Trials@uspto.gov
`571-272-7822
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` Paper 63
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` Entered: March 21, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`PATENT TRIAL AND APPEAL BOARD
`_______________
`
`COALITION FOR AFFORDABLE DRUGS V LLC;
`HAYMAN CREDES MASTER FUND, L.P.;
`HAYMAN ORANGE FUND SPC – PORTFOLIO A;
`HAYMAN CAPITAL MASTER FUND, L.P.;
`HAYMAN CAPITAL MANAGEMENT, L.P.;
`HAYMAN OFFSHORE MANAGEMENT, INC.;
`HAYMAN INVESTMENTS, LLC;
`NXN PARTNERS, LLC;
`IP NAVIGATION GROUP, LLC;
`J KYLE BASS, and ERICH SPANGENBERG,
`Petitioners,
`v.
`BIOGEN MA INC.,
`Patent Owner.
`__________
`
`Case IPR2015-01993
`Patent 8,399,514 B2
`__________
`Before RICHARD E. SCHAFER, SALLY GARDNER-LANE, and
`DEBORAH KATZ, Administrative Patent Judges.
`SCHAFER, Administrative Patent Judge.
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`Page 1 of 29
`
`Biogen Exhibit 2038
`Mylan v. Biogen
`IPR2018-01403
`
`

`

`I.
`This is a Final Written Decision on the inter parte review of Patent
`
`8,399,514. The ‘514 Patent is assigned to Biogen Ma, Inc. (Biogen). The
`Coalition for Affordable Drugs V LLC, et al., petitioned for the review seeking
`cancellation of Claims 1-20, all of the patent claims. Paper 1 (Pet.). In a Decision
`entered March 22, 2016, a Board panel held that there was a reasonable likelihood
`that the petitioner would prevail on the claims and grounds raised in the petition
`and initiated this proceeding. Paper 20 (Dec. Inst.), p. 27. Biogen subsequently
`filed a response to which Petitioner replied. Papers 38 and 46 (Biogen Res. and
`Pet. Reply, respectively). An oral argument was held on November 30, 2016.
`Paper 62.
`
`We have jurisdiction pursuant to 35 U.S.C. § 6(c). This Final Written
`Decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`
`For the reason detailed below, we determine that Petitioner has not satisfied
`its burden of establishing that the subject matter of Claims 1-20 would have been
`obvious and those claims, therefore, have not been shown to be unpatentable under
`35 U.S.C. § 103(a). Specifically, we hold that a preponderance of the evidence
`shows that the magnitude of the clinical efficacy of treatment of MS patients with
`480 mg/day of DMF would have been unexpected to one having ordinary skill in
`the art.1
`
`
`1Biogen was also authorized to file a motion to antedate one of the references
`(Kappos 2006) relied upon in the Petition. Paper 34. Biogen filed the motion
`(Paper 40). Petitioner filed an opposition (Paper 45) and Biogen replied (Paper 54).
`Biogen also argued that another reference (Joshi ‘999) was not eligible prior art
`under the provisions of 35 U.S.C. § 103(c). Biogen Res., Paper 38, pp. 17-24.
`Because post-filing date evidence demonstrates unexpected results, we did not
`reach the antedation and § 103(c) issues.
`
`
`
`
`2
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`Page 2 of 29
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`A.
`Biogen’s patent is also involved in pending Interference No. 106,023,
`
`captioned Biogen Ma, Inc. v. Forward Pharma A/S.
`B.
`The subject matter claimed in ‘514 patent is directed to methods of treating
`
`patients needing treatment for Multiple Sclerosis or MS. The heart of the
`treatment, and a requirement of every claim, is administering about 480 milligrams
`(mg) per day of certain fumarates. The fumarates are limited to dimethyl fumarate
`(DMF), monomethyl fumarate (MMF), or their combination. Biogen markets
`dimethyl fumarate under the tradename Tecfidera®. The drug is indicated for the
`treatment of patients with relapsing forms of MS (RRMS).
`C.
`The ‘514 patent has claims 1-20, with claims 1, 11, 15 and 20 being
`
`independent. We reproduce illustrative Claim 20, the broadest, below:
`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.
`
`Ex. 1001, 30: 22-28. (paragraphing added). Each remaining independent claim
`requires oral administration of about 480 mg per day of the fumarates. Claim 11
`specifies the treatment as “consisting essentially of” the oral administration of
`about 480 mg/day of the fumarates. Claim 1 requires oral administration of a
`composition “consisting essentially of” about 480 mg/day of the fumarates along
`with one or more excipients. Claim 15 specifies the oral administration of a
`3
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`composition “consisting essentially of” 480 mg/day of DMF and one or more
`excipients. All remaining claims depend directly or indirectly from the
`independent claims. Ex. 1001, 28:58 - 30:27.
`D.
`The following references are relied upon in support of the Petition:
`Name
`Exhibit
`Description
`No.
`1003A Efficacy of a Novel Oral Single-Agent
`Fumarate,BG00012, in Patients with
`Relapsing-Remitting Multiple Sclerosis: Results
`of a Phase 2 Study, J. NEUROL (2006) 253
`(SUPPL 2); II/1–II/170, page II27
`Double-Blind, Placebo-Controlled, Dose-
`Ranging Study to Determine the Effacacy and
`Safety of BG00012 in Subjects with Relapsing-
`Remitting Multiple Sclerosis,
`CLINICALTRIALS.GOV
`ARCHIVE
`U.S. Patent 7,320,999 B2
`
`Date
`
`May
`2006
`
`Sept. 14,
`2005
`
`Jan. 22,
`2008
`filed
`July 17,
`2002
`Mar. 10,
`1994
`
`Aug. 20,
`2002
`2004
`
`
`
`Kappos
`2006
`
`Clinical
`Trials
`
`1022
`
`Joshi
`ʼ999
`
`1030
`
`ICH
`
`1004
`
`Joshi
`ʼ992
`Begleiter
`
`
`1036
`
`1027
`
`
`Pet., Paper 1, pp. 7-8.
`
`ICH Harmonised Tripartite Guideline, DOSE-
`RESPONSE
`INFORMATION TO SUPPORT DRUG REGISTRATION
`E4
`U.S. Patent 6,436,992 B1
`
`Dietary Induction of NQOI Increases the
`Antitumour Activity of Mitomycin C in Human
`Colon Tumours in vivo,
`91 BRITISH J. CANCER 1624–1631
`
`
`
`4
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`Page 4 of 29
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`
`1
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`2
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`3
`
`E.
`The panel instituted inter parte review on the following grounds:
`Ground
`Statutory
`Prior Art
`Basis
`Kappos 2006, Clinical Trials,
`35 U.S.C. §
`Joshi ʼ999, and ICH
`103(a)
`Kappos 2006, Clinical Trials,
`35 U.S.C. §
`Joshi ʼ999, ICH, and Joshi ʼ992
`103(a)
`Kappos 2006, Clinical Trials,
`35 U.S.C. §
`Joshi ʼ999, ICH, and Begleiter
`103(a)
`Dec. Inst., Paper 20, pp. 27-28.
`
`Claims
`
`1–6, 8–16,
`and 20
`7
`
`17–19
`
`II.
`A.
`The parties disagree on the level of skill of the person ordinarily skilled in
`
`the art. Each proposes its own definition. Petitioner, relying on the testimony of
`Dr. Steven E. Linberg, argues that the person of ordinary skill would have an
`advanced degree such as an M.D., a D.O., a Pharm D. or a Ph.D. in a life science
`and would be experienced with clinical trial design and dose selection. Petition,
`Paper 1, pp. 16-17; Ex. 1005, ¶ 9. Biogen, relying on the testimony of Dr. Rudick,
`argues it would be someone with at least a medical degree, at least three years of
`training in neurology and at least three years of clinical experience treating MS.
`Biogen Opp., Paper 38, p. 4; Ex. ¶ 36.
`
`We recognize that the type of description provided by the parties as to the
`characteristics of the person having ordinary skill in the art is fairly typical in inter
`parte proceedings. However, in our experience, such descriptions are usually of
`little practical help in deciding obviousness questions. 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
`
`
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`5
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`1437, 1453 (Fed. Cir. 1984). Generalities that the person of ordinary skill is, for
`example, an M.D. with three years experience in some field or another, provides
`little help in establishing what that person knows or doesn’t know. It is the
`relevant references, along with any other evidence specifically identifying
`knowledge possessed by those working in the art, which substantially informs the
`level of ordinary skill. As long as the art relied upon is from the same or
`analogous fields the hypothetical person is presumed to be aware of it. In re
`Gorman, 933 F2d 982, 986 (Fed. Cir. 1991). Because there is no issue raised that
`the cited art is not from the same or an analogous field as the claimed invention,
`the person of ordinary skill is presumed to be aware of the content of the cited
`references. We hold that the cited references are representative of the level of
`ordinary skill in the art.
`
`B.
`To prevail in this inter partes review of the challenged claims, Petitioner
`
`must prove unpatentability by a preponderance of the evidence. 35 U.S.C.
`§ 316(e); 37 C.F.R. § 42.1(d). A patent claim is unpatentable under 35 U.S.C.
`§ 103(a) if the differences between the claimed subject matter and the prior art are
`such that the subject matter, as a whole, would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which the subject
`matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007). The
`question of obviousness is resolved on the basis of underlying factual
`determinations, including: (1) the scope and content of the prior art; (2) any
`differences between the claimed subject matter and the prior art; (3) the level of
`skill in the art; and (4) objective evidence of nonobviousness. Graham v. John
`Deere Co., 383 U.S. 1, 17–18 (1966). “All the evidence bearing on the issue of
`obviousness . . . must be considered and evaluated before the required legal
`
`
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`6
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`conclusion is reached.” W.L. Gore & Associates, Inc. v. Garlock, Inc., 721 F.2d
`1540, 1555 (Fed. Cir.1983).
`
`As a general rule, “discovery of an optimum value of a result effective
`variable in a known process is ordinarily within the skill of the art [and obvious.]”
`In re Boesch, 617 F.2d 272, 276 (C.C.P.A. 1980). Accordingly, “where 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
`Applied Materials, Inc., 692 F.3d 1289, 1295-96 (Fed. Cir. 2012) quoting In re
`Aller, 220 F.2d 454, 456 (CCPA 1955). The motivation to optimize comes from
`the natural desire of those skilled in the art to experiment with, and improve upon,
`known conditions taught in the prior art. In re Peterson, 315 F.3d 1325, 1330
`(Fed. Cir. 2003). However, there is an exception to the general rule where the
`results of optimizing the variable are shown to result in a property or benefit that a
`person of ordinary skill in the relevant art would have found to be unexpected. In
`re Antonie, 559 F.2d 618, 620 (CCPA 1977), In re Waymouth, 499 F.2d 1273,
`1276 (CCPA 1974). “Objective indicia of non-obviousness ‘may often establish
`that an invention appearing to have been obvious in light of the prior art was not.’”
`Institut Pasteur & Universite Pierre et Marie Curie v. Focarino, 738 F.3d 1337,
`1346 (Fed. Cir. 2013), quoting Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530,
`1538 (Fed. Cir.1983). Unexpected results need not have been fully recognized at
`the time the application was filed. Genetics Inst., LLC v. Novartis Vaccines &
`Diagnostics, Inc., 655 F.3d 1291, 1307 (Fed. Cir. 2011); Knoll Pharm. Co. v. Teva
`Pharms. USA, Inc., 367 F.3d 1381, 1385 (Fed.Cir.2004) (“There is no requirement
`that an invention's properties and advantages were fully known before the patent
`application was filed, or that the patent application contains all of the work done in
`studying the invention, in order for that work to be introduced into evidence in
`response to litigation attack.”).
`
`
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`7
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`C.
`Petitioner asserts that the subject matter of claim 20 is unpatentable under 35
`
`U.S.C. § 103(a) as obvious over the combined teachings of Kappos 2006 (Ex.
`1003), Clinical Trials (Ex. 1022), Joshi (Ex. 1030), and ICH Guideline E4 (Ex.
`1004). Petition, Paper 1, p. 24. Petitioner also supports its position with the
`declaration testimony of Dr. Steven E. Linberg (Ex. 1005). Petition, Paper 1, p. 8.
`1.
`Kappos 2006 describes results of a Phase II trial that treated MS patients
`
`with 120, 360 and 720 mg/day of a drug identified as BG00012 (BG12). Ex. 1003,
`p. 2. It is uncontested that the active ingredient of BG12 was recognized to be
`DMF. The clinical result of the trial was that administering 720 mg/day of DMF
`significantly reduced the mean number of new Gd+lesions (the
`primary end point) compared with placebo. In addition, [DMF]
`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.
`Ex. 1003A. p. 2. Gd+ and T2 and T1-hypointense lesions are brain lesions
`indicative of active inflammation of the type that occurs in patients with RRMS.
`While the only specific clinical result reported in Kappos 2006 was for the 720
`mg/day dose, the study concluded that:
`[DMF] significantly reduces brain lesion activity, in a
`dose-dependent manner, as measured by MRI in patients with
`RRMS over 24 weeks of treatment.
`Ex. 1003A, p. 2 (emphasis added).
`
`With its response Biogen submitted a press release (Press Release, Ex. 2057)
`that has relevance to the results of the phase II trial described in Kappos 2006.
`E.g., Biogen Res., Paper 38, p. 43. It was published on the same day as Kappos
`2006. Press Release, Ex. 2057. It adds that the “results of the 120 mg and 360 mg
`
`
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`8
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`BG-12-treated groups were not statistically significant versus placebo.” The press
`release also noted certain adverse side-effects that occurred during the trial:
`The most common adverse events were flushing,
`gastrointestinal disorders, headache, and
`nasopharyngitis.
`Press Release, Ex. 2057, p. 2.
`
`2.
`We find: (1) that the difference between Kappos 2006 and the subject matter
`
`of Claim 20 is the treatment of MS patients with about 480 mg/day of DMF instead
`of 720 mg/day; (2) that the dosage of DMF in treating MS patients is a result-
`effective variable with respect to reducing brain lesions of MS patients and (3) the
`administration of 720 mg/day of DMF resulted in not insignificant adverse side-
`effects.
`
`3.
`Joshi ‘999 (Ex. 1030) is titled “Dimethyl Fumarate for the Treatment of
`
`Multiple Sclerosis.” PTO records show that Joshi ‘999 is assigned to Biogen. The
`patent issued on January 22, 2008, based on application 10/197,077 filed July 17,
`2002. The ‘077 application was published on January 23, 2003, as patent
`application publication 2003/0018072. A copy of the published application is of
`record as Ex. 1031. The technical content of Ex. 1031 appears to be identical to
`that of the Joshi ‘999 patent. The content of the published application is 35 U.S.C.
`§ 102(b) prior art with respect to Biogen’s earliest possible effective filing date—
`February 8, 2007.
`
`Joshi ‘999 (Ex. 1030) relates the therapeutic use of dialkyl fumarates in
`pharmaceutical preparations for treatment of autoimmune diseases. Ex. 1030,
`1:16-20. DMF is a dialkyl fumarate where the “alkyl” is methyl. Joshi ‘999
`teaches providing fumarate preparations in the form of micro-tablets or micro-
`
`
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`9
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`pellets containing the dialkyl fumarates. Ex. 1030, 3:6-11. DMF is an
`“[e]specially preferred” active ingredient in the preparations. Ex. 1030, 4:26-27.
`The preparations “may be employed for treating autoimmune diseases,
`particularly . . . [MS] . . . .” Ex. 1030, 2: 2:65 – 3:5. The preferred treatment
`preparations (i.e., micro-tablets or micro-pellets) include 10 to 300 mg of DMF.
`Ex. 1030, 4:47-49. Joshi ‘999 describes formation of micro-tablets including 50
`mg, 110 mg, and 120 mg of DMF. Ex. 1030, 5:60 – 7:55. No other examples are
`presented. Joshi ‘999 does not teach or exemplify any specific dose of DMF or
`any other fumarate for treating MS or any other autoimmune disease.
`
`All the claims of the Joshi ‘999 patent are directed to methods of treating
`MS by administering an effective amount of DMF. Claim 1 of Joshi ‘999
`provides:
`
`1. A method of treating multiple sclerosis comprising
`treating a patient in need of treatment for multiple
`sclerosis with an amount of a pharmaceutical
`preparation effective for treating said multiple
`sclerosis,
`wherein the only active ingredient for the treatment of
`multiple sclerosis present in said pharmaceutical
`preparation is dimethyl fumarate.
`Ex. 1030, 8:14-19 (paragraphing added). Joshi gives neither suggestion nor
`guidance as to the appropriate doses for “treating a patient in need of treatment for
`multiple sclerosis.”
`
`Joshi ‘999 notes the existence of gastrointestinal irritations and other side
`effects due to administration of fumarates. The patent teaches that the use of a
`micro-tablet form of dialkyl fumarates reduces gastrointestinal irritations and side
`effects vis-à-vis those that occur with conventional fumarate tablets:
`By administration of the dialkyl fumarates in the form of micro-
`tablets, which is preferred, gastrointestinal irritations and side
`
`
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`10
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`effects, which are reduced already when conventional tablets
`are administered but is still observed, may be further reduced
`vis-a-vis fumaric acid derivatives and salts.
`Ex. 1030, 5:29-33. Specifically with respect to gastrointestinal irritations, the
`patent also suggests using enteric-coated microcapsules which reduce the local
`concentration of the fumarate. Ex. 1030, 5:39-42.
`4.
`Clinical Trials (Ex. 1022) is a printout from the ClinicalTrials.gov archive, a
`
`publically available database of clinical trials information. The document is titled
`“Double-Blind, Placebo-Controlled, Dose-Ranging Study to Determine the
`Effacacy [sic] and Safety of BG00012 in Subjects with Relapsing-Remitting
`Multiple Sclerosis.” Ex. 1022, p. 1. It is dated September 14, 2005. Id. It
`identifies DMF as the active ingredient in BG12. Id.
`
`The document describes a two-part study. Part 1 describes investigating the
`effectiveness of the same dosages of DMF tested and reported in Kappos 2006. Ex.
`1022, p. 2; Ex. 1003A, p. 2. The study included three treatment groups and a
`placebo group:
`Treatment Group BG00012 Dosing Regimen BG00012 Total
`Daily Dose
`
`1 120 mg once a day (qd) 120 mg
`
`2 120 mg three times a day (tid) 360 mg
`
`3 240 mg tid 720 mg
`
`4 Placebo
`Ex. 1022, p. 2. As part of the study, all subjects were to be evaluated for tolerance
`to the drug. Ex. 1022, p. 2. Group 3 subjects were to begin with 120 mg three
`times a day. After Ex. 1022, p. 2. “After 1 week, Group 3 subjects who tolerate
`120 mg tid (as determined by the subject’s tolerance of flushing episodes and
`gastrointestinal [GI] disturbances) will have their dose increased to 240 mg tid.”
`
`
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`Ex. 1022, p. 2. The study notes that “[d]ose reduction will be allowed for subjects
`who are unable to tolerate investigational drug.” Ex. 1022, p. 2.
`5.
`ICH is a document issued by the International Conference on Harmonisation
`
`of Technical Requirements for Registration of Pharmaceuticals for Human Use. It
`is titled “Dose-Response Information to Support Drug Registration E4.” It is dated
`March 10, 1994. Ex. 1004, p. 1.
`
`ICH is not specific as to any particular disease or drug. It presents general
`guidance to those developing new drugs or drug treatments in determining
`appropriate and acceptable drug doses. The publication describes general
`guidelines and techniques relating to determining the dose-response of
`pharmaceuticals in support of drug approval and registration. Determining the
`dose-response is significant because “[k]nowledge of the relationships among
`dose, drug-concentration in blood, and clinical response (effectiveness and
`undesirable effects) is important for the safe and effective use of drugs in
`individual patients.” Ex. 1004, p. 5 (emphasis added). We find that information in
`the document would have been part of the general knowledge possessed by one
`having ordinary skill in the art.
`
`ICH notes that the determination of the most appropriate dose for any
`treatment is not straight forward:
`Historically, drugs have often been initially marketed at what
`were later recognized as excessive doses (i.e., doses well onto
`the plateau of the dose-response curve for the desired effect),
`sometimes with adverse consequences . . . . This situation has
`been improved by attempts to find the smallest dose with a
`discernible useful effect or a maximum dose beyond which no
`further beneficial effects is seen, but practical study designs do
`not exist to allow for precise determination of these doses.
`Further, expanding knowledge indicates that the concepts of
`minimum effective dose and maximum useful dose do not
`12
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`adequately account for individual differences and do not allow
`a comparison, at various doses, of both beneficial and
`undesirable effects. Any given dose provides a mixture of
`desirable and undesirable effects, with no single dose
`necessarily optimal for all patients.
`Ex. 1004, p. 5 (emphasis added). We understand the “dose-response curve” to
`represent the relationship of the effect of the drug—beneficial or undesirable—to
`the dose of the drug. We understand the “plateau of the dose-response curve” to be
`the portion of the curve in which the increase in the dose does not significantly
`change the effect of the drug.
`
`ICH teaches the importance of evaluating both beneficial effects and side
`effects in determining the dose to be administered:
`What is most helpful in choosing the starting dose of a drug is
`knowing the shape and location of the population (group)
`average dose-response curve for both desirable and undesirable
`effects. Selection of dose is best based on that information,
`together with a judgement about the relative importance of
`desirable and undesirable effects.
`Ex. 1004, p. 5. Additionally, when evaluating the dose for individual patients the
`determination of the individual’s dose-response curve is also important:
`In adjusting the dose in an individual patient after observing the
`response to an initial dose, what would be most helpful is
`knowledge of the shape of individual dose-response curves,
`which is usually not the same as the population (group) average
`dose-response curve. Study designs that allow estimation of
`individual dose-response curves could therefore be useful in
`guiding titration, although experience with such designs and
`their analysis is very limited.
`Ex. 1004, p. 6 (emphasis added).
`
`ICH describes a number of different trial designs for assessing dose-
`response. Ex. 1004, pp. 9-12. ICH notes that as a general matter, “useful dose-
`response information is best obtained from trials specifically designed to compare
`
`
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`several doses.” Ex. 1004, p. 9. Additionally, “[i]t is important to choose as wide a
`range of doses as is compatible with practicality and patient safety to discern
`clinically meaningful differences.” Ex. 1004, p. 10. ICH also identifies exemplary
`trial designs that can be used:
`A number of specific study designs can be used to assess dose-
`response. . . . Although not intended to be an exhaustive list, the
`following approaches have been shown to be useful ways of
`deriving valid dose-response information. Some designs
`outlined in this guidance are better established than others, but
`all are worthy of consideration. These designs can be applied to
`the study of established clinical endpoints or surrogate
`endpoints.
`Ex. 1004, p. 10. ICH specifically describes four different types of trials: (1)
`parallel dose-response, (2) cross-over dose-response, (3) forced titration and (4)
`optional titration (placebo-controlled titration to end-point). Ex. 1004, pp. 10-12.
`ICH notes that the parallel dose-response trials gives population-average dose-
`response data and not individual dose-response curves. Ex. 1004, p. 10.
`Additionally, with respect to parallel dose-response trials, ICH notes that multiple
`trials may be necessary:
`It is all too common to discover, at the end of a parallel dose-
`response study, that all doses were too high (on the plateau of
`the dose-response curve), or that doses did not go high enough.
`A formally planned interim analysis (or other multi-stage
`design) might detect such a problem and allow study of the
`proper dose range.
`Ex. 1004, p. 10.
`
`D.
`Petitioner argues the difference between the claimed method and that of
`
`Kappos 2006 would not have been unobvious. According to petitioner, the person
`of ordinary skill in the art would have been motivated to conduct further tests to
`optimize the effective dose: “a POSITA would have been motivated to conduct
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`routine experiments at a range of doses, including 480 mg/day, by orally
`administering that dose of a pharmaceutical to subjects in need of treatment for
`MS.” Petition, Paper 1, p. 53. Relying on the testimony of Dr. Linberg, petitioner
`notes that “side effects are always a concern in drug development.” Petition, Paper
`1, pp. 52-53; Ex. 1005, ¶ 69. Petitioner directs us to Joshi ‘999 for the disclosure
`that it was known that treatments of fumarates, such a DMF, may result in
`gastrointestinal irritations and undesired side effects. Petition, Paper 1, p. 52; Ex.
`1030, 5:29-33. Petitioner also directs us to the teaching in Clinical Trials that if the
`administration of DMF is not well tolerated due to flushing episodes and
`gastrointestinal disturbances, the dose may be lowered. Petition, Paper 1, p. 52;
`Ex. 1022, p. 2. Petitioner also relies on ICH as providing a basis for modifying the
`trial described in Kappos 2006 to investigate alternative doses to minimize side
`effects:
`
`the purpose of the ICH Guideline E4 was to provide
`instructions to help identify “an appropriate starting dose, the
`best way to adjust dosage to the needs of a particular patient,
`and a dose beyond which increases would be unlikely to
`provide added benefit or would produce unacceptable side
`effects.”
`Petition, Paper 1, p. 53 quoting ICH, Ex. 1004, p. 5.
`E.
`Biogen argues, inter alia, that “[t]he magnitude of the clinical efficacy
`
`exhibited by administering the 480 mg/day dose was unexpected.” Biogen Res.,
`Paper 38, pp. 43-49. Biogen relies on the results of post-filing date Phase III trials
`for DMF. The results of the Phase III trial are presented in Exs. 2025 and 2026.
`The documents are referred to as the DEFINE Study and the CONFIRM Study,
`respectively. The trials treated MS patients with both 480 and 720 mg/day of
`DMF. Ex. 2025, p. 1; Ex. 2026, p. 2. According to Biogen, DEFINE and
`
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`CONFIRM establish “surprisingly—that a 480 mg/day dose of DMF proved to
`have similar efficacy” to the 720 mg/day taught by Kappos 2006 for almost every
`end point measured. Biogen Res, Paper 38, p. 43.
`1.
`Biogen’s evidence of unexpected results includes the testimony of Ronald A.
`
`Thisted, Ph.D (Thisted Test., Ex. 2038); Richard C. Brundage, Pharm. D., Ph.D
`(Brundage Test., Ex. 2042) and Richard A. Rudick, M.D. (Rudick Test., Ex. 2044).
`a.
`Dr. Thisted testifies that he is a Professor and Vice Provost, Academic
`Affairs, at the University of Chicago and holds faculty appointments in the
`departments of Statistics, Public Health Sciences, and Anesthesia & Critical Care.
`He received bachelor’s degrees in mathematics and philosophy from Pomona
`College, and a master’s degree and a doctorate of philosophy in statistics from
`Stanford University. He has more than forty years of research, academic, and
`practical experience in the area of biostatistics. His research focuses on
`biostatistics and epidemiology, statistical computation, and the effectiveness of
`medical intervention from a statistical perspective. He has been on the faculty of
`the University of Chicago since 1976. His positions included Scientific Director
`for the Biostatistics Core Facility at the University of Chicago Cancer Research
`Center from 1999–2014. He has taught courses in biostatistics for over 35 years
`and also taught courses on statistical methods, epidemiology, and clinical research
`methods. He is an Elected Fellow of the American Association for the
`Advancement of Science (1992) and of the American Statistical Association
`(1988). He has authored over one hundred publications in the area of biostatistics
`and epidemiology, many in peer-reviewed journals including the New England
`Journal of Medicine, the Journal of the American Medical Association, and The
`Lancet. He has acted as a referee for the National Institutes of Health and the
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`National Science Foundation reviewing grant proposals for potential funding.
`Since the late 1970s, he has consulted for the pharmaceutical and medical device
`industries on the design of clinical trials and statistical analysis of clinical trial
`results. He has consulted regarding the design of Phase I, Phase II, and Phase III
`clinical trials; designed data collection methods; planned and overseen statistical
`analysis of results; prepared reports for use by the FDA; and presented statistical
`aspects of clinical studies to the FDA. He has consulted as the principal
`biostatistician for studies involving MS patients including as principal
`biostatistician on two randomized clinical trials for treating specific symptoms in
`MS patients. Thisted Test., Ex. 2038, ¶¶ 2-11; Ex. 2039.
`b.
`Dr. Brundage testifies that is Professor of Experimental and Clinical
`
`Pharmacology at the College of Pharmacy at the University of Minnesota and has
`held that position since 2008. He received a Bachelor of Science degree in
`Pharmacy and a Pharm. D. from the University of Minnesota College of Pharmacy
`in 1977 and 1985, respectively. He also obtained a Ph.D. in Pharmaceutics from
`the University of Minnesota in 1996. He was an Assistant Professor of Pharmacy
`at the Medical University of South Carolina researching clinical pharmacokinetics.
`His instructional responsibilities included Clinical Pharmacokinetics, Advance
`Disease Processes and Pharmacotherapeutics: Neurology Module. His current
`research involves the quantitative modeling of pharmacological systems for better
`understanding of dose-response relationships. During his tenure at the University
`of Minnesota, he has taught both professional and graduate courses, including
`Applied Pharmacokinetics, Pharmacometrics, and Advanced Clinical
`Pharmacology. He has also taught Clinical Trials Simulations, which involves
`designing and conducting computer-based clinical trials to explore optimal design
`elements (e.g., sample size, timing of sample collection, and timing of outcome
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`measures). Additionally, he has taught numerous lectures, short courses, and
`workshops on topics including population pharmacokinetics, applications of
`nonlinear mixed-effects modeling in drug development, and a lecture entitled
`“Center for Forecasting Drug Response: The Role of Pharmacometrics” at the
`Institute for Therapeutics Discovery and Development. His research has been
`funded by grants and contracts, including grants from the National Institutes of
`Health and several pharmaceutical companies. He has published over 90 papers in
`peer-reviewed and refereed journals and authored of several book chapters in the
`field of Pharmacokinetics and Pharmacodynamics. He is a fellow of the
`International Society of Pharmoacometrics and regularly presents at conferences as
`an invited speaker. He is a member of and has served on committees of several
`professional societies, including the International Society of Pharmacometrics, the
`American College of Clinical Pharmacology, the American Society of Clinical
`Pharmacology and Therapeutics, and the American Association of Pharmaceutical
`Scientists. He has served on the editorial boards of the British Journal of
`Pharmacology, the Journal of Pharmacokinetics and Pharmacodynamics, and the
`International Journal of Clinical Pharmacology and Therapeutics. He has also
`been an ad hoc manuscript reviewer for over 20 other journals, including Clinical
`Therapeutics, Journal of the American Pharmaceutical Association, and
`Pharmaceutical R