Filed: October 7, 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.
`____________________________
`Case No. IPR2018-01431
`U.S. Patent No. 8,399,514
`____________________________
`
`
`PETITIONER’S REPLY TO BIOGEN’S
`PATENT OWNER RESPONSE
`
`
`
`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.
`____________________________
`Case No. IPR2018-01431
`U.S. Patent No. 8,399,514
`____________________________
`
`
`PETITIONER’S REPLY TO BIOGEN’S
`PATENT OWNER RESPONSE
`
`
`
`1 Case IPR2019-00789 has been joined with this proceeding.
`
`
`
`
`
`TABLE OF CONTENTS
`
`
`Page
`
`B.
`
`
`INTRODUCTION .................................................................................................... 1
`I.
`The Claims of the ’514 Patent Were Obvious ..................................... 2
`A.
`POSAs Were Motivated to Optimize the DMF Daily
`Dose............................................................................................ 2
`POSAs Would Have Reasonably Expected 480 mg/day
`to Be Efficacious ........................................................................ 4
`1.
`Schimrigk Demonstrated 360 mg/day and 720
`mg/day Were Efficacious ................................................ 4
`The January 2006 Press Release Confirmed
`Successful RRMS Treatment with DMF
`Monotherapy .................................................................... 6
`DMF’s Use to Treat Psoriasis Supports
`Obviousness ..................................................................... 7
`Kappos 2006 Abstract Confirmed that 360 mg/day
`and 720 mg/day Were Efficacious .................................. 7
`The Kappos Presentation Provided More
`Confirmation That 360 mg/day Was Efficacious ............ 8
`Petitioner Has Not Relied on Fox/Gold or the
`EMA to support its Prima Facie Case ........................... 10
`POSAs Would Not Have Looked to Doses Higher
`Than 720 mg/day ........................................................... 10
`8. WO ’342 Provides Additional Confirmatory
`Evidence of a Reasonable Expectation of Success ....... 11
`The Ground 4 References Likewise Provide a
`Reasonable Expectation of Success ............................... 12
`C. All Dependent Claims Are Obvious ........................................ 12
`D.
`Biogen’s Secondary Considerations Fail to Overcome the
`Prima Facie Case ...................................................................... 12
`1.
`Biogen Has Not Established Unexpected Results ......... 12
`2.
`Biogen Has Not Established Commercial Success ....... 13
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
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`7.
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`9.
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`
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`
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`-i-
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`TABLE OF CONTENTS
`(continued)
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`Page
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`3.
`
`Biogen Has Not Established Long-Felt Need or
`Praise of Others.............................................................. 14
`Petitioner’s Grounds Rely Exclusively on Prior Art .......................... 15
`A.
`Petitioner’s Ground 1 Relies on § 102(b) Prior Art ................. 15
`B.
`The Kappos Trial Was Not Solely Dr. O’Neill’s Work .......... 16
`C.
`Petitioner Did Not Raise a Priority Date Challenge in this
`IPR............................................................................................ 22
`Biogen’s Own Press Releases are Prior Art............................. 23
`
`D.
`
`-ii-
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`II.
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`
`
`TABLE OF AUTHORITIES
`
`
`Page
`
`
`CASES
`Acceleration Bay, LLC v. Activision Blizzard Inc.,
`908 F.3d 765 (Fed. Cir. 2018) ............................................................................ 24
`Acorda Therapeutics, Inc. v. Roxane Labs., Inc.,
`903 F.3d 1310 (Fed. Cir. 2018) .......................................................................... 13
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) ............................................................................ 16
`Biogen Int’l GmbH v. Mylan Pharm., Inc.,
`No. 17-cv-116-IMK (N.D.W. Va.) ..................................................................... 21
`Biogen MA Inc. v. Forward Pharma A/S,
`Interference 106,023 (PTAB Mar. 31, 2017) (Paper 813) ................................. 11
`Coalition for Affordable Drugs (ADROCA) LLC v. Acorda
`Therapeutics, Inc.,
`IPR2015-01850, 2017 WL 950736 (PTAB Mar. 9, 2017) ................................. 18
`Coriant (USA) Inc. v. Oyster Optics, LLC,
`IPR2018-00258, 2018 WL 2761411 (PTAB June 6, 2018) ............................... 24
`E.I. Dupont de Nemours & Co. v. Synvina C.V.,
`904 F.3d 996 (Fed. Cir. 2018) .......................................................................... 2, 7
`EmeraChem Holdings, LLC v. Volkswagen Group of Am., Inc.,
`859 F.3d 1341 (Fed. Cir. 2017) .......................................................................... 22
`Ex Parte ePlus, Inc.,
`No. 2010-00784, 2011 WL 1918594 (BPAI May 18, 2011), aff’d
`per curiam, In re ePlus, Inc., 540 F. App’x 998 (Fed. Cir. 2013) ............... 24, 25
`Fisher & Paykel Healthcare Ltd. v. ResMed Ltd.,
`IPR2017-00062, 2018 WL 1605264 ................................................................... 25
`FWP IP APS v. Biogen MA, Inc.,
`749 F. App’x 969 (Fed. Cir. 2018) ..................................................................... 11
`
`
`
`
`
`-iii-
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`
`
`
`
`TABLE OF AUTHORITIES
`(continued)
`
`Page
`
`
`Haliburton Energy Servs., Inc. v. Dynamic 3D Geosolutions LLC,
`IPR2014-01186, slip op. (PTAB Feb. 18, 2015) ................................................ 24
`In re Cronyn,
`890 F.2d 1158 (Fed. Cir. 1989) .......................................................................... 24
`In re Katz,
`687 F.2d 450 (C.C.P.A. 1982) ............................................................................ 17
`In re Morsa,
`713 F.3d 104 (Fed. Cir. 2013) ............................................................................ 23
`Intel Corp. v. Alacritech, Inc.,
`IPR2017-01392, 2018 WL 6190430 (PTAB Nov. 26, 2018) ............................. 25
`Johns Manville Corp. v. Knauf Insulation, Inc.,
`IPR2015-01453, 2017 WL 378547 (PTAB Jan. 11, 2017), aff’d,
`730 F. App’x 934 (Fed. Cir. 2018) ..................................................................... 23
`Liberty Mutual Ins., Co. v. Progressive Casualty Ins. Co.,
`CBM2012-00010, 2013 WL 6665065 (PTAB Feb. 25, 2013) ........................... 23
`Mako Surgical Corp. v. Blue Belt Techs., Inc.,
`IPR2015-00630, 2016 WL 5098789 (PTAB Aug. 1, 2016) ............................... 22
`Merck & Co. v. Teva Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .......................................................................... 13
`SRI Int’l, Inc. v. Internet Sec. Sys., Inc.,
`511 F.3d 1186 (Fed. Cir. 2008) .......................................................................... 24
`Stored Value Solutions, Inc. v. Card Activation Techs., Inc.,
`499 F. App’x 5 (Fed. Cir. 2012) ................................................................... 23, 24
`Teva Pharm. USA, Inc. v. Sandoz, Inc.,
`789 F.3d 1335 (Fed. Cir. 2015) .......................................................................... 14
`Varian Med. Sys., Inc. v. William Beaumont Hosp.,
`IPR2016-00163, 2017 WL 2117016 (PTAB May 4, 2017) ............................... 17
`
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`-iv-
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`INTRODUCTION
`The ’514 patent claims are unpatentable as obvious. By February 2006
`
`persons of ordinary skill in the art (“POSAs”) had all they needed to optimize the
`
`dose of dimethyl fumarate (“DMF”) to treat relapsing-remitting multiple sclerosis
`
`(“RRMS”), would have looked to administer 480 mg/day, and reasonably expected
`
`efficacy. In 2004, Schimrigk disclosed results suggesting 360 mg/day and 720
`
`mg/day of DMF dosed as Fumaderm® were therapeutically efficacious. In
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`January 2006, Biogen reported positive results from Dr. Kappos’ trial of 120
`
`mg/day, 360 mg/day, and 720 mg/day DMF monotherapy. Given these
`
`disclosures, DMF administered between 360 mg/day and 720 mg/day to treat
`
`RRMS would be reasonably expected to be therapeutically effective. POSAs had
`
`also
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`long understood DMF caused uncomfortable side effects,
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`including
`
`gastrointestinal issues and flushing. Moreover, in the past DMF had been
`
`administered three times daily, raising patient compliance concerns. By February
`
`2006, POSAs were amply motivated to pursue routine dose optimization.
`
`After February 2006, but before the February 2007 priority application filing
`
`leading to the ’514 patent, Dr. Kappos published additional conclusions and data
`
`confirming what POSAs already expected—that 720 mg/day effectively treated
`
`RRMS, and DMF operated in a dose-dependent manner. Dr. Kappos also
`
`presented his results disclosing that patients receiving 360 mg/day DMF had
`
`1
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`
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`significantly heighted baseline RRMS disease activity. Correcting for that
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`heighted activity was a simple matter for POSAs. Doing so provided further
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`confirmation of an effective dose range from 360 mg/day to 720 mg/day. Within
`
`this range, 480 mg/day was an obvious choice.
`
`I.
`
`THE CLAIMS OF THE ’514 PATENT WERE OBVIOUS
`Biogen attempts to undercut Petitioner’s prima facie obviousness case, but
`
`its arguments cannot save the ’514 patent.
`
`POSAs Were Motivated to Optimize the DMF Daily Dose
`A.
`By February 2006, POSAs were motivated to pursue a 480 mg/day DMF
`
`dose based on general drug development principles in light of known side effects
`
`and convenience considerations. As described infra, POSAs knew the range of
`
`360 mg/day to 720 mg/day of DMF was efficacious to treat RRMS, and standard
`
`drug development principles motivated POSAs to optimize the dose within that
`
`range. Ex. 1002 ¶¶ 125-154; Ex. 1121 ¶¶ 198-213, 220-222; E.I. Dupont de
`
`Nemours & Co. v. Synvina C.V., 904 F.3d 996, 1006 (Fed. Cir. 2018) (“For
`
`decades, this court and its predecessor have recognized that ‘where the general
`
`conditions of a claim are disclosed in the prior art, it is not inventive to disclose
`
`optimum or workable ranges by routine experimentation.’” (citation omitted)).
`
`Even if, however, 720 mg/day of DMF had been the only known efficacious daily
`
`DMF dose, POSAs would not stop there. Instead, POSAs would have been
`
`2
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`
`
`
`
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`motivated to lower the DMF dose to account for known side effects. Ex. 1002 ¶¶
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`151-52; Ex. 1121) ¶ 223. Indeed, the Board already found in a Final Written
`
`Decision that “one having ordinary skill in the art would have had ample reason to
`
`use routine experimentation . . . to determine the optimum doses for MS
`
`treatment.”2 IPR2015-01993, Paper 63 (“FWD”), 25-26.
`
`As for side effects, even before February 2006 they were a well-known
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`problem. Ex. 1002 ¶¶ 151-152 (citing, e.g., Exs. 1019, 1026, 1028); Ex. 1121 ¶
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`223. Likewise, Biogen’s argument that side effects did not vary by dose in the
`
`Kappos trial is wrong. Paper 38 (“Resp.”), 39. The Kappos presentation provides
`
`the percentage of patients experiencing side effects but says nothing about
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`incidence of events or severity of side effects. Id.; Ex. 1126, 63:20-65:11; Ex.
`
`1121 ¶ 225. Instead, the Kappos presentation informs POSAs that more patients
`
`taking 720 mg/day experienced GI side effects like diarrhea, abdominal pain, and
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`vomiting than those taking 360 mg/day. Ex. 1046, 25; Ex. 1121 ¶ 226. This is
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`consistent with the Board’s conclusion that “those working in the art would have
`
`had sufficient reason to investigate doses between 720 mg/day and 360 mg/day in
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`2 The Board’s previous finding references Kappos 2006. FWD 25-26. However,
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`Schimrigk 2004 Abstract combined with the January 2006 press release also
`
`teaches dose-dependency. Ex. 1002 ¶¶ 125-150, 154; Ex. 1121 ¶¶ 198-213, 221-
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`223.
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`3
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`
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`hopes of identifying [an] effective dose with fewer side-effects.”3 FWD 26.
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`Moreover, administration in two equal doses, rather than three, would have
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`motivated POSAs to optimize the dose and to administer 480 mg/day. Ex. 1002 ¶
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`153; Ex. 1121 ¶¶ 191, 208.
`
`B.
`
`POSAs Would Have Reasonably Expected 480 mg/day to Be
`Efficacious
`The clinical data also demonstrates that, before February 2006, POSAs
`
`would have reasonably expected 480 mg/day of DMF would be efficacious to treat
`
`RRMS. After February 2006 but before the priority date, the Kappos trial results
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`confirmed this expectation. Ex. 1002 ¶¶ 173-174; Ex. 1121 ¶¶ 221-224.
`
`1.
`
`Schimrigk Demonstrated 360 mg/day and 720 mg/day Were
`Efficacious
`Biogen complains that Schimrigk disclosed administration of Fumaderm®,
`
`not DMF monotherapy; suggests Schimrigk’s study design renders its results
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`meaningless; and criticizes Schimrigk for not finding “statistically significant
`
`effects on any clinical endpoints.” Resp. 15 18-23. Biogen’s complaints fail.
`
`First, Schimrigk taught POSAs that the tested dosages—720 mg/day and
`
`360 mg/day—were efficacious in RRMS. Schimrigk found a reduction in Gd+
`
`
`3 Again, the Board’s previous finding references the Kappos 2006 trial. FWD 25-
`
`26. However, if the Board looks only to § 102(b) art, DMF’s side-effects were
`
`well established before February 2006. Ex. 1002 ¶¶ 151-152; Ex. 1121 ¶ 223, 226.
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`4
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`
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`
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`lesions from baseline over the course of each treatment. Ex. 1006 (“Significant
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`reductions from baseline in the number of Gd+ lesions were observed starting after
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`week 12 of treatment . . . [and] over 70 weeks of treatment”); Ex. 1121 ¶¶ 199,
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`205-207.
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`Second, Schimrigk’s Fumaderm® efficacy finding is akin to DMF
`
`monotherapy. Ex. 1002 ¶¶ 132-140, 145, n.4, n.5; Ex. 1121 ¶¶ 200-204. DMF has
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`long been known to the be most active Fumaderm® component. Exs. 1023-1024;
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`Ex. 1002 n.5; Ex. 1121 ¶¶ 200-204. Indeed, in all four study publications,
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`Schimrigk referred to the DMF amount in Fumaderm® when describing the
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`administered dose. Exs. 1006, 1012, 1014; Ex. 1018, 2. POSAs understood
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`Schimrigk as treating RRMS with DMF and would have reasonably expected
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`success in doing so. Ex. 1002 ¶¶ 128-131, 132-145, n.5; Ex. 1121 ¶¶ 198-213,
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`220-223.
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`Third, Schimrigk designed his study to demonstrate efficacy at 360 mg/day
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`and 720 mg/day. Ex. 1006. Patients were first administered 720 mg/day following
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`titration. Id. Then there was a four-week washout period to remove drug effect.
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`Ex. 1002 ¶ 145; Ex. 1121 ¶ 205; Ex. 1131, 44:6-46:1. After the washout period,
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`patients received 360 mg DMF for more than 10 months. Ex. 1006; Ex. 1018.
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`POSAs would have expected that 360 mg/day accounted for the effect seen over
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`the lengthy treatment phase. Ex. 1121 ¶¶ 205-207.
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`5
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`Biogen attempts to undermine Schimrigk’s findings by pointing to the
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`purported “small” and “baseline-controlled” nature of the study. These complaints
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`are meritless. The study employed a commonly used phase I study design and
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`provides useful teachings to optimize the dose. Ex. 1002 ¶¶ 128-131, 145; Ex.
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`1121 ¶¶ 209-212. The size and baseline-controlled design do not render the results
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`useless, nor does the phenomena known as regression to the mean. Ex. 1002 ¶¶
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`128-131, 145; Ex. 1121 ¶¶ 209-212. Regression to the mean would not prevent
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`POSAs from continued optimization. Ex. 1121 ¶¶ 209-212.
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`Fourth, Biogen’s comment regarding Schimrigk’s clinical efficacy findings
`
`ignores the primary endpoint results. Schimrigk found a statistically significant
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`reduction in Gd+ lesions—the study’s primary endpoint. Ex. 1006. Given that
`
`conclusion, POSAs would be motivated to optimize the dose of DMF within the
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`range of 360 mg/day and 720 mg/day with a reasonable expectation of success.
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`Ex. 1002 ¶ 145; Ex. 1121 ¶¶ 209-213.
`
`2.
`
`The January 2006 Press Release Confirmed Successful
`RRMS Treatment with DMF Monotherapy
`The January 2006 Press Release confirmed the reasonable expectation of
`
`success. It disclosed that the Kappos trial, in which RRMS patients were treated
`
`with placebo, 120 mg/day, 360 mg/day, or 720 mg/day of DMF monotherapy
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`resulted in a “statistically significant reduction in the total number of gadolinium-
`
`enhancing brain lesions,” the primary endpoint. Ex. 1005; Ex. 1034. Biogen’s
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`6
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`
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`complaint—that the 480 mg/day dose and DMF monotherapy are not mentioned—
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`is irrelevant. Resp. 15-16. Such a disclosure is not required for obviousness.
`
`DMF’s Use to Treat Psoriasis Supports Obviousness
`3.
`Petitioner’s use of psoriasis data is supported by the prior art. For example,
`
`Schimrigk and Kappos cited psoriasis studies. Ex. 1012; Ex. 1018; Ex. 1015; Ex.
`
`1046; Ex. 1126, 90:15-92:15; Ex. 1125, 74:7-78:20; Ex. 1121 ¶ 215. Thus,
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`POSAs at the time disagreed with Biogen’s experts’ hindsight critique of psoriasis
`
`data. Indeed, the relationship between psoriasis and MS is well-supported in the
`
`scientific literature. Ex. 1002 ¶¶ 133-137; Ex. 1121 ¶¶ 214-219.
`
`4. Kappos 2006 Abstract Confirmed that 360 mg/day and 720
`mg/day Were Efficacious
`While Schimrigk taught a 360 mg/day to 720 mg/day effective dose range,
`
`the Kappos 2006 Abstract reconfirmed it.
`
` Ex. 1002 ¶¶ 145, 167-169,
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`173-177; Ex. 1121 ¶¶ 184-187, 198-199, 205, 224-229. Kappos 2006 states
`
`“BG00012 (720 mg/day) significantly reduced the mean number of new Gd+
`
`lesions (the primary end point) compared with placebo.” Ex. 1007. Kappos 2006
`
`concludes, “BG00012 significantly reduces brain lesion activity, in a dose-
`
`dependent manner, as measured by MRI.” Id. (emphasis added). As the Board
`
`found, this teaches “the effectiveness of the 720 mg/day dose and that DMF is a
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`result-effective variable.” FWD 26; Synvina, 904 F.3d at 1009 (“[I]f the prior art
`
`does recognize that the variable affects the relevant property or result, then the
`
`7
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`
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`variable is result-effective.” (citation omitted)). Moreover, as the Board concluded
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`“[t]hose working the art would also have had a reasonable expectation of success
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`in determining additional therapeutically effective doses.” FWD 26. Thus, the
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`likely success of 480 mg/day was taught by the prior art. Ex. 1002 ¶¶ 145, 173-
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`177; Ex. 1121 ¶¶ 184-187, 198-199, 205, 224-229.
`
`5.
`
`The Kappos Presentation Provided More Confirmation
`That 360 mg/day Was Efficacious
`The Kappos 2006 Presentation provides still more support for a known 360
`
`mg/day to 720 mg/day effective dose range. The data confirm DMF’s dose-
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`dependency because POSAs would have immediately noticed the heightened
`
`baseline disease activity in the 360 mg/day group. Ex. 1002 ¶ 179; Ex. 1003 ¶
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`170; Ex. 1121 ¶ 149. Even without correcting for that imbalance, POSAs would
`
`have anticipated the heightened disease activity obscured a treatment effect in the
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`360 mg/day group. Ex. 1002 ¶¶ 179-180; Ex. 1121 ¶¶ 149, 153-154; Ex. 1125,
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`145:5-146:7, 149:18-150:12.
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`Moreover, when that heightened disease activity is addressed by employing
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`calculations well known to POSAs, the data strongly suggests efficacy with 360
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`mg/day. Ex. 1003 ¶¶ 170-178; Ex. 1121 ¶¶ 170-178. Biogen’s complaints
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`regarding the calculations are unfounded.
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`First, the alleged “transient” nature of Gd+ lesions ignores evidence well-
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`known at the priority date that current RRMS disease activity is predictive of
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`8
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`future disease activity. Resp. 32-33; Ex. 1121 ¶¶ 170-178; Ex. 1125, 145:5-146:7,
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`149:18-150:12. RRMS patients experiencing heightened disease activity are more
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`likely to experience additional disease activity. Ex. 1121 ¶ 177. Moreover, while
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`Biogen brushes aside the more than three-fold baseline lesion difference, that
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`imbalance is significant, particularly because it impacts the primary endpoint. Id.
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`¶¶ 149-154. The heightened disease activity in the 360 mg/day group called out
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`for correction. Id. ¶ 153-154.
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`Second, Biogen’s allegation that Petitioner failed “to consider the large
`
`standard deviations reported for the Gd+ baseline data” is wrong. Resp. 33. The
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`standard deviation for the 360 mg/day group indicates that the group experienced
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`variation, but regardless requires correction. Ex. 1121 ¶¶ 173-174.
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`Third, Biogen’s concerns with patient populations (i.e., the “enrolled” group
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`versus the group that completed), is unfounded. Resp. 33-34. There is nothing
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`unusual about the number of patients in the enrolled versus completed group, and
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`nothing on the slides indicates that those who dropped out were not representative
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`of the group. Ex. 1121 ¶ 173. POSAs would appropriately assume that the
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`characteristics of the enrolled and completed groups were comparable.
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`Fourth, Biogen’s allegations that Petitioner’s calculations are “untested,
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`unsupported, and without clinical relevance,” are insubstantial. Petitioner’s expert,
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`Dr. Benet, is a highly regarded clinical pharmacologist with ample drug
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`9
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`development expertise and an in-depth understanding of clinical trials. Ex. 1003,
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`Ex. A. Dr. Greenberg, an experienced neurologist, agrees with the calculations and
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`endorses their clinical relevance. Ex. 1121, Ex. A. Finally, while Fox/Gold,
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`Phillips, and the EMA Report are not offered in the prima facie case, it is notable
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`that those POSAs, and the EMA, have endorsed the adjustments.
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`Fifth, Petitioner’s calculations are not “arbitrary” or “inconsistent,” as
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`Biogen contends. Resp. 35-36. They are commonly accepted ways to correct for
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`a baseline imbalance. Ex. 1121 ¶¶ 171-183.
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`6.
`
`Petitioner Has Not Relied on Fox/Gold or the EMA to
`support its Prima Facie Case
`Biogen argues Fox/Gold and the EMA are not relevant to prima facie
`
`obviousness. Resp., 28-31. Petitioner agrees. Petitioner references those in
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`addressing Biogen’s unexpected results arguments. Paper 2 (“Pet.”) 54-59.
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`Moreover, in the unexpected results context, Petitioner has submitted those as
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`evidence of their respective authors’ agreement with Petitioner’s experts, casting
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`doubt on Biogen’s criticisms. Id.; Ex. 1121 ¶¶ 158-170.
`
`7.
`
`POSAs Would Not Have Looked to Doses Higher Than 720
`mg/day
`Biogen argues wrongly that POSAs would have looked to doses higher than
`
`720 mg/day. The highest dose tested anywhere in the prior art was 720 mg/day,
`
`with nothing supporting a higher dose. Ex. 1121 ¶ 226. Moreover, known side
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`10
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`
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`effects caused POSAs to look to doses lower than 720 mg/day. Ex. 1002 ¶¶ 151-
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`152; Ex. 1121 ¶¶ 223-229. Nor would the reduction in Gd+ lesions in the Kappos
`
`trial encourage exploration of higher doses. The reduction was the Phase II study’s
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`primary endpoint and reached statistical significance. Ex. 1121 ¶ 188; Ex. 1002
`
`¶¶ 175-177. The study was not powered to look at clinical efficacy endpoints, so
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`POSAs would not be dissuaded by a lack of statistically significant clinical effects.
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`Ex. 1121 ¶¶ 188, 227-229.
`
`8. WO ’342 Provides Additional Confirmatory Evidence of a
`Reasonable Expectation of Success
`WO ’342 also supports a reasonable expectation of success. Ex. 1002 ¶¶
`
`184-186, 188; Ex. 1121 ¶¶ 230-232. Biogen’s assertion that the Federal Circuit
`
`has found otherwise is wrong. The Federal Circuit considered written description,
`
`a different legal question. FWP IP APS v. Biogen MA, Inc., 749 F. App’x 969
`
`(Fed. Cir. 2018). The Board has, however, previously commented on WO ’342 in
`
`the context of the ’514 patent, noting there is a significant difference between
`
`evaluating written description and “what might have been obvious.” Decision at
`
`28, Biogen MA Inc. v. Forward Pharma A/S, Interference 106,023 (PTAB Mar. 31,
`
`2017) (Paper 813) (“Using the prior art in the way urged by FP may show that the
`
`claimed subject matter, when considered with the prior art, might have been
`
`obvious to one skilled in the art,” even if it “fails to show … that FP’s inventors
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`11
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`had possessed and described the specific treatment method they now claim.”
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`(emphasis added)). WO ’342 thus supports obviousness.
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`9.
`
`The Ground 4 References Likewise Provide a Reasonable
`Expectation of Success
`Despite Biogen’s criticisms of the Ground 4 references, the Board already
`
`found based on those references that “[t]hose working in the art would have . . .
`
`had a reasonable expectation of success in determining additional therapeutically
`
`effective doses [between 720 mg/day and 360 mg/day].” FWD 26. Biogen offers
`
`nothing new. The Ground 4 references support a finding of prima facie
`
`obviousness.
`
`C. All Dependent Claims Are Obvious
`Biogen does not appear to dispute that the prior art discloses all limitations
`
`in the ’514 patent’s dependent claims. As set forth in Petitioner’s opening papers,
`
`all dependent claim elements are obvious. Pet. 38-44.
`
`D. Biogen’s Secondary Considerations Fail to Overcome the Prima
`Facie Case
`Biogen Has Not Established Unexpected Results
`1.
`Biogen’s assertion that it was unexpected that the “480 mg/day dose of DMF
`
`had efficacy . . . similar to the . . . 720 mg/day dose” fails to overcome Petitioner’s
`
`prima facie case. Resp. 49-55. The arguments set forth in Biogen’s response are
`
`functionally the same as what Biogen has said before, and what Petitioner
`
`preemptively rebutted in its opening papers. Pet. 53-61. Ex. 1002 ¶¶ 201-215; Ex.
`
`12
`
`
`
`
`
`
`1003 ¶¶ 201-229; Ex. 1004 ¶¶ 24-36. Despite having already rebutted Biogen’s
`
`arguments, submitted with this reply are Dr. Greenberg’s positions, in agreement
`
`with Drs. Corboy and Benet. Ex. 1121 ¶¶ 139-236. As detailed therein, Biogen’s
`
`results were entirely expected. Id.
`
`Petitioner’s challenge to unexpected results does not rely “primarily” on Dr.
`
`McKeague’s analysis. Resp. 49-55. Drs. Corboy, Benet, and Greenberg have all
`
`provided extensive opinions showing that the efficacy of 480 mg/day DMF was
`
`not unexpected. Ex. 1121 ¶¶ 139-236; Ex. 1002 ¶¶ 201-215; Ex. 1003 ¶¶ 201-229.
`
`Biogen Has Not Established Commercial Success
`2.
`Biogen cannot demonstrate commercial success. Biogen ignores the DMF
`
`intellectual property rights in place before the priority date. These rights, and
`
`Biogen’s development of Tecfidera, would have discouraged others from
`
`developing the DMF monotherapy claimed in the ’514 patent. Ex. 1120 ¶¶ 39-44.
`
`Biogen tries to blur the issue, asserting it had no rights related to “Aubagio® and
`
`Gilenya®.” Resp. 60. But the relevant inquiry is whether Biogen had rights
`
`covering products practicing the ’514 claims, not the development of competitive
`
`technologies. Acorda Therapeutics, Inc. v. Roxane Labs., Inc., 903 F.3d 1310,
`
`1340 (Fed. Cir. 2018) (“the risk of infringement . . . would have provided an
`
`independent incentive for a patentee not to develop the invention of the . . . patents,
`
`even if those inventions were obvious.” (alterations and citations omitted)); Merck
`
`13
`
`
`
`
`
`
`& Co. v. Teva Pharm. USA, Inc., 395 F.3d 1364, 1377 (Fed. Cir. 2005) (others
`
`were “legally barred” “from practicing [the claimed invention]”).
`
`Moreover, Biogen’s assertion that commercial success was tied to “the
`
`strong Phase III results” and “Tecfidera’s unique combination of oral efficacy and
`
`safety” is irrelevant. The ’514 patent does not claim tolerability, safety, or
`
`convenience. Moreover, DMF’s efficacy—and oral administration route—was
`
`known in the prior art, and so cannot establish nexus. Ex. 1002. ¶¶ 11–14, 47-56,
`
`66–74.
`
`Additionally, Biogen’s marketing and promotion of Tecfidera and the
`
`discounts and allowances it offered, are sales drivers. Ex. 1120 at ¶¶ 55-77. Thus,
`
`commercial success cannot be found.
`
`3.
`
`Biogen Has Not Established Long-Felt Need or Praise of
`Others
`Finally, the patent satisfied no long-felt but unmet need, because the prior art
`
`satisfied any need “for a safe and clinically effective oral MS treatment.” Resp.
`
`56. The claims recite methods of using DMF, a compound covered by other MS
`
`method patents at the priority date. Teva Pharm. USA, Inc. v. Sandoz, Inc., 789
`
`F.3d 1335, 1338 (Fed. Cir. 2015). Therefore, no other entity could have brought it
`
`to market. Had others been allowed to compete, the prior art disclosed the
`
`treatment of MS with oral DMF. Ex. 1002 ¶ 215; Ex. 1121 ¶¶ 237-243.
`
`14
`
`
`
`
`
`
`II.
`
`PETITIONER’S GROUNDS RELY EXCLUSIVELY ON PRIOR ART
`Biogen argues wrongly that Petitioner’s Grounds fail for relying on non-
`
`prior art. Resp. 4-11. Petitioner’s Ground 1 relies on § 102(b) prior art only.
`
`Petitioner’s Grounds 2-4 rely on § 102(a) prior art because certain references
`
`describe the Kappos trial—the work of many, not solely Biogen’s Dr. O’Neill.
`
`Petitioner’s Ground 1 Relies on § 102(b) Prior Art
`A.
`Despite Biogen’s contention that Petitioner’s Ground 1 “invokes” § 102(a)
`
`Kappos prior art, the record is clear that it relies only on prior art under § 102(b).
`
`Ground 1 asserts obviousness over a January 2006 Biogen press release and the
`
`Schimrigk 2004 Abstract. It is undisputed that neither reference is § 102(a) prior
`
`art. As to Ground 1, Mylan’s experts stated in no uncertain terms that POSAs
`
`“would have had motivation to pursue and a reasonable expectation of success in
`
`treating patients with MS with 480 mg/day of DMF based on prior art references
`
`available before February 8, 2006.” Ex. 1002 ¶ 173; Ex. 1003 ¶ 135; Ex. 1121 ¶
`
`221. Moreover, Dr. Corboy stated—in discussing separate Ground 2—that
`
`“[a]dditional art, including Kappos 2006, that was available after February 8, 2006
`
`but before the claimed priority date of the ’514 patent” serves as confirmatory
`
`obviousness evidence. Ex. 1002 ¶ 174 (emphasis added). Biogen plucks from a
`
`single Petition footnote a citation to one paragraph (¶153, cited among 18
`
`paragraphs) of Dr. Corboy’s declaration, and that paragraph itself discusses
`
`15
`
`
`
`
`
`
`numerous pre-February 2006 references. Biogen never explains how this citation
`
`shows that Ground 1 is “built upon” § 102(a) references. Resp. 4-5. Biogen’s
`
`argument related to Ground 1 is easily rejected.4
`
`The Kappos Trial Was Not Solely Dr. O’Neill’s Work
`B.
`Exhibits 1007, 1046, and 1016 do not describe the work solely of Dr.
`
`O’Neill. Instead, the Kappos Phase II trial was the work of many, including Dr.
`
`Kappos and members of Biogen’s Clinical Trial Review Board (“CTRB”). Ex.
`
`1048, Ex. 1073. Exhibit 1007 is an abstract describing the results of the trial, with
`
`Dr. Kappos as the first of thirteen authors. Ex. 1007, 27. Exhibit 1046 is a power
`
`point presentation, delivered by Dr. Kappos, not Dr. O’Neill, describing the results.
`
`Ex. 1046. Exhibit 1016 is a press release reporting those same results, listing
`
`Biogen Idec and Fumapharm AG as trial sponsors. Ex. 1016. None of these
`
`materials suggest the clinical trial and resulting publications “were solely [Dr.
`
`O’Neill’s] work and [his] alone.” Allergan, Inc. v. Apotex Inc., 754 F.3d 952, 969
`
`(Fed. Cir. 2014). Instead, they show that Dr. Kappos and others played a leading
`
`role in the trial and resulting publications.
`
`A 2008 publication describing the Kappos Phase II trial results confirms Dr.
`
`Kappos’s leadership role. It states, “[a]s chair of this study’s steering committee,
`
`Biogen’s citations
`4
`
`to
`
`the Petition, which discusses
`
`the Grounds
`
`simultaneously, likewise misinterprets Petitioner’s arguments. Resp., n.2, n.3.
`
`16
`
`
`
`
`
`
`[Dr. Kappos] was involved in drafting and amending the study protocol and
`
`statistical analysis plan, overseeing the conduct of the study, and reviewing
`
`statistical analysis. [Dr. Kappos] was also involved in and contributed to the
`
`writing and review of the manuscript. As corresponding author, [Dr. Kappos] had
`
`full access to all data in the study and had final responsibility for the decision to
`
`submit for publication.” Ex. 1048, 9. The paper describes the numerous
`
`contributions of all authors, and with respect to Dr. O’Neill simply notes that he
`
`“participated in study design, patient recruitment, data collection and analysis,
`
`safety review, and writing, review, and approval of the manuscript.” Id. (referring
`
`to O’Neill as “GNO”) (emphasis added).
`
`This is a far cry from Katz and Varian Medical, relied on by Biogen, where
`
`students and administrators were working only at the direction of others. In re
`
`Katz, 687 F.2d 450, 455 (C.C.P.A. 1982) (co-authors were students); Varian Med.
`
`Sys., Inc. v. William Beaumont Hosp., IPR2016-00163, 2017 WL 2117016, at *9
`
`(PTAB May 4, 2017) (co-authors were students, post-doctoral assistants, or a
`
`department administrator who authorized use of equipment). Here,
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