S. Patent No. 8,399,514
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`I.
`
`Introduction
`The Board has expended significant resources over the past several years
`
`evaluating Biogen’s ’514 patent. The Board declined to institute in a first IPR,
`
`denied another challenge in an interference, and issued a final written decision
`
`upholding the patentability of all claims in a second IPR.1 Repackaging previously
`
`considered references and obviousness challenges from these proceedings, Mylan’s
`
`Petition now seeks a fourth post-grant challenge to the ’514 patent that should be
`
`denied—both on the merits and as an appropriate exercise of the Board’s discretion
`
`under either 35 U.S.C. § 325(d) or § 314(a).
`
`The ’514 patent is directed to a method of treating multiple sclerosis (“MS”)
`
`with a therapeutically effective amount of 480 mg per day of DMF and/or MMF. It
`
`covers Biogen’s groundbreaking MS drug Tecfidera®. During prosecution, the
`
`Examiner credited Biogen’s extensive evidence of unexpected results supported by
`
`two Phase III clinical trials in over 2000 patients, which demonstrated that the
`
`
`1
`Coalition for Affordable Drugs V LLC v. Biogen MA Inc., IPR2015-01136
`
`(“Coalition I”) (McKelvey, APJ) (Ex. 2027); Biogen MA Inc. v. Forward Pharma
`
`A/S, Intf. No. 106,023 (“FP Interference”) (Schafer, APJ) (Ex. 2030), aff’d, No.
`
`2017-2109 (Fed. Cir. Oct. 24, 2018); Coalition for Affordable Drugs V LLC v.
`
`Biogen MA Inc., IPR2015-01993 (“Coalition II”) (Schafer, APJ) (Ex. 2032).
`
`1
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`claimed 480 mg/day dose of Tecfidera® was unexpectedly as efficacious as a much
`
`higher 720 mg/day dose. The Board similarly relied on these unexpected results
`
`when upholding the ’514 patent claims in Coalition II. The Federal Circuit—when
`
`affirming the Board’s interference decision—further confirmed that Biogen’s
`
`unexpected results are “significant.” FWP IP ApS v. Biogen MA Inc., No. 2017-
`
`2109, slip op. at 15 (Fed. Cir. Oct. 24, 2018). Tecfidera®’s impressive therapeutic
`
`benefits at a dose of 480 mg/day have permitted patients to receive life-changing
`
`medication at lower doses and through fewer daily administrations, propelling
`
`Tecfidera® to become the most prescribed oral MS medication in the United States
`
`within six months of its launch in 2013. It remains the leading oral MS medication
`
`on the market today.
`
`Lacking any new prior art or obviousness challenges, Mylan’s Petition
`
`purports to rebut the extensive evidence of unexpected results. Mylan asserts that
`
`the efficacy of the 480 mg/day dose of DMF was not unexpected because Biogen’s
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`Phase II results should be adjusted after-the-fact to allegedly show that the tested
`
`360 mg/day dose was “likely” efficacious. Mylan’s position is improperly based on
`
`references dated four and six years after the unchallenged February 8, 2007 filing
`
`date of Biogen’s priority application. Federal Circuit law is clear that unexpected
`
`results must be evaluated from the perspective of what would have been expected at
`
`the time of the invention. Mylan’s argument also contradicts the express disclosure
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`of every pre-filing date document reporting on the 360 mg/day dose, which failed to
`
`achieve any statistically significant results on any endpoint in Biogen’s Phase II trial.
`
`Further, Mylan’s speculative, hindsight assertion of “likely” efficacy of the
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`360 mg/day dose does not address the basis for the Office’s prior conclusions of
`
`unexpected results: the surprising magnitude of the efficacy of a 480 mg/day dose
`
`of Tecfidera® as compared to a much higher 720 mg/day dose. In addition, Mylan
`
`inaccurately characterizes its hindsight-based challenge as “new evidence,” but it
`
`was previously raised in an earlier IPR, extensively discussed by Biogen’s expert,
`
`Dr. Ronald Thisted, and briefed to the Board before it upheld all claims of the ’514
`
`patent.
`
`Finally, it would be inefficient for the Board to institute inter partes review
`
`because Mylan is litigating the same issues in concurrent ANDA litigation in the
`
`Northern District of West Virginia. Twenty-two other defendants have also
`
`challenged the ’514 patent in the District of Delaware. Here, Mylan delayed for
`
`nearly a year in filing the Petition, waiting until after it received a trial date for
`
`February 2020 in the West Virginia litigation. Mylan’s delay likely places the
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`Board’s statutory one-year deadline for a final written decision (if instituted) within
`
`the same month as the trial, February 2020. Expending Office resources to institute
`
`and conduct an IPR while multiple other tribunals consider the same issues in
`
`3
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`parallel would be an inefficient use of Office resources, which justifies a denial of
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`Mylan’s Petition under § 314(a).
`
`Consequently, Biogen respectfully requests that the Board deny Mylan’s
`
`Petition on the merits or as an appropriate exercise of its discretion under 35 U.S.C.
`
`§ 325(d) and/or § 314(a).
`
`II. Background
`A. The Challenge of Multiple Sclerosis
`MS is a debilitating neurologic autoimmune disease targeting the central
`
`nervous system. Ex. 2001, 8.2 MS leads to the loss of the myelin sheathing around
`
`neuronal axons (demyelination), loss of axons, and eventual neuronal death. Ex.
`
`1001, 1:15-20. Typical symptoms of MS include cognitive and ambulatory
`
`dysfunction, as well as visual loss, weakness, and numbness. Ex. 2001, 91-92.
`
`Treatment seeks to reduce neurodegeneration by, e.g., preventing or reducing axonal
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`loss and neuronal death. Ex. 1001, 5:47-59.
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`The most common form of MS is relapsing-remitting MS (“RRMS”). Patients
`
`with RRMS may experience “attacks” of active neurodegeneration alternating with
`
`periods of remission and improvement of symptoms. Ex. 2002, 3; Ex. 2001, 85.
`
`
`All citations to exhibits submitted in this proceeding appear in bold font.
`2
`
`Citations refer to the stamped-on page numbers.
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`4
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`Attacks may occur, remit, and recur “seemingly randomly over many years.” Ex.
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`1001, 1:28-34.
`
`The relapsing and remitting nature of RRMS complicates treating the disease.
`
`Ex. 2002, 5 (“Relapse rate, relapse duration, [and] recovery after relapses are all
`
`highly variable between patients and within one patient.”). A clinician may be
`
`unable to discern whether a patient is responding to pharmaceutical treatment or
`
`simply experiencing a period of remission. Id. (attributing observed stabilization in
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`MS patients to “regression to the mean phenomenon, and by a real placebo effect,
`
`as well as [to] the natural course of the disease”). Large-scale Phase III clinical trials
`
`are therefore required for MS drug approval, where each dosing arm can be
`
`evaluated for statistically significant efficacy on clinically validated endpoints, such
`
`as relapse rate and disability progression, as compared to placebo. Id.; Ex. 1038, 1;
`
`Ex. 1039, 1. Indeed, the European Medicines Agency’s (“EMA”) guidelines for
`
`investigating treatments for RRMS require long-term trials that are “sufficiently
`
`large and long to overcome this inter and intra-individual variability.” Ex. 2002, 5.
`
`By contrast, noninferiority studies, which analyze a drug for equivalence against
`
`another known MS treatment, “are insufficient.” Id., 5, 11.
`
`B.
`Biogen’s Phase II Clinical Trial
`In 2004, Biogen initiated a randomized, double-blind, placebo-controlled
`
`clinical trial to evaluate three orally administered doses of DMF in MS patients: 120,
`
`5
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`U.S. Patent No. 8,399,514
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`360, and 720 mg/day. Ex. 1046, 2-3. Several of Mylan’s references describe aspects
`
`of this Phase II trial, including the lead reference in each of Mylan’s proposed
`
`grounds (i.e., January 2006 Press Release or Kappos 2006). The Phase II trial has
`
`already been extensively considered by the Office, as shown in the table below:
`
`Mylan
`Exhibit
`Ex. 1005
`
`Reference Related
`to Phase II Trial
`January 2006 Press
`Release
`Ex. 1007, 27 Kappos 2006
`
`Ex. 1010
`
`ClinicalTrials
`
`Ex. 1015
`
`Kappos 2005
`
`Ex. 1016
`
`Ex. 1034
`
`Ex. 1046,
`8-29
`
`May 2006 Press
`Release
`Kappos 2005
`Presentation
`Kappos 2006
`Presentation
`
`Prior Consideration by:
`Examiner3
`Board
`-
`✓
`
`✓
`
`✓
`
`-
`
`✓
`
`-
`
`✓
`
`Lead reference in
`Coalition II as Ex. 1003
`Asserted reference in
`Coalition I as Ex. 1022
`and Coalition II as
`Ex. 1022
`in
`reference
`Lead
`Coalition I as Ex. 1003
`Submitted in Coalition II
`as Ex. 2057
`Submitted in Coalition II
`as Exs. 2005, 2014
`Submitted in Coalition
`II as Ex. 1007, 56-77
`
`
`Ex. 1001, 3, 7, 8, 10.
`3
`
`6
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`

`

`Mylan
`Exhibit
`
`Reference Related
`to Phase II Trial
`
`Ex. 1048
`
`Kappos 2008
`Lancet Article
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`U.S. Patent No. 8,399,514
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`Prior Consideration by:
`Examiner3
`Board
`and FP Interference as
`Ex. 2025
`Submitted in Coalition II
`as Ex. 2058
`
`✓
`
`The 720 mg/day dose tested in Biogen’s Phase II trial met the primary
`
`endpoint, “significantly reduc[ing] the mean number of new Gd+ lesions . . .
`
`compared with placebo” by 69%. Ex. 1007, 27; Ex. 1046, 4, 19. The 720 mg/day
`
`dose also produced statistically significant results on several secondary endpoints.
`
`Ex. 1046, 20-22. By contrast, the 120 mg/day and 360 mg/day dose groups did not
`
`achieve statistical significance for any of the primary or secondary endpoints. Id., 4,
`
`19-22; Ex. 1016, 1.
`
`C. Biogen’s Phase III Clinical Trials
`Following its Phase II trial, Biogen moved forward with the 720 mg/day dose
`
`and a 480 mg/day dose—not the 360 or 120 mg/day doses—in its two randomized,
`
`double-blind, placebo-controlled Phase III clinical trials named DEFINE and
`
`CONFIRM. Ex. 1038; Ex. 1039. The DEFINE study enrolled 952 patients and
`
`lasted two years. Ex. 1038, 3-4. The CONFIRM study enrolled 1417 patients and
`
`also lasted two years. Ex. 1039, 3.
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`7
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`The results of the DEFINE and CONFIRM trials were published in the New
`
`England Journal of Medicine. Ex. 1038; Ex. 1039. These trials demonstrated that
`
`the 480 mg/day dose (240 mg BID) had a similar magnitude of efficacy compared
`
`to the higher 720 mg/day dose (240 mg TID) on all primary and secondary endpoints.
`
`Ex. 1038, 6-7; Ex. 1039, 6. The similar magnitude of efficacy for the 480 mg/day
`
`and 720 mg/day doses on all endpoints in both Phase III trials was unexpected and
`
`stands in sharp contrast to the 360 mg/day dose evaluated in Biogen’s Phase II trial,
`
`which failed to reach statistical significance (much less match the 720 mg/day dose’s
`
`magnitude of effect) for any endpoint. Ex. 1046, 4, 19-22; Ex. 1016, 1.
`
`D. The FDA Approves Tecfidera®
`After the successful DEFINE and CONFIRM studies, Biogen filed its NDA
`
`for Tecfidera®. The FDA compared the two dosing arms of the Phase III trials when
`
`analyzing the NDA, reporting that the 480 mg/day and 720 mg/day doses “had very
`
`comparable efficacy on the primary endpoints and all key secondary endpoints.” Ex.
`
`2003, 8. In addition, because the 720 mg/day dose “offered no additional efficacy”
`
`compared to the 480 mg/day dose, the FDA “recommend[ed] approval of the 240
`
`mg bid [i.e., 480 mg/day] dose only.” Id.
`
`8
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`E.
`
`Biogen Launches Tecfidera®—Embodied by the ’514 Patent
`Claims—to Great Success
`Biogen launched Tecfidera®, its 480 mg/day DMF treatment for MS, in April
`
`2013 following FDA approval. See Ex. 2005, 2-3. The New York Times described
`
`Tecfidera® as offering “a tantalizing combination of efficacy and safety” to patients,
`
`many of whom delayed MS treatment until Tecfidera® became available. Ex. 2006,
`
`5, 11. After just six months on the market, Tecfidera® eclipsed Gilenya®
`
`(fingolimod) and Aubagio® (teriflunomide) to become the leading oral MS therapy
`
`in the United States. Ex. 2005, 2. Reuters similarly reported that Tecfidera® had a
`
`“favorable” safety and efficacy profile compared to Gilenya® and Aubagio®. Ex.
`
`2007, 1. FirstWord Pharma reported that initial experiences with Tecfidera®
`
`“matched or exceeded . . . expectations and referrals for treatment are coming from
`
`both patient and physician initiated use.” Ex. 2008, 1.
`
`More than five years later, the commercial success of Tecfidera® has only
`
`strengthened. Tecfidera® remains the most prescribed oral MS therapy in the United
`
`States. Ex. 2009, 1. Tecfidera® currently generates approximately $4 billion in
`
`annual sales worldwide. See Ex. 2010, 2.
`
`III. The Prosecution and Issuance of the ’514 Patent
`Biogen filed U.S. Patent Application No. 13/372,426 (“the ’426 application”)
`
`on February 13, 2012, claiming benefit of priority through a chain of applications to
`
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`U.S. Provisional Application No. 60/888,921, filed on February 8, 2007. Biogen
`
`filed a preliminary amendment presenting a set of new claims, which remained
`
`unchanged during prosecution. Ex. 2015, 4-6; see also Ex. 2019, 2-5; Ex. 2022,
`
`2-5. The ’426 application issued as the ’514 patent on March 19, 2013.
`
`In its preliminary amendment, Biogen argued that it was “unexpected that the
`
`dose of about 480 mg/day DMF was similarly effective compared to the higher dose
`
`of about 720 mg/day.” Ex. 2015, 10. In support of these statements, Biogen
`
`submitted a Rule 132 declaration from Dr. Katherine Dawson, Senior Director of
`
`Medical Research at Biogen.4
`
`The Examiner agreed that “[t]he unexpected and advantageous results
`
`demonstrated for the claimed method relative to the other embodiments that are
`
`disclosed in the instant specification are not in dispute.” Ex. 2018, 7.5 Nevertheless,
`
`the Examiner maintained two obviousness rejections over Joshi ’072, the published
`
`application corresponding to Joshi ’999 and Schimrigk 2006, respectively, based on
`
`
`4 Mylan omitted many pages from its submitted version of the Declaration of
`
`Katherine T. Dawson, M.D. Ex. 1046. A complete version, previously submitted
`
`in Coalition II and the FP Interference, is submitted herewith. Ex. 2015, 15-87.
`
`5
`
`Emphases are added unless otherwise noted.
`
`10
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`a legally incorrect position that unexpected results must be documented in the
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`specification. Id., 7-9.
`
`Following Biogen’s submission of legal arguments illustrating that evidence
`
`of unexpected results need not be fully recognized at the time of filing, as well as
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`another Rule 132 declaration from Dr. Richard Rudick (then employed at the
`
`Cleveland Clinic) further supporting the unexpected results of Biogen’s 480 mg/day
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`dose, the Examiner allowed the ’426 application and the ’514 patent issued. Ex.
`
`2019, 18-26; Ex. 2020; Ex. 2023.
`
`IV. The Serial Challenges to the ’514 Patent Before the PTAB
`Over the past several years, the Board has vetted Biogen’s ’514 patent in
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`three post-grant challenges. During those proceedings and/or during prosecution,
`
`the Office has considered essentially every reference Mylan raises here:
`
`Mylan
`Ground
`1
`
`Mylan References Asserted
`
`January 2006 Press Release
`(Ex. 1005)
`
`
`Schimrigk 2004 (Ex. 1006)
`
`
`Prior Consideration by the
`Examiner or the Board
`Considered during prosecution
`(Ex. 1001, 7); cumulative of Kappos
`2006, Kappos 2005, and ClinicalTrials
`advanced in Coalition I and/or
`Coalition II (Ex. 2027, 5; Ex. 2038, 8)
`Cumulative of Schimrigk 2006 article
`applied during prosecution (Ex. 2018,
`
`11
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`

`

`Mylan References Asserted
`
`Mylan
`Ground
`
`2
`
`Kappos 2006 (Ex. 1007)
`
`
`Schimrigk 2004 (Ex. 1006)
`
`
`3
`
`Kappos 2006 (Ex. 1007)
`
`
`WO ’342 (Ex. 1008)
`
`4
`
`Kappos 2006 (Ex. 1007)
`
`
`ClinicalTrials (Ex. 1010)
`
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`Prior Consideration by the
`Examiner or the Board
`6) and addressed in Coalition I (Ex.
`2027, 5)
`Lead reference in Coalition II
`(Ex. 2038, 8) and considered during
`prosecution (Ex. 1001, 8)
`Cumulative of Schimrigk 2006 article
`applied during prosecution (Ex. 2018,
`6) and addressed in Coalition I (Ex.
`2027, 5)
`Lead reference in Coalition II
`(Ex. 2038, 8) and considered during
`prosecution (Ex. 1001, 8)
`Considered during prosecution
`(Ex. 1001, 2); identical U.S.
`application evaluated during FP
`Interference (Ex. 2030, 1)
`Lead reference in Coalition II
`(Ex. 2038, 8) and considered during
`prosecution (Ex. 1001, 8)
`Asserted reference in Coalition I
`(Ex. 2027, 5) and Coalition II
`(Ex. 2038, 8); considered during
`prosecution (Ex. 1001, 10)
`
`12
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`

`

`Mylan References Asserted
`
`Mylan
`Ground
`
`Joshi ’999 (Ex. 1009)
`
`
`ICH Guideline (Ex. 1011)
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`Prior Consideration by the
`Examiner or the Board
`Asserted reference in Coalition II
`(Ex. 2038, 8); corresponding published
`application applied during prosecution
`(Ex. 2018, 4)
`Asserted reference in Coalition I (Ex.
`2027, 5) and Coalition II (Ex. 2038, 8)
`
`A. Coalition for Affordable Drugs V LLC v. Biogen MA Inc., IPR2015-
`01136 (“Coalition I”)
`In the first of the three post-grant challenges against Biogen’s ’514 patent, an
`
`IPR petitioner asserted three obviousness grounds against claims 1-20 of the ’514
`
`patent based on the following combinations of references: (1) Kappos 2005 and ICH
`
`Guideline, (2) ClinicalTrials and ICH Guideline, and (3) ICH Guideline and
`
`statements in Biogen’s specification regarding Schimrigk 2006. Ex. 2027, 5
`
`(Coalition I, Decision Denying Institution); see also Ex. 2024 (Coalition I Petition).
`
`The Board denied institution in Coalition I, rejecting the petitioner’s routine-
`
`optimization arguments for obviousness. Id., 9-15; Ex. 2024, 23 (petitioner alleging
`
`that a POSA would have sought “to determine the appropriate dosing range of DMF
`
`or MMF”). The Board concluded that petitioner had not met its burden to show that
`
`there was a reasonable likelihood that it would prevail. See Ex. 2027, 9-15.
`
`13
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`The Board also rejected petitioner’s attempted reliance on background
`
`references describing the use of fumarates for psoriasis, a skin disease that is
`
`different than the neurological disease of MS. The Board concluded that “we find
`
`the connection between psoriasis and MS too speculative to support a finding that
`
`because DMF is effective for treating psoriasis that it also would be effective for
`
`treating MS.” Id., 13-14.
`
`The unsuccessful Coalition I grounds significantly overlap with Mylan’s
`
`proposed grounds in the Petition. Pet., 4-5. Mylan asserts ClinicalTrials and ICH
`
`Guideline in Ground 4. Id., 5. In Grounds 1 and 2, Mylan also asserts Schimrigk
`
`2004, which is a quarter-page abstract containing less disclosure than Schimrigk
`
`2006, a full seven-page article concerning the same Fumaderm® study. Id., 4.
`
`Kappos 2005 concerns the same Biogen Phase II trial as the quarter-page Kappos
`
`2006 abstract that Mylan cites as its lead reference in Grounds 2-4. Id., 4-5.
`
`B.
`
`Biogen MA Inc. v. Forward Pharma A/S, Intf. 106,023
`(“FP Interference”)
`In parallel with the Coalition I IPR, the Board declared an interference
`
`between the ’514 patent and a pending Forward Pharma A/S (“FP”) application, in
`
`which FP had substantially copied the ’514 patent’s claims and requested an
`
`interference.
`
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`In a patentability motion, FP asserted that all claims of the ’514 patent were
`
`anticipated or rendered obvious by the PCT publication corresponding to its
`
`involved application, WO ’342 (Ex. 1008)—i.e., the same reference Mylan asserts
`
`in Ground 3. Pet., 5. Biogen filed a threshold written description motion against the
`
`FP application, asserting that it failed to adequately describe the claims FP had
`
`copied from Biogen’s ’514 patent, including the feature of 480 mg/day DMF and/or
`
`MMF for treating MS. Ex. 2028.
`
`The Board granted Biogen’s written description motion, finding that FP’s
`
`specification (published as WO ’342) “does not indicate 480 mg/day is a
`
`therapeutically effective dose” with respect to MS or any other disease. Ex. 2030,
`
`22-24 (FP Interference Decision). The Federal Circuit affirmed the Board’s
`
`decision, “agree[ing] that [FP’s] application does not disclose” the claimed
`
`inventions in Biogen’s ’514 patent. FWP, slip op. at 10, 18. Rejecting FP’s reliance
`
`on the prior art to remedy deficiencies in the WO ’342 specification, the court
`
`additionally found that “the prior art does not teach the key limitation of the count:
`
`the 480 mg daily dosage.” Id. at 14.
`
`15
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`The court also referenced the unexpected results demonstrated in Biogen’s
`
`Phas