Trials@uspto.gov
`571-272-7822
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` Paper No. 98
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` Entered: February 5, 2020
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`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`BIOGEN MA INC,
`Patent Owner.
`____________
`
`Case IPR2018-01403
`Patent No. 8,399,514 B2
`____________
`
`
`Before SHERIDAN K. SNEDDEN, JENNIFER MEYER CHAGNON, and
`JAMIE T. WISZ, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`
`JUDGMENT
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`35 U.S.C. § 318(a)
`
`
`
`
`
`
`
`
`571-272-7822
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`
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` Paper No. 98
`
`
` Entered: February 5, 2020
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`BIOGEN MA INC,
`Patent Owner.
`____________
`
`Case IPR2018-01403
`Patent No. 8,399,514 B2
`____________
`
`
`Before SHERIDAN K. SNEDDEN, JENNIFER MEYER CHAGNON, and
`JAMIE T. WISZ, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`
`JUDGMENT
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`35 U.S.C. § 318(a)
`
`
`
`
`
`
`
`
`
`IPR2018-01403
`Patent No. 8,399,514 B2
`
`
`I.
`INTRODUCTION
`This Final Written Decision is issued pursuant to 35 U.S.C. § 318(a)
`and 37 C.F.R. § 42.73. Mylan Pharmaceuticals Inc. (“Petitioner”) bears the
`burden of proving unpatentability of the challenged claims, and that burden
`of persuasion never shifts to Biogen MA Inc. (“Patent Owner”). Dynamic
`Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375, 1378 (Fed. Cir.
`2015). The evidentiary standard is a preponderance of the evidence. See
`35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d).
`For the reasons that follow, we determine that Petitioner has not
`shown, by a preponderance of the evidence, that challenged claims 1–20 of
`U.S. Patent No. 8,399,514 B2 (Ex. 1001, “the ’514 patent”) are
`unpatentable.
`
`A. Procedural History
`Petitioner filed a Petition requesting an inter partes review of claims
`1–20 of the ’514 patent. Paper 2 (“Pet.”). Patent Owner filed a Preliminary
`Response. Paper 7. With prior authorization, Petitioner filed a Reply to
`Patent Owner’s Preliminary Response (Paper 9) to address the Federal
`Circuit’s decision in FWP IP APS v. Biogen MA Inc., 749 F. App’x 969, 972
`(Fed. Cir. 2018). Patent Owner filed a Sur-Reply. Paper 10.
`Upon consideration of the Petition, Preliminary Response, and the
`parties’ additional briefing, we instituted an inter partes review of claims
`1–20 of the ’514 patent on each ground of unpatentability set forth in the
`Petition, which are as follows:
`
`2
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`IPR2018-01403
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`
`Ground Claims
`
`1
`
`2
`3
`4
`
`1–20
`
`1–20
`1–20
`1–20
`
`References
`Basis1
`§ 103(a) Biogen Press Release2 and
`Schimrigk 20043
`§ 103(a) Kappos 20064 and Schimrigk
`2004
`§ 103(a) Kappos 2006 and WO ’3425
`§ 103(a) Kappos 2006, Clinical Trials6,
`Joshi ʼ9997, and ICH Guideline8
`
`
`1 The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29, 125
`Stat. 284, 287–88 (2011), amended 35 U.S.C. §§ 102 and 103. Because the
`’514 patent was filed before March 16, 2013 (the effective date of the
`relevant amendment), the pre-AIA version of § 103 applies.
`2 Ex. 1005, Biogen News Release, Phase II Study of Oral Compound BG-12
`Meets Primary Endpoint in Multiple Sclerosis (Jan. 9, 2006) (“Biogen Press
`Release”).
`3 Ex. 1006, S. Schimrigk et al., A Prospective, Open-Label, Phase II Study of
`Oral Fumarate Therapy for the Treatment of Relapsing-Remitting Multiple
`Sclerosis, 10 (Suppl. 2) MULTIPLE SCLEROSIS CLIN. & LAB. RES. S258,
`Abstract P642 (2004) (“Schimrigk 2004”).
`4 Ex. 1007, L. Kappos et al., Efficacy of a Novel Oral Single-Agent
`Fumarate, BG00012, in Patients with Relapsing-Remitting Multiple
`Sclerosis: Results of a Phase 2 Study, 253 (Suppl. 2) J. NEUROL. II27, O108
`(2006) (“Kappos 2006”).
`5 Ex. 1008, International Publication No. WO 2006/0037342 A2 (published
`Apr. 13, 2006) (“WO ’342”).
`6 Ex. 1010, NCT00168701, CLINICALTRIALS.GOV,
`https://clinicaltrials.gov/archive/NCT00168701/2005_09_14
`(“Clinical Trials”).
`7 Ex. 1009, R. K. Joshi et al., U.S. Patent No. 7,320,999, issued Jan. 22,
`2008 (“Joshi ʼ999”).
`8 Ex. 1011, ICH Harmonised Tripartite Guideline - Dose-Response
`Information to Support Drug Registration E4 (Mar. 10, 1994)
`(“ICH Guideline”).
`
`3
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`Paper 12.
`Subsequently, Patent Owner filed a Patent Owner Response
`(Paper 38; “PO Resp.”), Petitioner filed a Reply (Paper 68; “Reply”), and
`Patent Owner filed a Sur-Reply (Paper 79; “Sur-Reply”).
`Petitioner relies upon the Declarations of Dr. John R. Corboy
`(Ex. 1002), Dr. Leslie Z. Benet (Ex. 1003), and Dr. Ian McKeague
`(Ex. 1004) to support its contentions. On Reply, Petitioner relies on the
`Declarations of Dr. Benjamin M. Greenberg (Ex. 1121).9
`Patent Owner relies upon the Declaration of Dr. Richard C. Brundage
`(Ex. 2057), Dr. Martin Duddy (Ex. 2058), Dr. Ronald A. Thisted (Ex. 2060),
`and Dr. Daniel Wynn (Ex. 2061) to support its contentions.10
`Oral argument was conducted on November 13, 2019. A transcript is
`entered as Paper 93 (“Tr.”).
`We address herein the arguments and evidence set forth in the Papers
`to the extent necessary to resolve the dispute between the parties.
`
`B. Related Matters
`The parties identify the following litigation between the parties
`involving the ’514 patent: Biogen International GmbH v. Mylan
`Pharmaceuticals Inc., C.A. No. 17-cv-116-IMK (N.D. W.Va.). Pet. 2;
`
`
`9 Petitioner also relies on the Declaration of Joel W. Hay, Ph.D. (Ex. 1120)
`in support of its contentions rebutting portions of Patent Owner’s objective
`indicia evidence that we do not rely upon for this Final Written Decision.
`10 Patent Owner also relies on the Declaration of John C. Jarosz (Ex. 2202)
`in support of its contentions relating to objective indicia evidence that we do
`not rely upon for this Final Written Decision.
`4
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`Paper 11, 3. The parties also identify several other litigations involving
`the ’514 patent. See Pet. 2–3; Paper 11, 3.
`The ’514 patent has also been involved in the following proceedings
`before the Patent Trial and Appeal Board (“Board”): Coalition for
`Affordable Drugs V LLC v. Biogen MA Inc., IPR2015-01993; Coalition for
`Affordable Drugs V LLC v. Biogen MA Inc., IPR2015-01136; and Biogen
`MA Inc., v. Forward Pharma A/S, Patent Interference 106,023.
`
`C. The ’514 patent
`The subject matter claimed in the ’514 patent is directed to methods of
`treating patients needing treatment for Multiple Sclerosis (MS). Ex. 1001,
`27:59–30:27. The heart of the treatment, and a requirement of every claim,
`is administering about 480 milligrams (mg) per day of certain fumarates. Id.
`The fumarates are limited to dimethyl fumarate (DMF), monomethyl
`fumarate (MMF), or their combination. Id. Patent Owner markets dimethyl
`fumarate under the tradename Tecfidera®. See PO Resp. 1. Tecfidera® is
`indicated for the treatment of patients with MS, including relapsing forms of
`MS (RRMS). Ex. 2003, 7–8, 90.
`
`D. Illustrative Claims
`Independent claims 1, 11, 15, and 20, reproduced below, are
`illustrative of the challenged claims:
`1. A method of treating a subject in need of treatment for
`multiple sclerosis comprising orally administering to the subject
`in need thereof a pharmaceutical composition consisting
`essentially of
`(a) a therapeutically effective amount of dimethyl
`fumarate, monomethyl fumarate, or a combination thereof, and
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`(b) one or more pharmaceutically acceptable excipients,
`wherein the therapeutically effective amount of dimethyl
`fumarate, monomethyl fumarate, or a combination thereof is
`about 480 mg per day.
`Ex. 1001, 27:59–67.
`
`11. A method of treating a subject in need of treatment for
`multiple sclerosis consisting essentially of orally administering
`to the subject about 480 mg per day of dimethyl fumarate,
`monomethyl fumarate, or a combination thereof.
`Id. at 29:20–23.
`
`15. A method of treating a subject in need of treatment for
`multiple sclerosis comprising orally administering to the subject
`pharmaceutical composition consisting essentially of
`(a) a therapeutically effective amount of dimethyl
`fumarate and
`(b) one or more pharmaceutically acceptable excipients,
`wherein the therapeutically effective amount of dimethyl
`fumarate is about 480 mg per day.
`Id. at 30:1–7.
`
`20. A method of treating a subject in need of treatment for
`multiple sclerosis comprising treating the subject in need thereof
`with a therapeutically effective amount of dimethyl fumarate,
`monomethyl fumarate, or a combination thereof, wherein the
`therapeutically effective amount of dimethyl
`fumarate,
`monomethyl fumarate, or a combination thereof is about 480 mg
`per day.
`Id. at 30:22–28.
`
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`E. Abbreviations
`For convenience, we include a table of abbreviations used in this
`decision:
`DMF
`BG00012, BG-12,
`or BG12
`BID
`EDSS
`EMA
`MEF
`MMF
`MRI
`MS
`RRMS
`TID
`
`Dimethyl fumarate
`Dimethyl fumarate
`Twice daily
`Expanded disability status scale
`European Medicines Agency
`Monoethyl fumarate
`Monomethyl fumarate
`Magnetic resonance imaging
`Multiple sclerosis
`Relapsing-remitting multiple sclerosis
`Three times daily
`
`II. DISCUSSION
`A. Person of Ordinary Skill in the Art
`Petitioner asserts that a person having ordinary skill in the art
`(“POSA”)
`would have had (1) several years’ experience in designing
`clinical studies to meet regulatory expectations and/or analyzing
`data from such studies; (2) an advanced degree (PhD, MD,
`PharmD) and training in clinical pharmacology or experience
`treating MS; and (3) experience with the administration or
`formulation of therapeutic agents, their dosing, and the literature
`concerning drug developmental study and design.
`Pet. 10–11.
`Patent Owner contends that “Petitioner’s proposed definition omits
`any requirement that a clinician—much less an MS clinician—be included,”
`which is “inconsistent with the subject matter of the claimed invention.” PO
`7
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`Resp. 14. Patent Owner asserts that a person having ordinary skill in the art
`would have “a medical degree with at least three years of training in
`neurology and at least three years of clinical experience treating MS.” Id.
`(citing Ex. 2061 ¶¶ 35–36).
`Having considered the parties’ positions and evidence of record,
`summarized above, we agree with Patent Owner that the claims are limited
`to methods of treating MS and agree that the definition of a POSA should
`likewise be limited to those persons having the relevant education and
`sufficient clinical expertise in treating MS patients. Accordingly, we adopt
`Patent Owner’s definition of a POSA for the purposes of this decision. That
`said, we discern no appreciable difference in the respective definitions of a
`POSA as that definition relates to the dispositive issues of this case,
`discussed below.
`We further note that prior art may also demonstrate the level of skill
`in the art at the time of the invention. See Okajima v. Bourdeau, 261 F.3d
`1350, 1355 (Fed. Cir. 2001) (explaining that specific findings regarding
`ordinary skill level are not required “where the prior art itself reflects an
`appropriate level and a need for testimony is not shown”) (quoting Litton
`Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir.
`1985)).
`
`B. Claim Construction
`For petitions filed before November 13, 2018, we interpret the claims
`of an unexpired patent that will not expire before issuance of a final written
`decision using the broadest reasonable interpretation in light of the
`specification. See 37 C.F.R. § 42.100(b) (2018); Cuozzo Speed Techs., LLC
`8
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`v. Lee, 136 S. Ct. 2131, 2144–46 (2016). Under the broadest reasonable
`construction standard, claim terms are presumed to have their ordinary and
`customary meaning, as would be understood by one of ordinary skill in the
`art in the context of the entire disclosure. In re Translogic Tech., Inc.,
`504 F.3d 1249, 1257 (Fed. Cir. 2007). Only terms that are in controversy
`need to be construed, and then only to the extent necessary to resolve the
`controversy. Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803
`(Fed. Cir. 1999).
`Petitioner submits that none of the terms in the claims of the ’514
`patent require construction and, instead, all terms take on their plain
`meaning. Pet. 17. Patent Owner does not present any alternative claim
`construction arguments. See generally PO Resp.
`We independently determine that no explicit construction of any claim
`term is necessary to determine whether Petitioner has shown by a
`preponderance of the evidence that the claims are unpatentable in this case.
`
`C. Ground 1: Asserted Obviousness of Claims 1–20 over the
`Combination of the Biogen Press Release and Schimrigk 2004
`For the reasons set forth below, we determine that Petitioner has not
`shown by a preponderance of the evidence that claims 1–20 are unpatentable
`as obvious over the combination of the Biogen Press Release and Schimrigk
`2004.
`
`9
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`
`1. Summary of References Relied Upon
`a. Biogen Press Release (Ex. 1005)
`The Biogen Press Release11 reports as follows:
`Biogen . . . and Fumapharm AG today announced that a Phase II
`study designed to evaluate the efficacy and safety of BG-12, an
`oral fumarate, in patients with relapsing-remitting multiple
`sclerosis met its primary endpoint. Treatment with BG-12 led to
`a statistically significant reduction in the total number of
`gadolinium-enhancing brain lesions as measured by MRI with
`six months of treatment versus placebo. This Phase II multi-
`center, double-blind, placebo-controlled
`study
`enrolled
`approximately 250 patients at sites in 10 countries in Europe.
`Ex. 1005; Pet. 36.
`Petitioner additionally argues that skilled artisans would have
`understood that the Biogen Press Release reports the results of the study
`disclosed by Kappos 2005.12 Pet. 36 (citing Ex. 1002 ¶ 67; Ex. 1003 ¶ 132).
`Kappos 2005 describes a six month “randomized, double-blind, placebo-
`controlled, phase II study being conducted at 45 clinical centers in Europe”
`where daily dosages of 720 mg, 360 mg, and 120 mg were to be tested for
`efficacy and safety in treating RRMS. Ex. 1015, 2.
`
`
`11 Patent Owner asserts that Petitioner has not established that the Biogen
`Press Release was a printed publication. PO Resp. 16–17. Because we
`determine that Petitioner has not met its burden to show unpatentability of
`the claims based on any asserted ground relying on this document, we need
`not decide this issue for purposes of this Final Written Decision.
`12 Ex. 1015, L. Kappos et al., A Randomised, Placebo-controlled Phase II
`Trial of a Novel Oral Single-Agent Fumarate Therapy, BG00012, in Patients
`with Relapsing-Remitting Multiple Sclerosis, 252 (Suppl. 2) J. NEUROL.
`II/148, P574 (2005) (“Kappos 2005”).
`10
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`b. Schimrigk 2004 (Ex. 1006)
`Schimrigk 2004 discloses that
`Oral fumarate is an effective and safe therapy for the treatment
`of psoriasis. Similar to psoriasis, the inflammatory process in
`multiple sclerosis (MS) is thought to be mediated by a T helper I
`(THI)-type cytokine reaction due to global immune suppression
`or a TH2-mediated bystander suppression.
`Ex. 1006, 4–5.
`Schimrigk 2004 reports the results of a 70-week clinical trial
`involving the treatment of RRMS with oral fumarate therapy (Fumaderm®).
`Id. at 5. The study consisted of four phases: a 6-week baseline; an 18-week
`treatment; a 4-week wash-out; and a second 70-week treatment phase. Id.
`Patients received Fumaderm® in dosages that included up to 720 mg/day of
`DMF13 in the first treatment phase. Id. Patients received Fumaderm® in
`dosages that included up to 360 mg/day of DMF in the second treatment
`phase. Id. Schimrigk 2004 discloses that “[o]ral fumarate therapy
`significantly reduced the number and volume of [gadolinium enhancing
`(Gd+)] lesions over 70 weeks of treatment.” Id. More specifically,
`Schimrigk 2004 discloses that
`Significant reductions from baseline in the number of Gd+
`lesions were observed starting after week 12 of treatment with
`fumarate (p <0.05). In addition, there were significant reductions
`
`
`13 According to Petitioner, DMF is the most active component of
`Fumaderm®. Pet. 37; Ex. 1020 (Fumaderm® prescribing information);
`Ex. 1003 ¶¶ 134, 137, 141–145.
`
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`from baseline in Gd+ lesion volume starting after week 12
`(p <0.01).
`
`Id.
`
`c. Schimrigk 2004 Poster (Ex. 101214)
`According to Petitioner, the Schimrigk 2004 Poster15 concerns the
`same study disclosed in Schimrigk 2004. Pet. 37. Petitioner contends that
`Schimrigk 2004, when read in view of the Schimrigk 2004 Poster, discloses
`“that the fumarate therapy was effective to treat MS, describing a
`‘significant reduction in the number of Gd+ lesions . . . following 18 weeks
`of oral fumarate treatment, with a further reduction after 70 weeks.’” Id.
`(quoting Ex. 1012, 4).
`
`2. Petitioner’s Contentions
`Petitioner asserts that claims 1–20 are unpatentable under 35 U.S.C.
`§ 103 as obvious over the combination of the Biogen Press Release and
`Schimrigk 2004. Pet. 34–44. Petitioner contends that the Biogen Press
`Release discloses that a Phase II study designed to evaluate the efficacy and
`
`
`14 Ex. 1012, S. Schimrigk et al., A Prospective, Open-Label, Phase II Study
`of Oral Fumarate Therapy for the Treatment of Relapsing-Remitting
`Multiple Sclerosis (2004), available at
`http://web.archive.org/web/20041021033354/http://www.fumapharm.ch:80/
`pdf/BG-12_Schimrigk_Poster_Final.pdf (“Schimrigk 2004 Poster”).
`15 Patent Owner asserts that Petitioner has not established that the Schimrigk
`2004 Poster was publicly available. PO Resp. 17–18 n.7. Because we
`determine that Petitioner has not met its burden to show unpatentability of
`the claims based on any asserted ground relying on this document, we need
`not decide this issue for purposes of this Final Written Decision.
`12
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`safety of BG-1216 resulted in “a statistically significant reduction in the total
`number of gadolinium-enhancing brain lesions as measured by MRI.” Id. at
`36 (citing Ex. 1015).
`The Biogen Press Release does not disclose an effective dosage of
`DMF. As for the dose of DMF used in the study, Petitioner contends that a
`person of ordinary skill in the art would have understood that the Biogen
`Press Release reports the results of a study disclosed in Kappos 2005.
`Pet. 36 (citing Ex. 1002 ¶ 67; 1003 ¶ 132). As noted above, Kappos 2005
`describes a six month study testing daily dosages of 720 mg, 360 mg, and
`120 mg for efficacy and safety in treating MS. Ex. 1015, 2.
`The Biogen Press Release, even when read in view of Kappos 2005,
`does not indicate which of the tested dosages showed efficacy. In this
`regard, Petitioner directs our attention to Schimrigk 2004 and the Schimrigk
`2004 Poster and contends that those references show “that DMF doses of
`720 mg/day, 360 mg/day, and those in between, such as 480 mg/day, were
`likely to be efficacious to treat MS.” Pet. 36. Specifically, Petitioner
`contends that “[t]he authors reported that the fumarate therapy was effective
`to treat MS, describing a ‘significant reduction in the number of Gd+ lesions
`. . . following 18 weeks of oral fumarate treatment [where up to 720 mg/day
`of DMF was administered], with a further reduction after 70 weeks[, where
`
`
`16 Petitioner contends that a person of ordinary skill in the art would have
`known that BG-12 referred to DMF monotherapy. Pet. 18 n.2 (citing
`Ex. 1015 and Ex. 1010). For purposes of this Decision, we will interpret all
`references to BG-12 or the like to mean DMF.
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`up to 360 mg/day of was DMF administered].’” Id. at 37 (citing Ex. 1012,
`4) (emphasis added).17
`Petitioner contends that, because it was known that DMF was
`effective in treating MS based on the teachings of Schimrigk 2004, “[s]killed
`artisans would have been motivated to take the next obvious drug
`development step: optimize the dose of DMF, taking into account its known
`side-effect profile, patient compliance issues arising from three times daily
`dosing, and general principles of drug development.” Pet. 37. Petitioner
`also contends as follows:
`Given these results and the state of the art, skilled artisans would
`have been motivated to optimize the dose of what was known to
`be an effective treatment—a process that is part and parcel of
`routine drug development. Ex. 1002 ¶¶ 132–154; Ex. 1003
`¶¶ 135–148.
`Moreover, skilled artisans would be pursuing DMF dose
`optimization within an established effective range. Prior art
`pointed to a range of 360 mg/day to 720 mg/day to treat MS.[18]
`And skilled artisans had achieved success in treating psoriasis
`with 480 mg/day, providing a particular motivation to pursue that
`dose when treating MS. Ex. 1002 ¶¶ 136, 147; Ex. 1003 ¶¶ 38,
`
`17 We understand Petitioner’s argument to be that the study disclosed by the
`authors of Schimrigk 2004 showed that oral fumarate treatment was shown
`to be efficacious for both the first treatment period in which up to 720
`mg/day of DMF was administered and for the second treatment period in
`which up to 360 mg/day of DMF was administered. See Pet. 36–37; see also
`Tr. 9:22–12:1.
`18 According to Petitioner, “Schimrigk demonstrated the efficacy of
`Fumaderm® including 360 mg/day and 720 mg/day of DMF . . . in treating
`RRMS.” Pet. 30 (citing Ex. 1002 ¶¶ 47–56, 92–100, 114–116, 128–131,
`145 n.5; Ex. 1003 ¶¶ 36–38, 40–42, 61–67, 72–94, 137, 141–147).
`14
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`75-78, 143. For example, in the 1990s, Nieboer demonstrated
`that 480 mg/day of DMF administered twice daily is an effective
`daily dose to treat psoriasis. Ex. 1002 ¶¶ 136, 147; Ex. 1003
`¶¶ 78, 143.
`Pet. 32.
`Regarding a reasonable expectation of success, Petitioner contends
`
`that
`
`Skilled artisans would have also had a reasonable
`expectation of success in treating MS with 480 mg/day of DMF.
`Ex. 1002 ¶¶ 144–149; Ex. 1003 ¶¶ 144–147. Schimrigk had
`shown efficacy of 360 mg/day and 720 mg/day of DMF
`administered as Fumaderm®, and the January 2006 Press
`Release confirms efficacy of DMF monotherapy in treating MS.
`Ex. 1002 ¶¶ 144–149; Ex. 1003 ¶¶ 144–147. These findings, in
`light of the knowledge that 480 mg/day of DMF could be used to
`successfully treat psoriasis, would leave little to the skilled
`artisan’s imagination. Ex. 1002 ¶¶ 137–149; Ex. 1003 ¶¶ 144–
`147. The data all pointed towards successful administration of
`480 mg/day of DMF to treat MS. Ex. 1002 ¶¶ 137–149; Ex 1003
`¶¶ 135–148.
`Pet. 38.
`
`3. Patent Owner’s Contentions
`Patent Owner contends that Schimrigk 2004 does not teach that any
`range of DMF doses (e.g., from 360 to 720 mg/day) were effective to treat
`MS, “and certainly not 480 mg/day DMF monotherapy.” PO Resp. 15.
`Patent Owner contends that “Schimrigk 2004 is a short abstract reporting the
`results of an exploratory, open-label study of multiple active oral fumarates
`(not DMF monotherapy) for the treatment of RRMS.” Id. at 18 (citing
`Ex. 1006, 4–5; Ex. 2058 ¶ 25; Ex. 2061 ¶ 37; Ex. 2057 ¶ 21). Specifically,
`“Schimrigk 2004 administered Fumaderm®, a combination of four active
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`fumarate ingredients (56% DMF and 44% of three MEF salts) with its
`six-tablet dose containing 1290 mg of active fumarates (720 mg DMF and
`570 mg of the MEF salts).” Id. (citing Ex. 1020, 2; Ex. 2058 ¶¶ 45–47;
`Ex. 2061 ¶¶ 38, 74; Ex. 2057 ¶¶ 22, 35, 39). Thus, according to Patent
`Owner, “Schimrigk 2004 did not test a DMF-only product and thus could
`not disclose that 720 mg/day or any other dose of DMF was efficacious for
`the treatment of MS.” Id. at 19 (citing Ex. 2058 § VII.A.1; Ex. 2061 ¶ 41;
`Ex. 2057 § VI.A.2; Paper 12, 15).
`
`4. Analysis
`The question before us is whether discovery of the 480 mg/day dose
`of DMF in a method of treating multiple sclerosis was the result of DMF
`dose optimization within an established effective range (i.e., doses between
`360 mg/day and 720 mg/day). Pet. 27–32; PO Resp. 14–15. In this regard,
`we recognize that “discovery of an optimum value of a variable in a known
`process is usually obvious.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348,
`1368 (Fed. Cir. 2007); see also In re Aller, 220 F.2d 454, 456 (CCPA 1955)
`(“[W]here the general conditions of a claim are disclosed in the prior art, it is
`not inventive to discover the optimum or workable ranges by routine
`experimentation.”); In re Boesch, 617 F.2d 272, 276 (CCPA 1980)
`(“[D]iscovery of an optimum value of a result effective variable in a known
`process is ordinarily within the skill of the art.”); In re Geisler, 116 F.3d
`1465, 1470 (Fed. Cir. 1997) (“‘[I]t is not inventive to discover the optimum
`or workable ranges by routine experimentation.’” (quoting Aller, 220 F.2d at
`456)). However, for the optimization of a dosage within an established
`
`16
`
`
`
`IPR2018-01403
`Patent No. 8,399,514 B2
`
`range to be obvious, the asserted prior art must teach that such an established
`effective range was known.
`As mentioned above, the Biogen Press Release, even when read in
`view of Kappos 2005, does not indicate which of the tested dosages for
`BG-12 (DMF monotherapy) showed efficacy. Thus, the Biogen Press
`Release fails to establish any effective dose range for DMF monotherapy.
`To support its position that a person of ordinary skill in the art would
`have known that the 360 mg/day and 720 mg/day doses of DMF were
`efficacious, Petitioner relies on Schimrigk 2004. See, e.g., Pet. 30, 38.
`Schimrigk 2004, however, does not cure that deficiency of the Biogen Press
`Release because Schimrigk 2004 does not describe or suggest a DMF
`monotherapy in any particular dose. Ex. 2057 ¶¶ 22, 35, 39. Rather,
`Schimrigk 2004 discloses that patients were treated with oral fumarate
`therapy, known as Fumaderm. Ex. 1006, 5. Fumaderm contains
`“approximately 44% MEF salts and only 56% DMF,” where MEF refers to
`monoethyl fumarate compounds, compounds that are not encompassed by
`the challenged claims. Ex. 2058 ¶¶ 46–47; see also Ex. 1008, 3 (listing the
`components of Fumaderm). More specifically, Fumaderm contains DMF
`and three MEF salts—calcium MEF, zinc MEF, and magnesium MEF—
`each of which is an active ingredient. Ex. 2061 ¶ 74; Ex. 103719, 109–120
`(European Medicines Agency concluding that “DMF and the MEF salts are
`chemically distinct active substances” and that “dimethyl fumarate is
`
`
`19 Ex. 1037, European Medicines Agency, Assessment Report, Tecfidera
`(Nov. 26, 2013) (“EMA Report”).
`
`17
`
`
`
`IPR2018-01403
`Patent No. 8,399,514 B2
`
`different from Fumaderm composed of dimethyl fumarate, calcium salt of
`ethyl fumarate, magnesium salt of ethyl hydrogen fumarate and zinc salt of
`ethyl hydrogen fumarate. Therefore, the active substance of Tecfidera,
`dimethyl fumarate, is a new active substance.”). Thus, we find that
`Schimrigk 2004 does not teach or suggest anything about the effectiveness
`of any individual fumarate so as to guide a person of ordinary skill in the art
`to an effective dose range for DMF monotherapy.20
`Having considered the parties’ positions and evidence of record,
`summarized above, we determine that the evidence relied on by Petitioner
`does not support Petitioner’s position that a person of ordinary skill in the art
`would have understood that “doses between 360 mg/day and 720 mg/day
`were likely to be efficacious doses, and, in particular, 480 mg/day was likely
`to be an efficacious dose.” Pet. 38–39 (citing Ex. 1002 ¶¶ 125–154;
`Ex 1003 ¶¶ 132–148). Rather, we are persuaded by Patent Owner’s
`arguments and evidence that “[t]he presence of multiple active agents in
`Fumaderm® precludes extrapolation of Schimrigk 2004’s results to any dose
`of DMF monotherapy.” PO Resp. 19; Ex. 2058 ¶¶ 46–48, 51; Ex. 2057
`
`
`20 Petitioner argues on Reply that “Schimrigk’s Fumaderm® efficacy finding
`is akin to DMF monotherapy” because “DMF has long been known to
`[be the] most active Fumaderm® component.” Reply 5 (citing Ex. 1002
`¶¶ 132–140, 145 n.4 n.5; Ex. 1121 ¶¶ 200–204; Ex. 1023; Ex. 1024).
`Petitioner does not dispute, however, Patent Owner’s contention that there
`are components in Fumaderm other than DMF. Patent Owner’s expert
`testimony in this regard is consistent with the other record evidence.
`Ex. 2058 ¶ 46 (“Fumaderm® tablets contained approximately 44% MEF
`salts and only 56% DMF.”); see also, Ex. 1008, 3:12–24 (same).
`18
`
`
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`IPR2018-01403
`Patent No. 8,399,514 B2
`
`¶¶ 22, 35, 37–29; Ex. 2062, 33:1–25. We, thus, determine that Petitioner has
`failed to establish that a person of ordinary skill in the art would have relied
`on the combination of the Biogen Press Release and Schimrigk 2004 to
`optimize the dose for DMF for the treatment of MS within an established
`effective range because the art does not support a finding that any such range
`was known. Ex. 2058 ¶¶ 50, 69–70, 92–95, 116–147; Ex. 2061 ¶¶ 56–58;
`Ex. 2057 ¶¶ 37–42, 65, 67–84. Having failed to establish the facts predicate
`to its articulated theory of obviousness, Petitioner’s obviousness challenge to
`claims 1–20 also fails.
`
`D. Ground 2: Asserted Obviousness of Claims 1–20 over the
`Combination of Kappos 2006 and Schimrigk 2004
`For the reasons set forth below, we determine that Petitioner has not
`shown by a preponderance of the evidence that claims 1–20 are unpatentable
`as obvious over the combination of Kappos 2006 and Schimrigk 2004.
`
`1. Summary of Additional Reference Relied Upon
`a. Kappos 2006 (Ex. 1007)
`Kappos 200621 describes results of a Phase II trial that treated MS
`patients with 120, 360, and 720 mg/day of a drug identified as BG00012
`
`
`21 Patent Owner asserts that Kappos 2006, along with related Exhibits 1016
`and 1046, are not available as prior art against the challenged claims because
`they describe inventor Dr. O’Neill’s own work. See PO Resp. 4–13;
`Ex. 2097; Ex. 2098; Ex. 2099; Ex. 2100. Because we determine that
`Petitioner has not met its burden to show unpatentability of the claims based
`on any asserted ground relying on these documents, we need not decide this
`issue for purposes of this Final Written Decision.
`19
`
`
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`IPR2018-01403
`Patent No. 8,399,514 B2
`
`(BG12). Ex. 1007, 27. The relevant portion of Kappos 2006 provides as
`follows (emphasis added):
`Objective: To determine the efficacy of three dose levels
`of BG00012, a novel oral fumarate preparation, on brain lesion
`activity as measured by magnetic resonance imaging (MRI) in
`patients with relapsing-remitting multiple sclerosis (RRMS).
`Methods: This was a randomised, double-blind, placebo-
`controlled clinical trial of BG00012 in patients with RRMS.
`Men and women 18 to 55 years of age were eligible for the study
`if they had a diagnosis of RRMS and an Expanded Disability
`Status Scale (EDSS) score between 0.0 and 5.0. In addition,
`patients must have had either ≥ 1 relapse within 12 months prior
`to randomisation or gadolinium-enhancing (Gd +) lesions on
`cranial MRI at screening. Patients were assigned to four
`treatment groups and received BG00012 capsules 120 mg by
`mouth (PO) once daily (120 mg/day), 120 mg three times daily
`(360 mg/day), 240 mg three times daily (720 mg/day), or placebo
`for 24 weeks. The treatment period was followed by a 24-week
`dose-blinded safety-extension period during which all patients
`received BG00012. The primary end point was the total number
`of Gd+ lesions over four MRI scans at weeks 12, 16, 20, and 24
`(calculated as the sum of the four scans). Secondary end points
`included the cumulative number of new Gd+ lesions from week
`4 to week 24 and the number of new/enlarging T2-hyperintense
`lesions at week 24. Additional end points included the number
`of new T1-hypointense lesions at week 24, relapse rate, and
`disability progression as measured by EDSS.
`Results: A total of 257 patients were enrolled in the study;
`64 patients each were randomly assigned to receive one of the
`three BG00012 doses and 65 patients to placebo. Approximately
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