Trials@uspto.gov
`571-272-7822
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` Paper No. 12
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` Entered: February 6, 2019
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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
`JACQUELINE T. HARLOW, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
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`571-272-7822
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`
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` Paper No. 12
`
`
` Entered: February 6, 2019
`
`
`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
`JACQUELINE T. HARLOW, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`
`
`
`IPR2018-01403
`Patent No. 8,399,514 B2
`
`I.
`
`INTRODUCTION
`Mylan Pharmaceuticals Inc. (“Petitioner” or “Mylan”), filed a Petition
`requesting an inter partes review of claims 1–20 of Patent No. 8,399,514 B2
`(Ex. 1001, “the ’514 patent”). Paper 2 (“Pet.”). Biogen MA Inc. (“Patent
`Owner” or “Biogen”) filed a Preliminary Response. Paper 7 (“Prelim.
`Resp.”).
`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., No. 2017-2109, 2018 WL 5292070
`(Fed. Cir. Oct. 24, 2018). Patent Owner filed a Sur-Reply. Paper 10.
`To institute an inter partes review, we must determine that the
`information presented in the Petition shows “a reasonable likelihood that the
`petitioner would prevail with respect to at least 1 of the claims challenged in
`the petition.” 35 U.S.C. § 314(a). The Supreme Court has held that a
`decision to institute under 35 U.S.C. § 314 may not institute on less than all
`claims challenged in the petition. SAS Inst., Inc. v. Iancu, 138 S. Ct. 1348,
`1359–60 (2018) (“SAS”). After considering the evidence and arguments
`presented in the Petition, we determine that Petitioner has demonstrated a
`reasonable likelihood of success in proving that at least claim 1 of the ’514
`patent is unpatentable. Accordingly, an inter partes review of all of the
`claims and all of the grounds presented in the Petition is hereby instituted.
`In this Decision, we address all issues raised by the parties in the
`pre-trial briefing. Our factual findings and conclusions at this stage of the
`proceeding are based on the evidentiary record developed thus far. This is
`not a final decision as to the patentability of claims for which inter partes
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`review is instituted. Our final decision will be based on the record as fully
`developed during trial.
`
`A. 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;
`Paper 11, 3. The parties also identify several other litigations involving
`the ’514 patent. Pet. 2–3; Paper 11, 3.
`The ’514 patent has also been involved in the following proceedings
`before the Patent Trial and Appeal Board (“PTAB” or “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.
`
`B. The ’514 patent
`The subject matter claimed in the ’514 patent is directed to methods of
`treating patients needing treatment for Multiple Sclerosis or 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. Biogen markets dimethyl
`fumarate under the tradename Tecfidera®. Prelim. Resp. 1–2. The drug is
`indicated for the treatment of patients with MS, including relapsing forms of
`MS (RRMS). Ex. 2003, 7–8.
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`C. 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
`(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.
`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.
`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.
`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.
`
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`
`D. Evidence Relied Upon
`Petitioner relies upon the following prior art references:
`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”).
`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”).
`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”).
`Ex. 1008, International Publication No. WO 2006/0037342 A2 (published
`Apr. 13, 2006) (“WO ’342”).
`Ex. 1009, R. K. Joshi et al., U.S. Patent No. 7,320,999, issued Jan. 22, 2008
`(“Joshi ʼ999”).
`Ex. 1010, NCT00168701, CLINICALTRIALS.GOV,
`https://clinicaltrials.gov/archive/NCT00168701/2005_09_14
`(“Clinical Trials”).
`Ex. 1011, ICH Harmonised Tripartite Guideline - Dose-Response
`Information to Support Drug Registration E4 (Mar. 10, 1994)
`(“ICH Guideline”).
`Petitioner also relies upon the Declarations of Dr. John R. Corboy
`(Ex. 1002), Dr. Leslie Z. Benet (Ex. 1003), and Dr. Ian McKeague (Ex. 1004
`(“McKeague Decl.”)) to support its contentions.
`
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`E. Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability (Pet. 4–5):
`
`Ground Claims
`
`1
`
`2
`3
`4
`
`1–20
`
`1–20
`1–20
`1–20
`
`References
`Basis
`§ 103(a) Biogen Press Release and
`Schimrigk 2004
`§ 103(a) Kappos 2006 and Schimrigk
`2004
`§ 103(a) Kappos 2006 and WO ’342
`§ 103(a) Kappos 2006, Clinical Trials,
`Joshi ʼ999, and ICH Guideline
`
`F. Abbreviations
`DMF
`BG00012, BG-12,
`or BG12
`BID
`EDSS
`EMA
`MMF
`MRI
`MS
`RRMS
`TID
`
`Dimethyl fumarate
`Dimethyl fumarate
`Twice daily
`Expanded disability status scale
`European Medicines Agency
`Monomethyl fumarate
`Magnetic resonance imaging
`Multiple sclerosis
`Relapsing-remitting multiple sclerosis
`Three times daily
`
`II. PETITIONER’S UNPATENTABILITY GROUNDS
`A. 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) (2016); Cuozzo Speed Techs., LLC
`v. Lee, 136 S. Ct. 2131, 2144–46 (2016). Under the broadest reasonable
`
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`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. At this stage of the proceeding, Patent Owner does not
`present any alternative claim construction arguments.
`We independently determine that no explicit construction of any claim
`term is necessary to determine whether to institute a trial in this case.
`
`B. Person of Ordinary Skill in the Art
`The person having ordinary skill in the art is a hypothetical person
`that is presumed to be aware of all the relevant prior art. Custom
`Accessories, Inc. v. Jeffrey-Allan Indust., Inc., 807 F.2d 955, 962 (Fed. Cir.
`1986); Kimberly-Clarke Corp. v. Johnson & Johnson, 745 F.2d 1437, 1453
`(Fed. Cir. 1984). Moreover, the prior art itself is generally sufficient to
`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)).
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`
`Petitioner asserts that a “person of ordinary skill in the art 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.
`At this stage of the proceeding, and absent opposition from Patent
`Owner, we adopt Petitioner’s definition of the level of ordinary skill in the
`art for purposes of determining whether to institute a trial.
`
`C. Petitioner’s Patentability Challenges
`1. Ground 1: Obviousness of Claims 1–20 over the Combination
`of Biogen Press Release and Schimrigk 2004
`a. Summary of References Relied Upon
`i. Biogen Press Release
`Biogen Press Release 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 Biogen Press Release reports the results of the study
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`disclosed by Kappos 2005.1 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 RRMS. Ex. 1015, 2.
`
`ii. Schimrigk 2004
`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 up to 720 mg/day of DMF2 in the first treatment phase. Id.
`Patients received up to 360 mg/day of DMF in the second treatment phase.
`Id. Schimrigk 2004 discloses that “[o]ral fumarate therapy significantly
`
`
`1 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”).
`2 According to Petitioner, DMF is the most active component of
`Fumaderm®. Pet. 37; Ex. 1020; Ex. 1003 ¶¶ 134, 137, 141–145.
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`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
`from baseline in Gd+ lesion volume starting after week 12
`(p <0.01).
`
`Id.
`
`iii. Schimrigk 2004 Poster3
`According to Petitioner, Schimrigk 2004 Poster concerns the same
`study disclosed in Schimrigk 2004. Pet. 37. Petitioner contends that
`Schimrigk 2004, when read in view of 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).
`
`b. Petitioner’s Contentions
`Petitioner asserts that claims 1–20 are unpatentable under 35 U.S.C.
`§ 103 as obvious over the combination of Biogen Press Release and
`Schimrigk 2004. Pet. 34–44. In particular, Petitioner contends that Biogen
`
`
`3 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”).
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`Press Release discloses that a Phase II study designed to evaluate the
`efficacy and safety of BG-12 resulted in “a statistically significant reduction
`in the total number of gadolinium-enhancing brain lesions as measured by
`MRI.” Pet. 36 (citing Ex. 1005). Biogen Press Release does not disclose an
`effective dosage of BG–12, however, Petitioner contends that a person of
`ordinary skill in the art would have understood that Biogen Press Release
`reports the results of a study disclosed in Kappos 2005. Kappos 2005
`describes a six month study testing daily dosages of 720 mg, 360 mg, and
`120 mg for efficacy and safety in MS. Pet. 36 (citing Ex. 1002 ¶ 67; 1003
`¶ 132); Ex. 1015, 2.
`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 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 720 mg/day of
`DMF administered], with a further reduction after 70 weeks[, where 360
`mg/day of DMF administered].’” Id. at 37 (citing Ex. 1012) (emphasis
`added).4
`
`
`4 We understand Petitioner’s argument to be that the study disclosed by the
`authors of Schimrigk 2004 showed that oral fumarate treatment was shown
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`Having identified that DMF was effective in treating MS, Petitioner
`contends that “[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. 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, 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
`
`to be efficacious for both the first treatment period in which 720 mg/day of
`DMF administered and for the second treatment period in which 360 mg/day
`of DMF administered.
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`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.
`
`c. Patent Owner’s Contentions
`Patent Owner contends that the asserted references do not support
`Petitioner’s position that a person of ordinary skill in the art would have
`expected a 360 mg/day dose to be efficacious. Prelim. Resp. 25. Relevant
`to Ground 1, Patent Owner contends that
`The January 2006 Press Release does not identify any doses of
`BG-12 at all, much less any results for specific dose groups.
`Ex. 1005, 1. . . . As other pre-filing date documents confirm, the
`360 mg/day dose was “not statistically significant versus
`placebo” for any endpoint. See, e.g., Ex. 1016,[5] 1; Ex. 1046,[6]
`19–22.
`Id. at 25–26.
`
`5 Ex. 1016, Biogen News Release, Oral Compound BG-12 Achieves Primary
`Endpoint in Phase II Study of Relapsing-Remitting Multiple Sclerosis;
`Treatment with BG-12 Led to Statistically Significant Reductions in MRI
`Measures (May 30, 2006).
`6 Ex. 1046, L. Kappos et al., Efficacy of a Novel Oral Single-Agent
`Fumarate, BG00012, in Patients with Relapsing-Remitting Multiple
`Sclerosis: Results of a Phase II Study (16th Meeting of the European
`Neurological Society, May 30, 2006), attached as Exhibit C to the
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`Relevant to each of Petitioner’s Grounds, Patent Owner further
`contends that Petitioner fails to meaningfully address the Phase III trial
`results establishing unexpected results. Prelim. Resp. 29–31. In particular,
`Patent Owner contends that the 480 mg/day dose had an unexpected
`magnitude of efficacy compared to a much higher 720 mg/day dose, which
`was appreciated by the FDA, European Medicines Agency, and Australia’s
`Therapeutic Goods Administration. Id. at 29–30 (citing Ex. 2003,7 8 (noting
`that the 720 mg/day dose “offered no additional efficacy” compared to
`480 mg/day); Ex. 1037, 75 (“[c]onsistent statistically significant effects with
`both doses of BG00012 of similar direction and magnitude were seen across
`the studies at each 6-month period”); Ex. 2004,8 48 (“Efficacy results for the
`240 mg TID regimen were generally similar to the 240 mg BID regimen.”)).
`
`d. Analysis
`The legal question before us, in each of Petitioner’s Grounds, 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. Pet. 27–32; Prelim. Resp. 38. In this regard, we
`recognize that “discovery of an optimum value of a variable in a known
`
`
`Declaration of Katherine T. Dawson in Biogen U.S. Patent App. No.
`12/526,296 (“Kappos 2006 Presentation”).
`7 Ex. 2003, FDA Clinical Review for NDA 204063 (BG-12), Heather Fitter,
`M.D. (Review Completion Date: 11/08/2012).
`8 Ex. 2004, Australian Government, Department of Health, Therapeutic
`Goods Administration, Australian Public Assessment Report for Dimethyl
`Fumarate, Proprietary Product Name: Tecfidera (October 2013).
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`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)).
`With regard to Ground 1, the parties do not dispute that 480 mg/day is
`an efficacious dose. Pet. 59. The parties do not dispute that neither
`Schimrigk 2004 nor Biogen Press Release discloses 480 mg/day of DMF in
`the treatment of MS. We understand that the parties do not dispute that
`Schimrigk 2004 discloses that 720 mg/day DMF was effective for the
`treatment of MS. However, whether Schimrigk 2004 discloses that the
`360 mg/day dose of DMF was effective for the treatment of MS is a factual
`dispute between the parties. In this regard, Petitioner presents evidence in
`support of its contention that Schimrigk 2004 discloses efficacy of 360
`mg/day and 720 mg/day of DMF administered as Fumaderm® (Pet. 37
`(citing Ex. 1012, 4)), and that the Biogen Press Release confirms efficacy of
`DMF monotherapy generally in treating MS. This evidence includes
`testimony of Dr. Corboy and Dr. Benet. Ex. 1002 ¶¶ 144–149; Ex. 1003
`¶¶ 133–147. For example, Dr. Corboy testifies that Schimrigk 2004
`“suggested a range of effective DMF doses in the treatment of MS from
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`360 mg/day and 720 mg/day.” Ex. 1002 ¶ 147. Dr. Benet testifies that
`Schimrigk 2004 teaches that “doses of 360 mg/day and 720 mg/day DMF
`was effective in treating patients with RMMS.” Ex. 1003 ¶ 133. Both
`experts testify that a person of ordinary skill in the art would have likewise
`expected the 480 mg/day dose of DMF to be similarly effective in view of,
`inter alia, the knowledge that the 480 mg/day dose of DMF was previously
`successfully used (i.e., safe and effective) to treat psoriasis. Ex. 1002
`¶¶ 139, 147; Ex. 1003 ¶¶ 137, 143–144.
`At this stage of the proceeding, we are persuaded that the information
`presented by Petitioner supports its position that the 720 mg/day dose of
`DMF was shown to be effective in the treatment of MS. Furthermore, at this
`stage of the proceeding, we recognize Petitioner’s currently unrebutted
`testimonial evidence that Schimrigk 2004 establishes efficacy at 360
`mg/day.
`We acknowledge Patent Owner’s argument and evidence in support of
`its position that the 480 mg/day dose had an unexpected magnitude of
`efficacy compared to a much higher 720 mg/day dose. Prelim. Resp. 29
`(citing Ex. 2003, 8; Ex. 1037, 75; Ex. 2004, 48). However, whether
`unexpected results have been established is a question of fact. In re Harris,
`409 F.3d 1339, 1341 (Fed. Cir. 2005) (whether an invention produces an
`unexpected result is a question of fact); In re Geisler, 116 F.3d at 1469 (Fed.
`Cir. 1997) (same). For purposes of deciding whether to institute an inter
`partes review, we view a genuine issue of material fact in the light most
`favorable to the petitioner. 37 C.F.R. § 42.108(c). Thus, for purposes of this
`
`16
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`IPR2018-01403
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`
`Decision, we resolve the parties’ dispute regarding unexpected results in
`favor of Petitioner.
`As set forth in the discussion of Grounds 3 and 4, below, we
`determine that Petitioner has shown a reasonable likelihood of establishing
`that at least one of the challenged claims is unpatentable. Accordingly, we
`institute trial as to all claims and all grounds presented in the Petition. See
`SAS, 138 S. Ct. at 1359–60. Issues for resolution at trial include whether
`Schimrigk 2004 establishes efficacy at 360 mg/day, and whether knowledge
`of efficacy of DMF for the treatment of MS at the 720 mg/day dose and/or
`360 mg/day dose would have provided sufficient motivation to a person of
`ordinary skill in the art to optimize the dose of DMF in the treatment of MS.
`See Pfizer, 480 F.3d at 1368 (The motivation to optimize a range or other
`variable within the claims may flow from the “normal desire of scientists or
`artisans to improve upon what is already generally known.”).
`
`2. Ground 2: Obviousness of Claims 1–20 over the Combination
`of Kappos 2006 and Schimrigk 2004
`a. Summary of Additional Reference Relied Upon
`i. Kappos 2006
`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
`17
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`IPR2018-01403
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`
`
`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
`90% of patients completed the 24-week treatment period.
`BG00012 (720 mg/day) significantly reduced the mean number
`of new Gd+ lesions (the primary end point) compared with
`placebo. In addition, BG00012 reduced the cumulative number
`of new Gd+ lesions, the number of new/enlarging T2-
`hyperintense lesions, and the number of new T1-hypointense
`lesions compared with placebo.
`Conclusion: BG00012 significantly reduces brain lesion
`activity, in a dose-dependent manner, as measured by MRI in
`patients with RRMS over 24 weeks of treatment.
`Ex. 1007, 27.
`
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`IPR2018-01403
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`
`b. Petitioner’s Contentions
`Petitioner asserts that claims 1–20 are unpatentable under 35 U.S.C.
`§ 103 as obvious over the combination of Kappos 2006 and Schimrigk 2004.
`Pet. 44–48. In particular, Petitioner contends that Kappos 2006 “explicitly
`discloses that 720 mg/day of DMF monotherapy is an effective MS
`treatment” and that Kappos 2006 further states that “[DMF] significantly
`reduces brain lesion activity, in a dose-dependent manner.” Pet. 44–45
`(citing Ex. 1007, 27).
`Additionally, Petitioner contends that a person of ordinary skill in the
`art would have understood at the time of the invention that the 360 mg/day
`dose was an efficacious dose. Specifically, Petitioner contends that,
`in May 2006, Kappos presented the results of his research to
`skilled artisans at a leading neurology conference. Ex. 1046. In
`his slides, Kappos revealed that the patients who had been treated
`with 360 mg/day of DMF had baseline disease activity that was
`markedly higher than those patients receiving 720 mg/day, 120
`mg/day, and placebo. Ex. 1002 ¶¶ 178–180; Ex. 1003 ¶¶ 169–
`170. Skilled artisans would have immediately recognized that
`when assessing whether the 360 mg/day dose was effective, a
`correction for the higher baseline disease activity in that group
`would be necessary. Ex. 1002 ¶¶ 178–180; Ex. 1003 ¶¶ 169–
`172. Skilled artisans would have at a minimum questioned the
`efficacy conclusions reported for the 360 mg/day dose, and could
`have performed easy calculations suggesting that 360 mg/day
`was efficacious. Ex. 1002 ¶¶ 178–180; Ex. 1003 ¶¶ 169–179.
`Id. at 46. Thus, in addition to Kappos 2006 providing the statement that
`DMF was effective in treating RRMS in a dose-dependent manner,
`Petitioner contends that a person of ordinary skill in the art would have been
`aware of the data contained in the 2006 slide presentation by the same author
`
`19
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`IPR2018-01403
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`(Ex. 1046, 8–29) and “would have immediately recognized from the Kappos
`2006 slides that MS patients who received 360 mg/day DMF during the
`study had significantly higher disease activity at the start of the study
`(baseline) than the patients in the other treatment groups.” Pet. 54–55
`(citing Ex. 1002 ¶¶ 178–180, 203–204; Ex. 1003 ¶¶ 169–172, 207–209).
`Petitioner contends that when this flaw is accounted for in the Kappos 2006
`phase II study results, a dose response curve becomes apparent. Id. at 56–57
`(citing Ex. 1036,9 6; Ex. 1003 ¶¶ 215-219; Ex. 1004 ¶¶ 24–26); see also
`Ex. 1037,10 34 (The 360 mg/day dose “also provided statistically significant
`results for the primary endpoint.”). Thus, according to Petitioner, a person
`of ordinary skill in the art would have appreciated the flaw in reporting the
`results of the Kappos 2006 phase II study and would have understood from
`Kappos 2006 that 360 mg/day was also an efficacious dose. Pet. 58 (citing
`Ex. 1002 ¶¶ 139–140, 209–211; Ex. 1003 ¶¶ 133–134, 220–222; Ex. 1004
`¶¶ 24, 27–28).
`For the same reasons set forth in Ground 1, Petitioner contends that
`Schimrigk 2004 reports efficacy in RRMS of 360 mg/day DMF. Pet. 45–46.
`Petitioner contends that “[w]ith doses of 720 mg/day and 360
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