Trials@uspto.gov
`571-272-7822
`
`
`
`
`
`
`
`
`
`
` Paper 20
`
`
` Entered: 22 March 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`BEFORE THE 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 FRED E. McKELVEY, SALLY GARDNER LANE, and
`DEBORAH KATZ, Administrative Patent Judges.
`
`McKELVEY, Administrative Patent Judge.
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`Page 1 of 29
`
`Biogen Exhibit 2032
`Mylan v. Biogen
`IPR2018-01403
`
`

`

`
`IPR2015-01993
`Patent 8,399,514 B2
`
`
`
`I. Introduction
`
`A. Background
`
`
`
`A second petition seeking to institute an inter partes review in
`
`connection with U.S. Patent No. 8,399,514 B2 (“ʼ514 patent”) is before the
`
`Board. Paper 1.
`
`
`
`A first petition seeking to institute an inter partes review was denied.
`
`Coalition for Affordable Drugs V LLC v. Biogen MA Inc., IPR2015-01136,
`
`2015 WL 5169256 (Paper 23) (PTAB Sept. 2, 2015), reh’g denied,
`
`IPR2015-01136 (Paper 29) (PTAB Oct. 23, 2015).
`
`
`
`The ʼ514 patent is also involved in Biogen MA Inc. v. Forward
`
`Pharma, Interference 106,023 (PTAB Declared Apr. 13, 2015).
`
`
`
`
`
`
`
`
`
`Patent Owner timely filed a Preliminary Response. Paper 11.
`
`Petitioner was invited to file a Reply. Paper 13.
`
`Petitioner timely filed the Reply.1 Paper 17.
`
`B. The Parties
`
`Petitioner is:
`
`(1) Coalition for Affordable Drugs V LLC,
`
`(2) Hayman Credes Master Fund, L.P.,
`
`
`1 The Reply is styled REPLY TO PATENT OWNER’S PRELIMINARY
`RESPONSE IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT 8,399,514 UNDER 35 U.S.C. §§ 311-319. In the future
`the style of any paper filed in this IPR shall not exceed one line. A more
`appropriate style would have been REPLY TO PRELIMINARY
`RESPONSE. Use of a single line renders entry of papers into Board data
`records much easier. Failure to adhere to the one-line rule established in this
`IPR may result in a paper being expunged.
`
` 2
`
`
`
`
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`Page 2 of 29
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`

`

`
`IPR2015-01993
`Patent 8,399,514 B2
`
`
`
`(3) Hayman Orange Fund SPC – Portfolio A,
`
`(4) Hayman Capital Master Fund, L.P.,
`
`(5) Hayman Capital Management, L.P.,
`
`(6) Hayman Offshore Management, Inc.,
`
`(7) Hayman Investment, LLC,
`
`(8) NXN Partners, LLC,
`
`(9) IP Navigation Group, LLC,
`
`(10) J. Kyle Bass, and
`
`(11) Erich Spangenberg.
`
`Paper 1, pages 1–2.
`
`
`
`Patent Owner is Biogen MA Inc. Paper 11, page 1.
`
`BG00012 or BG12
`
`Dimethyl fumarate
`
`C. Abbreviations
`
`Dimethyl fumarate
`
`International Conference on Harmonisation
`
`Monomethyl fumarate
`
`Magnetic resonance imaging
`
`Relapsing-remitting multiple sclerosis
`
` 3
`
`
`
`DMF
`
`ICH
`
`MMF
`
`MRI
`
`RRMS
`
`
`
`
`
`Page 3 of 29
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`

`

`
`IPR2015-01993
`Patent 8,399,514 B2
`
`
`
`D. Evidence Relied Upon2
`
`
`
`The following evidence is relied upon in support of the Petition:
`
`Name
`
`Exhibit
`No.
`
`Description
`
`Date
`
`
`
`
`Kappos 2006
`
`
`
`
`1003
`
`
`
`
`May 2006
`
`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
` Kappos 2006 is prior art under 35 U.S.C. § 102(b) based on the filing
`date of Biogen’s PCT application (7 February 2008). If Biogen is entitled to
`a benefit date of its Provisional Application (8 February 2007), Kappos 2006
`is prior art under 35 U.S.C. § 102(a).
` Further discussion of Kappos 2006 occurs later in this opinion.
`
`
`Double-Blind, Placebo-
`
`
`Controlled, Dose-Ranging
`
`
`Study to Determine the
`Clinical Trials
`1022
`Effacacy and Safety of
`BG00012 in Subjects with
`Relapsing-Remitting Multiple
`Sclerosis,
`CLINICALTRIALS.GOV
`ARCHIVE
`Clinical Trials is prior art under 35 U.S.C. § 102(b).
`
`
`
`
`
`14 Sept. 2005
`
`
`2 Because the application maturing into the ʼ514 patent was filed before
`the enactment of the Leahy-Smith America Invents Act (“AIA”), Pub. L.
`No. 112-29, 125 Stat. 284 (2011), we apply the pre-AIA version of 35 U.S.C.
`§§ 102, 103, 112, and 119.
`
` 4
`
`
`
`
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`
`IPR2015-01993
`Patent 8,399,514 B2
`
`
`
`Name
`
`Exhibit
`No.
`
`Description
`
`Date
`
`
`Joshi ʼ999
`
`
`1030
`
`
`U.S. Patent 7,320,999 B2
`
`22 Jan. 2008
`filed
`17 July 2002
`Joshi ʼ999 is prior art under 35 U.S.C. § 102(a) having issued prior to
`Biogen’s PCT filing date (7 February 2008). If Biogen is entitled to a
`benefit date of its Provisional Application (8 February 2007), then Joshi
`ʼ999 is prior art under 35 U.S.C. § 102(e) based on its filing date (17 July
`2002).
`
`
`ICH Guideline
`
`
`1004
`
`Joshi ʼ992
`
`1036
`
`ICH Harmonised Tripartite
`Guideline, DOSE-RESPONSE
`INFORMATION TO SUPPORT
`DRUG REGISTRATION E4
`U.S. Patent 6,436,992 B1
`
`
`10 Mar. 1994
`
`20 Aug. 2002
`
`
`
`Begleiter
`
`
`
`1027
`
`
`
`Dietary Induction of NQOI
`Increases the Antitumour
`Activity of Mitomycin C in
`Human Colon Tumours in
`vivo,
`91 BRITISH J. CANCER 1624–
`1631
`ICH Guideline, Joshi ʼ992, and Begleiter are prior art under 35 U.S.C.
`§ 102(b).
`
`
`
`2004
`
`
`
`E. Grounds of Unpatentability
`
`
`
`Claims 1–20 appear in the ʼ514 patent. Ex. 1001, col. 27:58 through
`
`col. 30:27.
`
`The following grounds of unpatentability are urged in the Petition.
`
` 5
`
`
`
`
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`Page 5 of 29
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`

`
`IPR2015-01993
`Patent 8,399,514 B2
`
`
`
`
`
`Statutory
`Basis
`
`Prior Art
`Relied On
`
`Claims
`
`
`1–6, 8–16, and 20
`
`
`
`
`
` 7
`
`
`
`17–19
`
`Kappos 2006
`ClinicalTrials,
`Joshi ʼ999, and
`ICH Guideline
`Kappos 2006,
`ClinicalTrials,
`Joshi ʼ999,
`ICH Guideline, and
`Joshi ʼ992
`Kappos 2006,
`ClinicalTrials,
`Joshi ʼ999,
`ICH Guideline and
`Begleiter
`
`F. Kappos 2006
`
`The application maturing into the ʼ514 patent was filed on
`
`13 February 2012. Ex. 1001, page 1.
`
`
`
`Biogen claims benefit of Provisional Application 60/888,921, filed
`
`8 February 2007.
`
`
`
`The Petition has not challenged Patent Owner’s 7 February 2008
`
`claim to priority based on Patent Owner’s PCT application. Paper 1, page 4.
`
`
`
`The Petition alleges that Patent Owner is not entitled to benefit of its
`
`Provisional Application based on Patent Owner having not been accorded
`
`benefit in Interference 106,023. Id.
`
`
`
`Patent Owner was accorded benefit of its Provisional Application at
`
`the time Interference 106,023 was declared. Interference 106,023, Paper 1,
`
` 6
`
`
`
`
`
`
`Ground 1
`
`
`§ 103(a)
`
`
`
`Ground 2
`
`
`
`§ 103(a)
`
`
`
`Ground 3
`
`
`
`§ 103(a)
`
`
`
`
`
`Page 6 of 29
`
`

`

`
`IPR2015-01993
`Patent 8,399,514 B2
`
`
`page 4. There came a time in Interference 106,023 when the Board
`
`determined that Patent Owner was not entitled to claim benefit of its
`
`Provisional Application filing date of 8 February 2007. Interference
`
`106,023, Paper 171. Subsequent to the Board’s determination, Biogen was
`
`authorized to file a motion to revive its abandoned application 12/526,296
`
`for the purpose of entry of an amendment to make a specific reference to its
`
`Provisional Application. Interference 106,023, Paper 197. The motion to
`
`revive was timely filed. Interference 106,023, Paper 122. Upon
`
`consideration of the motion to revive, the Board ordered that application
`
`12/526,296 be revived and further ordered that an amendment making a
`
`specific reference to Biogen’s Provisional Application be entered.
`
`Interference 106,023, Paper 611. In ordering revival and entry of the
`
`amendment, the Board did not determine on the merits whether Biogen is
`
`entitled to the benefit of its Provisional Application 60/888,921 under
`
`35 U.S.C. § 119(e)(1)—in other words, the Board did not determine in
`
`Interference 106,023 whether the invention claimed in the ʼ514 patent is
`
`disclosed in the Provisional Application in the manner required by the first
`
`paragraph of 35 U.S.C. § 112.
`
`
`
`The prior art date of Kappos 2006 is May of 2006. As noted earlier in
`
`this opinion, Kappos 2006 is prior art under 35 U.S.C. § 102(b) if Biogen is
`
`not entitled to benefit of the 7 February 2007 filing date of its Provisional
`
`Application. Kappos 2006 is prior art under 35 U.S.C. § 102(a) if Biogen is
`
`entitled to benefit of the 8 February 2007 filing date of its Provisional
`
`Application—less than one year after May of 2006.
`
` 7
`
`
`
`
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`
`IPR2015-01993
`Patent 8,399,514 B2
`
`
`
`In its Preliminary Response, Patent Owner does not assert that it is
`
`entitled to benefit of its Provisional Application.
`
`At this stage, Kappos 2006 will be treated as prior art under 35 U.S.C.
`
`§ 102(b), without prejudice to Patent Owner establishing its right to a benefit
`
`date as of the filing date of its Provisional Application. The mere fact that
`
`Petitioner has not challenged the sufficiency of the PCT application does not
`
`establish that Patent Owner is entitled to benefit of its Provisional
`
`Application. There was no need for Petitioner to challenge benefit of the
`
`PCT because Kappos 2006 is prior art under 35 U.S.C. § 102(b) as to the
`
`PCT application.
`
`Should Patent Owner elect to seek benefit of its Provisional
`
`Application, it is noted that the written description portion of the
`
`Specification of the ʼ514 patent contains the following:
`
`For example, an effective dose of DMF or MMR [sic—
`MMF] to be administered to a subject orally can be from
`about 0.1 g to 1 g per pay, 200 mg to about 800 mg per
`day (e.g., from about 240 mg to about 720 mg per day; or
`from about 480 mg to about 720 mg per day; or about
`720 mg per day). For example, the 720 mg per day may
`be administered in separate administrations of 2, 3, 4, or
`6 equal doses.
`
`Ex. 1001, page 24, col. 18:58–64 (italics added).
`
`
`
`Atofina v. Great Lakes Chemical Corp., 441 F.3d 991, 1000 (Fed. Cir.
`
`2006), states that a disclosure of a range of 150 to 350 C does not constitute
`
`a specific disclosure of the endpoints of that range, i.e., 150ºC and 350º C;
`
`the disclosure is only that of a range, not a specific temperature in that range
`
` 8
`
`
`
`
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`Page 8 of 29
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`IPR2015-01993
`Patent 8,399,514 B2
`
`
`and the disclosure of a range is not a disclosure of end points of the range
`
`any more than it is of each of the intermediate points.
`
`
`
`Since the description of 480 mg in the ʼ514 patent is an end point, in
`
`the event Patent Owner elects to seek benefit of its Provisional Application,
`
`it should address why benefit should be accorded in light of Atofina.
`
`II. Analysis
`
`A. Challenge—Claims 1, 11, 15, and 20
`
`
`
`According to Petitioner, claims 1–6, 8–16, and 20 are unpatentable
`
`under 35 U.S.C. § 103(a) over a combination of (1) Kappos 2006,
`
`(2) ClinicalTrials, (3) Joshi ʼ999, and (4) ICH Guideline.
`
`B. Claims 1, 11, 15, and 20
`
`
`
`The invention can be readily understood by reference to independent
`
`claims 1, 11, 15, and 20, all reproduced below (indentation added; principal
`
`limitation in dispute italicized):
`
`Claim 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,
`
`
` 9
`
`
`
`
`
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`IPR2015-01993
`Patent 8,399,514 B2
`
`
`
`wherein the therapeutically effective amount of
`dimethyl
`fumarate, monomethyl
`fumarate, or a
`combination thereof is about 480 mg per day.
`
`Ex. 1001, col. 27:59–67.
`
`Claim 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.
`
`
`Claim 15
`
`A method of treating a subject in need of treatment
`for multiple sclerosis comprising
`
`orally administering to the subject [a] pharma-
`ceutical 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.
`
`
`Claim 20
`
`A method of treating a subject in need of treatment
`for multiple sclerosis comprising
`
`
`
`
`
`10
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`IPR2015-01993
`Patent 8,399,514 B2
`
`
`
`thereof with a
`in need
`the subject
`treating
`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.
`
`C. Kappos 2006
`
`Kappos 2006 is a 27 page document. Ex. 1003. The only relevant
`
`
`
`
`
`parts of Kappos 2006 are (1) page 1 of 27 identifying the publication date of
`
`Kappos 2006 and (2) article number O108 in column 2 of page 27 of 27.
`
`
`
`The remaining parts of Kappos (1) have not been relied upon by
`
`Petitioner, (2) sua sponte are excluded from evidence, (3) will not be
`
`considered and (4) are not considered to be part of the record before the
`
`Board.
`
`
`
`Petitioner is directed to forthwith refile Exhibit 1003 as Exhibit
`
`1003A containing only pages 1 and 27. Upon filing of Exhibit 1003A,
`
`Exhibit 1003 will be expunged.
`
`
`
`The relevant description in Kappos 2006 is generally self-explanatory
`
`and reads as follows (some indentation 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
`
`
`
`
`11
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`IPR2015-01993
`Patent 8,399,514 B2
`
`
`
`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)
`
`[1] once daily (120 mg/day),
`[2] 120 mg three times daily (360 mg/day),
`[3] 240 mg three times daily (720 mg/day), or
`[4] 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
`
`
`
`
`12
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`IPR2015-01993
`Patent 8,399,514 B2
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`the number of new
`lesions, and
`T2-hyperintense
`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.
`
`
`This study was sponsored by Biogen Idec and
`Fumapharm AG.
`
`Ex. 1003, page 27, col. 2.
`
`“BG00012” and “BG12” are designations for dimethyl
`
`fumarate (also referred to the record as “DMF”). See Linberg
`
`Testimony, Ex. 1005, ¶ 23, last three lines referring to Ex. 1002,
`
`page 1 and Ex. 1022, page 1.
`
`Kappos 2006 differs from the subject matter of claims 1, 11, 15,
`
`and 20 of the ʼ514 patent in that Kappos 2006 does not explicitly
`
`describe the use of a therapeutically effective amount of dimethyl
`
`fumarate that is “about 480 mg per day.”
`
`D. Joshi ʼ999
`
`
`
`Joshi ʼ999 (Ex. 1030) relates to the use of dialkyl fumarates,
`
`including dimethyl fumarate (col. 6:16–17 and 60; col. 8:19), for preparing
`
`pharmaceutical preparations for use in transplantation medicine or the
`
`therapy of autoimmune diseases, including multiple sclerosis (col. 1:29;
`
`col. 4:45; and col. 8:15), and pharmaceutical preparations in the form of
`
`micro-tablets or micro-pellets containing dialkyl fumarates.
`
`Joshi ʼ999 claim 1 reads [indentation added]:
`
`
`13
`
`
`
`
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`IPR2015-01993
`Patent 8,399,514 B2
`
`
`
`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,
`
`ingredient for
`the only active
`wherein
`treatment of multiple
`sclerosis present
`in
`pharmaceutical preparation is dimethyl fumarate.
`
`Ex. 1030, col. 8:14–19.
`
`the
`said
`
`
`
`Claim 2 reads:
`
`The method of claim 1, wherein 10 to 300 mg of
`
`dimethyl fumarate is present in said pharmaceutical
`preparation.
`
`Ex. 1030, col. 8:20–22.
`
`
`
`Claim 9 reads:
`
`The method of claim 1, wherein 120 mg of
`dimethyl fumarate is present in said pharmaceutical
`preparation.
`
`Ex. 1030, col. 8:38–39.
`
`
`
`Claim 18 reads:
`
`The method of claim 1, wherein the
`pharmaceutical preparation comprises one or more
`excipients.
`
`Ex. 1030, col. 8:62–63.
`
`
`
`
`14
`
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`IPR2015-01993
`Patent 8,399,514 B2
`
`
`
`
`According to Joshi ʼ999:
`
`The dialkyl fumarates used according to the
`invention may be used alone or as a mixture of several
`compounds, optionally
`in combination with
`the
`customary carriers and excipients. The amounts to be
`used are selected in such a manner that the preparations
`obtained contain the active ingredient in an amount
`corresponding to 10 to 300 mg of fumaric acid.
`
`Preferred preparations according to the invention
`contain a total amount of 10 to 300 mg of dimethyl
`fumarate and/or diethyl fumarate.
`
`Ex. 1030, col. 4:39–48 (italics added).
`
`
`
`Joshi ʼ999 differs from the subject matter of claims 1, 11, 15,
`
`and 20 of the ʼ514 patent in that Joshi ʼ999 does not describe the use
`
`of a therapeutically effective amount of dimethyl fumarate that is
`
`“about 480 mg per day.”
`
`E. ICH Guideline
`
`
`
`ICH Guideline (Ex. 1004) describes guidelines for determining
`
`appropriate dosages of pharmaceutical products.
`
`ICH means “International Conference on Harmonisation.”
`
`
`
`According to ICH:
`
`Knowledge 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.
`This information can 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
`
`
`
`
`15
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`IPR2015-01993
`Patent 8,399,514 B2
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`would be unlikely to provide added benefit or would
`produce unacceptable side effects. . . .
`
`
`initially
`Historically, drugs have often been
`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 (e.g. hypokalemia and other
`metabolic disturbances with thiazide-type diuretics in
`hypertension). 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 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, page 5 of 14 (italics added).
`
`
`
`Further according to ICH:
`
`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.
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`IPR2015-01993
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`is
`it
`information,
`In utilizing dose-response
`important to identify, to the extent possible, factors that
`lead to differences in pharmacokinetics of drugs among
`individuals, including demographic factors (e.g. age,
`gender, race), other diseases (e.g. renal or hepatic
`failure), diet, concurrent
`therapies, or
`individual
`characteristics (e.g. weight, body habitus, other drugs,
`metabolic differences).
`
`Ex. 1004, page 6 of 14 (italics added).
`
`
`
`“The choice of the size of an individual dose is often
`
`intertwined with the frequency of dosing.” Ex. 1004, page 7 of 14.
`
`
`
`ICH teaches that:
`
`Assessment of dose-response should be an integral
`component of drug development with studies designed to
`assess dose-response an inherent part of establishing the
`safety and effectiveness of the drug.
`
`Ex. 1004, page 7 of 14; Ex. 1005, ¶ 32.
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`
`
`Following up on discussion on page 7 of 15, second paragraph, ICH
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`further teaches:
`
`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, page 10 of 27; Ex. 1005, ¶ 32.
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`
`
`Pages 13 of 14 and 14 of 14 describe guidance and advice for
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`determining dosages.
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`IPR2015-01993
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`F. ClinicalTrials
`
`
`
`ClinicalTrials addresses a proposed study of a “Double-Blind,
`
`Placebo-Controlled, Dose-Range Study to Determine the Effacacy and
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`Safety of BG00012 in Subjects with Relapsing-Remitting Multiple
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`Sclerosis.” Ex. 1022, page 1 of 7.
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`
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`As noted earlier, BG00012 is dimethyl fumarate. Ex. 1022, page 1
`
`of 7; Ex. 1005, ¶ 28.
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`
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`In Part 1 of the study, the described dose ranges to be tested are
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`essentially the same as the dosages described as having been tested by
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`Kappos 2006. Ex. 1022, page 2 of 7; Ex. 1003, page 27 of 27; Ex. 1005,
`
`¶ 31.
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`
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`In Part 2, ClinicalTrials notes that “[d]ose reduction will be allowed
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`for subjects who are unable to tolerate investigational drug.” Ex. 1022,
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`page 2 of 7; Ex. 1005, ¶ 31.
`
`G. Dr. Steven E. Linberg
`
`
`
`Petitioner relies on the direct Declaration testimony of Dr. Steven E.
`
`Linberg. Ex. 1005.
`
`
`
`With respect to differences between (1) the subject matter of claim 1
`
`of the ʼ514 patent vis-à-vis (2) Joshi ʼ999 and Kappos 2006, Dr. Linberg
`
`testifies:
`
`
`
`In my opinion, the ICH Guideline E4 would have
`instructed a POSITA [“person of skill in the art”] as
`follows: “Assessment of dose-response should be an
`integral component of drug development with studies
`designed to assess dose-response [being] an inherent part
`of establishing the safety and effectiveness of the drug.
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`If development of dose-response information is built into
`the development process it can usually be accomplished
`with no loss of time and minimal extra effort compared
`to development plans
`that
`ignore dose-response.”
`Ex. 1004, 7[ of 14]:27–32. ICH Guideline E4 also would
`have instructed that: “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.” Ex. 1004, 10[ of
`14]:39–41. In my opinion, the ICH Guideline E4
`instructed a POSITA to perform dosing studies as a
`standard procedure in drug development in order to
`“allow study of the proper dose range” in phase III.
`Kappos 2006 . . . [does] not disclose doses between 360
`mg/day and 720 mg/day. However, in my opinion,
`Kappos 2006 . . . disclose[s] that single dosage forms
`were readily available in 120 mg units (“120 mg by
`mouth once daily”), making dose ranges of 480 mg daily
`and 600 mg daily readily apparent intervals for further
`testing. Further, ClinicalTrials . . . indicates that side
`effects such as gastrointestinal distress were known and
`were enough of a concern, that dosing could be reduced
`“for subjects who are unable to tolerate investigational
`drug” (Ex. 1022, page 2). Joshi also discloses unwanted
`side effects from the administration of the drug (“By
`administration of the dialkyl fumarates in the form of
`micro-tablets, which
`is preferred, gastrointestinal
`irritations and side 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, col. 5:29–33.) Because
`side effects are always a concern in drug development, as
`they were for DMF, and because doses in multiples of
`120 mg were readily available, a POSITA, in my opinion,
`would have been motivated to develop a method of
`treating a subject in need of treatment for multiple
`
`
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`sclerosis by administering dimethyl fumarate at about
`480 mg per day (as well as 600 mg per day) in order to
`identify an appropriate dose of DMF that minimized side
`effects. It would have been apparent to a POSITA that
`the teaching of Kappos 2006 in view of at least
`ClinicalTrials . . . , Joshi, and ICHGuideline E4 would
`have enabled just such a development of a method such
`as described at alternative dosing levels with a reasonable
`expectation of success because the intervals were readily
`available for a standard process of drug development.
`
`Ex. 1005, ¶ 32.
`
`H. Discussion
`
`1. Case for Likelihood of Obviousness
`
`
`
`Consistent with applicable precedent, a claimed range within a range
`
`described by the prior art is typically prima facie obvious. In re Boesch,
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`617 F.2d 272, 275 (CCPA 1980) (where ranges overlap, a prima facie case
`
`of obviousness is made out). The Federal Circuit has consistently followed
`
`Boesch. See, e.g., In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (a
`
`prima facie case of obviousness typically exists when the ranges of a
`
`claimed composition overlap the ranges disclosed in the prior art); In re
`
`Harris, 409 F.3d 1339, 1341 (Fed. Cir. 2005) (a prima facie case of
`
`obviousness arises when the ranges of a claimed composition are completely
`
`encompassed by the prior art); In re Huang, 100 F.3d 135, 139 (Fed. Cir.
`
`1996) (same).
`
`
`
`In the case before us, Patent Owner’s range of “about 480 mg per
`
`day” squarely falls within the combined ranges described by Kappos 2006
`
`(720 mg/day on the high end) and Joshi ʼ999 (10 to 300 mg/day on the low
`
`
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`end, it being noted that Joshi ʼ999 claim 1 calls for a broader “amount of a
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`pharmaceutical preparation effective for treating . . . multiple
`
`sclerosis . . . .”). The combined “effective” ranges described by Kappos
`
`2006 and Joshi ʼ999 are consistent with Patent Owner’s statement in its
`
`Specification that “an effective dose of DMF or MMR . . . can be from about
`
`0.1 to 1 g [1000 mg] per [d]ay.” Ex. 1001, page 24, col. 18:59–60.
`
`
`
`The ICH Guideline provides convincing evidence of how a person of
`
`ordinary skill in the art likely would go about determining an appropriate
`
`dosage for a particular person having multiple sclerosis.
`
`
`
`For example, if a dose is too high for a particular individual, one
`
`skilled in the art likely would have tested lower dosages for that individual
`
`in an attempt to find a most appropriate dose to achieve a result, all the while
`
`minimizing side-effects.
`
`
`
`Petitioner has made out a sufficient case to establish a reasonable
`
`likelihood of success as to each of the independent claims.
`
`2. Preliminary Response
`
`
`
`The Preliminary Response asserts numerous reasons why an
`
`inter partes review should not be instituted.
`
`(a) Non-merits Arguments
`
`
`
`In determining whether to institute an inter partes review, “the
`
`Director may take into account whether, and reject the petition . . . because,
`
`the same or substantially the same prior art or arguments previously were
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`presented to the Office.” 35 U.S.C. § 325(d).
`
`
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`According to Patent Owner, the prior art and arguments here are
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`the same as those made in IPR2015-01136 involving the same parties.
`
`Paper 11, pages 5–14. An inter partes review was not instituted in
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`IPR2015-01136. Coalition for Affordable Drugs V LLC v. Biogen MA Inc.,
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`IPR2015-01136, 2015 WL 5169256 (PTAB Sept. 2, 2015), reh’g denied,
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`IPR2015-01136 (Paper 29) (PTAB Oct. 23, 2015).
`
`
`
`In IPR2015-01136, Petitioner did not cite or rely on (1) the two Joshi
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`patents relied upon in this IPR or (2) Kappos 2006.
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`
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`Kappos 2006 has a highly relevant and significant teaching not
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`present in Kappos 2005 (Ex. 1003A of IPR2015-01136). Compare the
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`(1) “Results” in Kappos 2006, which states that BG00012 at 720 mg/day
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`significantly reduced Gd+ lesions, with (2) the “Results” in Kappos 2005
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`detailing only what a paper based on tests might reveal.
`
`
`
`We have taken into account the differences in prior art cited and relied
`
`upon in IPR2015-01136 vis-à-vis the different prior art cited and relied upon
`
`in this IPR. In view of those differences, and because we find the prior art
`
`cited and relied upon in this IPR to be considerably more persuasive, we see
`
`no reason for not instituting an inter partes review in this IPR.
`
`
`
`In support of its position, Patent Owner cites numerous decisions in
`
`other IPRs. Whether an inter partes review is instituted in a particular IPR
`
`based on alleged obviousness manifestly depends on the precise facts.
`
`Cf. In re Jones, 958 F.2d 347, 350 (Fed. Cir. 1992). Accordingly, institution
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`or non-institution decisions in other IPRs based on different facts are of little
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`help in resolving whether to institute in the IPR before us.
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`According to Patent Owner, “[t]he Board’s practice is to prevent
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`petitioners from using failed institution attempts as ‘how-to guide(s)’ in
`
`preparing later challenges.” Paper 11, page 15. We are unaware of any
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`established per se rule of this Board declining to institute based on so-called
`
`“how-to guide(s).” While it may be true that some cases determined that it
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`was inappropriate to institute based on a second petition, § 325(d) gives the
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`Director discretion to consider the merits of a second petition, apart from
`
`any refusal to institute on the basis of a first petition. As noted earlier,
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`because the prior art here is significantly different from that in IPR2015-
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`01136, we find that it is appropriate to institute an inter partes review in this
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`proceeding.
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`
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`We have considered all the remaining non-merits arguments presented
`
`by Patent Owner, but find them unpersuasive on the issue of whether an
`
`inter parties review should be ord