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`Paper No. __
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`For the Petitioner
`Lead counsel: James T. Carmichael, Reg. No. 45,306
`Backup counsel: Carol A. Spiegel, Reg. No. 68,033
`Carmichael IP, PLLC
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`
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`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 FUND, 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
`____________________
`
`PETITIONER REPLY TO BIOGEN OPPOSITION
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`Case No. IPR2015-01993
`Patent 8,399,514
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`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ............................................................................................ 1
`
`II. PERSON OF ORDINARY SKILL IN THE ART ............................................ 3
`
`III. ORDINARY MEANING OF DOSING TERMS ............................................. 4
`
`IV. BIOGEN IS NOT ENTITLED TO THE EARLIER 2007 FILING DATE OF
`ITS PROVISIONAL APPLICATION 60/888,921 .................................................. 4
`
`A. The ‘921 Provisional Does Not Provide Written Descriptive Support for the
`‘514 Patent Claims ................................................................................................ 5
`
`1. The ‘921 provisional fails to describe DMF or MMF being
`therapeutically effective when administered in a dosage of about 480 mg/day
`to an MS patient ................................................................................................ 6
`
`2. The ‘921 provisional does not describe a dosage of about 480 mg/day
`administered in 2, 3, 4 or 6 equal doses .......................................................... 11
`
`B. The ‘921 Provisional Does Not Enable the ‘514 Patent Claims ................. 12
`
`JOSHI ’999 CANNOT BE DISQUALIFIED AS PRIOR ART UNDER
`V.
`§103(c)(1) ............................................................................................................... 13
`
`VI. KAPPOS 2006 IS PRIOR ART UNDER §102(b) ......................................... 14
`
`VII. THE ‘514 PATENT CLAIMS ARE OBVIOUS ........................................ 15
`
`A. Overview of the Primary References .......................................................... 15
`
`B. POSA Would Have Selected a Dosage of About 480 mg/day DMF .......... 17
`
`1.
`
`2.
`
`ICH Guideline Suggests Conventional Dose-Response Study ............... 17
`
`ICH Guideline Emphasizes Dose-Response Function ............................ 18
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`ICH Guideline is Applied in Combination with Kappos 2006, Joshi ‘999
`3.
`and ClinicalTrials ............................................................................................ 19
`
`4. Safety Concerns Provide Motivation for About 480 mg/day ................. 20
`
`C. POSA Would Have Had a Reasonable Expectation a Dosage of About 480
`mg/day Would Be Successful ............................................................................. 22
`
`VIII. ASSERTED SECONDARY CONSIDERATIONS DO NOT OVERCOME
`THE PRIMA FACIE OBVIOUSNESS .................................................................. 24
`
`IX. CONCLUSION ............................................................................................... 26
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`TABLE OF AUTHORITIES
`
`Page(s)
`
`Federal Cases
`Atofina v. Great Lakes Chemical Corp.,
`441 F.3d 991, 1000 (Fed. Cir. 2006) ............................................................. 7
`
`
`In re Deuel,
`51 F.3d 1552, 1560 (Fed. Cir. 1995) ............................................................ 19
`
`KSR International Co. v. Teleflex, Inc.,
`550 U.S. 398, 421 (2007) ....................................................................... 19, 20
`
`Lockwood v. American Airlines, Inc.,
`107 F.3d 1565, 1571-72 (Fed. Cir. 1997) ..................................................... 11
`
`
`Streck, Inc. v. Research and Diagnostic Systems, Inc.,
`665 F.3d 1269, 1285 (Fed. Cir. 2012) ............................................................ 5
`
`In re Ruschig,
`379 F.3d 990, 995 (CCPA 1967) .................................................................... 7
`
`
`In re Wands,
`858 F.2d 731, 737 (Fed. Cir. 1988) .............................................................. 12
`
`
`Federal Statutes
`35 U.S.C. §102 .................................................................................................. 13, 14
`
`35 U.S.C. §103 ........................................................................................ 1, 13, 14, 20
`
`35 U.S.C. §112 .................................................................................................... 5, 10
`
`35 U.S.C. §119 ...................................................................................................... 4, 5
`
`35 U.S.C. §120 .......................................................................................................... 4
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`Patent 8,399,514
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`Other Authorities
`Recro Tech., LLC v Purdue Pharma L.P.,
`Interference 106,022, Paper 243 at 24 (April 29, 2016) ................................. 7
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`TABLE OF ABBREVIATIONS
`
`
`Abbreviation
`
`Definition
`
`BG-12 or BG00012
`
`dimethyl fumarate
`
`United States Food and Drug Administration
`
`gadolinium-enhancing
`
`International Conference on Harmonisation
`
`inter partes review
`
`monomethyl fumarate
`
`magnetic resonance imaging
`
`multiple sclerosis
`
`nuclear factor E2-related factor 2
`
`NAD(P)H dehydrogenase, quinone (1)
`
`person of ordinary skill in the art
`
`relapsing-remitting multiple sclerosis
`
`secondary progressive multiple sclerosis
`
`FDA
`
`Gd+
`
`ICH
`
`IPR
`
`MMF
`
`MRI
`
`MS
`
`Nrf2
`
`NQO1
`
`POSA
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`RRMS
`
`SPMS
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`Case No. IPR2015-01993
`Patent 8,399,514
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`I.
`
`INTRODUCTION
`
`The Board correctly instituted an inter partes review of claims 1-20 of US
`
`Patent 8,399,514 (“the ‘514 patent”) (Paper 20) on three grounds. Ground 1:
`
`claims 1-6, 8-16 and 20 as unpatentable under 35 U.S.C. §103(a) over Kappos
`
`2006, Clinical Trials, Joshi ‘999 and ICH Guideline. Ground 2: claim 7 as
`
`unpatentable under §103(a) over Kappos 2006, Clinical Trials, Joshi ‘999, ICH
`
`Guideline and Joshi ‘992. Ground 3: claims 17-19 as unpatentable under §103(a)
`
`over Kappos 2006, Clinical Trials, Joshi ‘999, ICH Guideline and Begleiter.
`
`Kappos 2006 disclosed the results of a phase 2 trial wherein RRMS patients
`
`orally receiving capsules of dimethyl fumarate (DMF) at a dosage of 240 mg three
`
`times daily (TID) showed a significantly reduced occurrence of new brain lesions
`
`versus placebo (Ex. 1003A). Certain side effects, e.g., flushing and
`
`gastrointestinal (GI) disturbances, were known to occur when administering DMF.
`
`(ClinicalTrials, Ex. 1022 1-2; Joshi ‘999, Ex. 1030 5:29-33). Thus, POSA would
`
`have been motivated to modify the dosing disclosed in Kappos 2006 by
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`administering DMF at a reduced dosage of about 480 mg/day (i.e., 240 mg twice
`
`daily (BID) rather than 240 mg TID) to minimize side effects with a reasonable
`
`expectation of success given the known efficacy of DMF, as explained by Drs.
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`Linberg (see e.g., Ex. 1005 ¶31; Ex. 2071 109:25-110:13) and Pleasure (see e.g.,
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`Ex. 1045 ¶¶62-64, 67).
`
`Biogen attempts to disqualify Kappos 2006 and Joshi ‘999 by arguing the
`
`‘514 patent is entitled to the filing date of provisional application 60/888,921 (the
`
`‘921 provisional). Biogen’s argument is based on impermissibly expanding the
`
`disclosure of the ‘921 provisional which fails to provide written description
`
`support or enablement for the ‘514 patent claims. Biogen is not entitled to an
`
`effective filing date earlier than 7 February 2008 based on the rebuttal evidence
`
`below.
`
`Finally, Biogen opposes the petition with spurious patentability arguments
`
`and supposed secondary considerations of nonobviousness. As demonstrated in
`
`both the Petition and the Reply, POSA would have had both motivation and a
`
`reasonable expectation of success in selecting a daily DMF dosage of about 480
`
`mg. Moreover, there were no unexpected results, unmet needs, or widespread
`
`industry praise for using this drug in a known and understood context.
`
`Thus, the PTAB should cancel claims 1-20 of the ‘514 patent in view of the
`
`asserted prior art.
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`II.
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`PERSON OF ORDINARY SKILL IN THE ART
`
`According to Biogen, POSA is someone having at least a medical degree
`
`with at least three years of training in neurology and at least three years of clinical
`
`experience treating MS (Ex. 2044 ¶36). According to Petitioner, POSA would
`
`have an advanced degree in the life sciences, e.g., an M.D., a Ph.D., a D.O., or a
`
`Pharm.D., with some experience with clinical trial designs for dose selection (Ex.
`
`1005 ¶9).
`
`Petitioner’s definition of POSA is appropriate. The prior art involves
`
`clinical trial designs for dose selection. While a dose ranging study may involve a
`
`team of physicians, biostatisticians, and pharmacologists (see e.g., Ex. 1050 33:4-
`
`35:1), understanding the prior art in this case calls for experience with clinical trial
`
`design. With the Petition, Dr. Linberg provided that perspective. His experience
`
`working on such teams allows him to opine on understandings held by persons
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`satisfying Biogen’s definition of POSA as well as Petitioner’s definition (see e.g.,
`
`Ex. 2071 36:18-37:8; 60:4-17). Dr. Linberg’s opinions are reinforced and
`
`supplemented herein by Dr. Samuel Pleasure, M.D., Ph.D. To the extent the
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`PTAB adopts Biogen’s definition of POSA, Dr. Pleasure satisfies that definition.
`
`Dr. Pleasure is a practicing MS clinician with all the overlapping qualifications of
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`both Biogen’s and Petitioner’s definitions of POSA. Ex. 1045 ¶¶4-15. Among
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`other things, Dr. Pleasure herein rebuts opinions of Biogen’s clinicians presented
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`in Biogen’s Opposition and Motion to Antedate.
`
`III.
`
` ORDINARY MEANING OF DOSING TERMS
`
`Three different terms are commonly used when describing drug
`
`administration – unit dose, i.e., the amount of a drug in a particular pharmaceutical
`
`preparation; point dose, i.e., the amount of drug given at a single time; and dosage,
`
`i.e., the combination of point dose and frequency of administration. For example,
`
`two capsules each containing 120 mg of a drug taken three times a day have a unit
`
`dose of 120 mg, a point dose of 240 mg and a dosage of 720 mg/day (see e.g., Ex.
`
`1053 71:4-19; Ex. 1045 ¶65 at fn. 1). Using “dose” (whether unit or point) and
`
`“dosage” interchangeably, as Biogen does, confuses what is being said.
`
`IV. BIOGEN IS NOT ENTITLED TO THE EARLIER 2007 FILING
`DATE OF ITS PROVISIONAL APPLICATION 60/888,921
`
`
`
`Biogen’s Opposition alleges that “[p]etitioner has never once contested the
`
`sufficiency of the provisional application’s disclosure.” Opp. at 6. However, as
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`explained in the PTAB decision on institution, Petitioner heretofore had no need to
`
`do so. Decision at 6-8.
`
`A claim in a patent application is entitled to the filing date of prior
`
`applications if the statutory requirements of 35 U.S.C. §§119(e)(1) and 120 are
`
`met. To receive benefit of a provisional application’s filing date, the provisional
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`application must provide §112 support for later-claimed subject matter. 35 U.S.C.
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`§119(e)(1) (pre-AIA). The ‘921 provisional does not fully describe or enable the
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`‘514 patent claims.
`
`A. The ‘921 Provisional Does Not Provide Written Descriptive
`Support for the ‘514 Patent Claims
`
`The test for sufficiency of written description is whether the disclosure of
`
`the application relied upon reasonably conveys to those skilled in the art that the
`
`inventor had possession, i.e., had made, the claimed invention at the time of filing.
`
`Streck, Inc. v. Research and Diagnostic Systems, Inc., 665 F.3d 1269, 1285 (Fed.
`
`Cir. 2012).
`
`Biogen essentially argues the ‘921 provisional describes methods for
`
`screening, evaluating and comparing neuroprotective properties of compounds
`
`based on Nrf2 pathway upregulation with the specific goal of treating MS
`
`(Opposition 8-9). The ‘921 provisional allegedly directs POSA to administer DMF
`
`or MMF at a specific daily dosage of “about 480 mg” by describing a series of
`
`progressively narrower dosage ranges. Relying on selected paragraphs of the ‘921
`
`provisional and the testimony of its expert, Dr. Wynn, Biogen concludes the ‘921
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`provisional singles out and describes the preferred, discrete dosage of about 480
`
`mg/day as a therapeutically effective amount of DMF or MMF (id. 8-10). Biogen
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`overstates the invention described in the ‘921 provisional and Dr. Wynn relies on
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`material not part of the ‘921 provisional.
`
`1.
`
`The ‘921 provisional fails to describe DMF or MMF being
`therapeutically effective when administered in a dosage of
`about 480 mg/day to an MS patient
`
`Biogen argues the following paragraph describes a dosage of DMF or MMF
`
`of “about 480 mg” through a series of progressively narrower dosing ranges:
`
`For example, an effective dose of DMF or MMR [sic] to
`be administered to a subject orally can be from about 0.1
`g to 1 g per day, 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. 1012 ¶[0116]).
`This paragraph provides five nested ranges of hypothetical daily dosages (in
`
`mg): about 100 to 1000; 200 to about 800; about 240 to about 720; about 480 to
`
`about 720; and about 720. Biogen’s own expert, Dr. Wynn, concedes that “about
`
`720 mg per day,” is the narrowest of these ranges. (Ex 1050 80:14-16; 83:9-13).
`
`The paragraph gives equal prominence to 200 mg/day, about 240 mg/day, and
`
`about 480 mg/day, which are all lower endpoints of intermediate ranges. Dr.
`
`Wynn admitted 240 mg/day is not an effective dosage. (Ex. 1050 86:2-8). If 240
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`mg/day is not effective, neither is 200 mg/day. Identifying a set of ranges in this
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`manner, including ineffective amounts as lower endpoints, did not disclose to
`
`POSA that the ‘921 inventors were in possession of a particular lower endpoint of
`
`one of the intermediate ranges as a therapeutically effective amount. (Ex. 1045
`
`¶57).
`
`Any fair reading of the ‘921 provisional’s fleeting mention of about 480
`
`mg/day as a lower endpoint of an intermediate range does not provided any blaze
`
`marks singling out about 480 mg/day as a preferred, discrete dosage. See In re
`
`Ruschig, 379 F.3d 990, 995 (CCPA 1967) (requiring “blaze marks”). At most, the
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`‘921 provisional blazes a trail to a dosage of about 720 mg/day. A dosage of about
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`720 mg/day is reiterated four times, including once by itself, while the dosage of
`
`about 480 mg/day is only mentioned once, and never by itself and always in the
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`phrase “from about 480 mg/day to about 720 mg/day”. (Ex. 1045 ¶57).
`
`Biogen argues the holding in Atofina v. Great Lakes Chemical Corp., 441
`
`F.3d 991, 1000 (Fed. Cir. 2006) (the disclosure of a range is no more a disclosure
`
`of the endpoints of the range than it is of each of the intermediate points) is limited
`
`to prior art anticipation and not applicable to the written description. However, the
`
`Board has cited Atofina as applicable to written description (see Recro Tech., LLC
`
`v Purdue Pharma L.P., Interference 106,022, Paper 243 at 24 (April 29, 2016)).
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`Dr. Wynn testified that 480 mg/day is the preferred dosage in the ’921
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`provisional because it is the lowest endpoint of the narrowest range. (Ex. 1050
`
`95:9-22). That testimony contradicts his earlier testimony admitting “about 720
`
`mg/day” was actually the narrowest recited range (Ex 1050 80:14-16; 83:9-13).
`
`Even if the ‘921 provisional somehow conveyed that the inventors were in
`
`possession of about 480 mg/day as an effective dosage amount, it still failed to
`
`convey that dosage was effective to treat an MS patient. Paragraph [0116] of the
`
`‘921 provisional does not refer to MS or any other indication. Thus, POSA would
`
`not understand it as disclosing possession of administering about 480 mg/day as
`
`effective in treating MS in particular. (Ex. 1045 ¶¶57 and 60)
`
`Further, the ‘921 provisional invention is said to be based on the discovery
`
`that DMF and MMF are potent activators of the Nrf2 pathway and the finding that
`
`DMF and MMF are neuroprotective in a mouse model of autoimmune
`
`neurodegenerative disease (id. ¶[0029]). The ‘921 provisional provides two
`
`methods of screening, evaluating and comparing test compounds to determine
`
`whether Nrf2 is upregulated in response to DMF or MMF (id. ¶[0013]).
`
`In Example 1, human colon carcinoma DLD1 cells were treated with DMF
`
`or MMF and assayed for levels of endogenously expressed Nrf2 and NOQ1 (id.
`
`¶[0122]). The results shown in Figure 1 are said to demonstrate DMF and MMF
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`activated Nrf2 and NOQ1 in DLD1 cells at concentrations of 5, 15, and 50 µM (see
`
`also Ex. 1050 109:2-110:21). This example does not disclose DMF or MMF being
`
`therapeutically effective when administered to a subject in need of treatment for
`
`MS. (Ex. 1045 ¶¶55-56)
`
`When asked what guidance Example 1 provided POSA about treating a
`
`subject with MS, Dr. Wynn agreed it showed DMF and MMF are efficacious in
`
`activating an Nrf2 pathway in a cancer cell line in vitro and added it also showed
`
`activation at concentrations within a clinical exposure range, i.e., “a range at which
`
`– you know, could be given to treat multiple sclerosis, or at least in the range used
`
`in this assay” (id. 110:22-111:8). Dr. Wynn did not refer to “about 480 mg/day”
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`DMF and/or MMF.
`
`In Example 2, DLD1 cells were transfected with Nrf2 siRNA or Keap1
`
`siRNA, treated with 30 µM DMF, and assayed for levels of endogenously
`
`expressed NQO1 (Ex.1012 ¶¶[0123]-[0124]). The results shown in Figure 2 are
`
`said to demonstrate DMF acts as an Nrf2 agonist. This example does not disclose
`
`DMF or MMF being therapeutically effective when administered to a subject in
`
`need of treatment for MS. (Ex. 1045 ¶¶55-56).
`
`Asked what guidance Example 2 provided POSA about treating a subject
`
`with MS, Dr. Wynn concluded “the concept is that activating Nrf2 may be a good
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`place to look for compounds which may be effective in enlisting neuroprotection
`
`as having an effective neuroprotection agent as a long sought after goal in living
`
`with multiple sclerosis” (id. 113:1-114:6). Providing “a good place to look” may
`
`provide a good plan to obtain the claimed invention but it is insufficient under
`
`§112.
`
`Biogen admits the ‘921 provisional described methods for “screening,
`
`evaluating, and comparing” neuroprotective properties of compounds with a goal
`
`of treating MS inter alia. Opposition at 9. In other words, the ‘921 provisional
`
`was no more than an invitation to experiment and did not convey the inventors
`
`were in possession of the claimed invention.
`
`Dr. Wynn admitted the ‘921 provisional did not describe an example of Nrf2
`
`activation in an experimental autoimmune encephalomyelitis (EAE) rodent model
`
`of MS, whereas all the later non-provisional applications did (Ex. 2046 ¶4; Ex.
`
`1050 22:22-25, 23:5-22). He stated the EAE model is the most commonly used
`
`model for studying compounds to treat MS (Ex. 1050 54:8-16; 66:9-11), DMF and
`
`MMF were subsequently studied in EAE models (id. 78:7-14), and was added to
`
`the later non-provisional applications (id. 22:10-22).
`
`Thus, the ‘921 provisional describes upregulation of endogenous NQO1
`
`production by DMF or MMF via Nrf2 in DLD1 cells, a hypothetical mechanism of
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`action by which DMF modulates the immune system, and an experimental plan
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`(Ex. 1045 ¶¶50-56). It does not describe DMF or MMF as neuroprotective in a
`
`mouse model of autoimmune neurodegenerative disease, e.g., EAE, let alone
`
`effective to treat an MS patient (id. ¶60).
`
`2.
`
`The ‘921 provisional does not describe a dosage of about
`480 mg/day administered in 2, 3, 4 or 6 equal doses
`
`Claims 3-5, 13-14, and 16 require the therapeutically effective amount of
`
`
`
`480 mg/day be administered in 2, 3, 4 or 6 equal doses. Biogen’s expert relies on
`
`paragraph [0116] of the ‘921 provisional to describe this feature (“[f]or example,
`
`the 720 mg per day may be administered in separate administrations of 2, 3, 4, or 6
`
`equal doses”). Dr. Wynn opines POSA would understand the same administration
`
`concept would apply to the “about 480 mg/day” dosage (Ex. 1050 101:12-15). Dr.
`
`Wynn is apparently applying an obviousness standard, not addressing what was
`
`actually disclosed. This is insufficient. Lockwood v. American Airlines, Inc., 107
`
`F.3d 1565, 1571-72 (Fed. Cir. 1997).
`
`The ‘921 provisional provides no information regarding multiple equal point
`
`doses totaling 480 mg/day effective to treat MS. It did not convey to POSA the
`
`inventors were in possession of about 480 mg/day administered in 2, 3, 4 or 6
`
`equal point doses effective to treat MS as required by Claims 3-5, 13-14, and 16.
`
`Regardless, there would still be no written description of administering exactly 3
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`equal point doses totaling about 480 mg/day as recited in claims 5 and 14. See Ex.
`
`1045 ¶¶57-58.
`
`The ‘921 Provisional Does Not Enable the ‘514 Patent Claims
`
`B.
`
`To be enabling, a patent specification must teach those skilled in the art how
`
`to make and use the full scope of the claimed invention without undue
`
`experimentation. Among the factors to consider when determining whether a
`
`disclosure requires undue experimentation are the quantity of experimentation
`
`necessary, the amount of direction or guidance presented, the presence or absence
`
`of working examples, the nature of the invention, the state of the prior art, the
`
`relative skill of those in the art, the predictability or unpredictability of the art, and
`
`the breadth of the claims. In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
`
`The ‘921 provisional does not enable POSA to make and use the full scope
`
`of the ‘514 patent claims (Ex. 1045 ¶¶59-61). As admitted by Biogen’s expert, the
`
`claims broadly include both therapeutic and prophylactic/preventive methods of
`
`treating MS (Ex. 1001 5:47-51; Ex. 1050 46:19-22) in “an obviously complex
`
`field” where “we don’t know exactly what causes” MS in humans (Ex. 1050
`
`66:16-18) (see also Ex. 1045 ¶¶17-18, 25, 32). The working examples in the ‘921
`
`provisional show upregulation of endogenous NQO1 production by DMF or MMF
`
`via the Nrf2 pathway in DLD1 cells (Ex. 1045 ¶55-56). There is no description of
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`DMF or MMF being neuroprotective in an EAE mouse model, e.g., let alone in an
`
`MS patient (Ex. 1045 ¶¶50-57). Even if the ‘921 provisional did, EAE models
`
`rarely predict success in clinical trials (Ex. 1045 ¶¶31-33; Exs. 1048 and 1049)
`
`(see also Ex. 1050 66:14-16).
`
`The claims broadly recite treating any form of MS in children or adults.
`
`Biogen’s own expert admitted that whether a therapeutically effective treatment for
`
`one type of MS, e.g., RRMS, would also be efficacious for treating another type,
`
`e.g., SPMS or RRMS, is unpredictable (Ex. 1050 63:14-64:1, 64:6-13). See also
`
`Ex. 1045 ¶¶60-61. The ‘921 provisional does not enable the full scope of the
`
`claims.
`
`Accordingly, the ‘921 provisional does not teach POSA how to make and
`
`use the full scope of the methods of ‘514 patent claims 1-20 without undue
`
`experimentation (Ex. 1045 ¶¶60-61).
`
`V.
`
`
`
`JOSHI ’999 CANNOT BE DISQUALIFIED AS PRIOR ART UNDER
`§103(c)(1)
`
`Under pre-AIA 35 U.S.C. §103(c)(1), prior art only under § 102(e), (f), or
`
`(g) cannot preclude patentability when the prior art subject matter and the claimed
`
`invention were, at the time the claimed invention was made, owned by or subject
`
`to an obligation of assignment to the same person. Joshi ‘999 issued January 22,
`
`2008 (Ex. 1030 1). The earliest possible effective filing date of the ‘514 patent
`
`13
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`Case No. IPR2015-01993
`Patent 8,399,514
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`claims is February 8, 2008 since patent owner is not entitled to benefit of the
`
`February 7, 2007 filing date of the ‘921 provisional (see Section IV). Therefore,
`
`Joshi ‘999 qualifies as prior art under § 102(a) and cannot be disqualified as under
`
`pre-AIA §103(c)(1).
`
`Biogen argues disqualifying Joshi ‘999 would automatically terminate all
`
`three instituted grounds. Opposition at 17. To the contrary, since Biogen earlier
`
`alleged that Joshi ‘999 is cumulative (Patent Owner Preliminary Response at 12-
`
`13, 18-19), the claims would still be unpatentable over the remaining references
`
`even without Joshi ‘999. The remaining references show it would have been
`
`obvious to administer Kappos 2006’s 240 mg point dose BID instead of TID to
`
`reduce side effects. (Ex. 1005 ¶¶37, 46, 69; Ex. 1045 ¶¶67-69).
`
`VI. KAPPOS 2006 IS PRIOR ART UNDER §102(b)
`
`The ‘514 patent claims are not entitled to benefit of the February 7, 2007,
`
`filing date of the ‘921 provisional (see Section IV). Therefore, the earliest
`
`possible effective filing date for the ‘514 patent is February 8, 2008. Accordingly,
`
`Kappos 2006 is prior art under §102(b) and cannot antedated.
`
`
`
`14
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`Case No. IPR2015-01993
`Patent 8,399,514
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`VII. THE ‘514 PATENT CLAIMS ARE OBVIOUS
`
`A. Overview of the Primary References
`
`Kappos 2006 discloses results of a 24-week double-blind, placebo-controlled
`
`phase 2 clinical study of the efficacy of oral BG-12 (DMF) in RRMS patients.
`
`Patients were randomized into four groups – placebo, 120 mg BG-12 QD (120 mg
`
`per day), 120 mg BG-12 TID (360 mg/day), and 240 mg BG-12 TID (720 mg/day).
`
`The primary endpoint was the total number of Gd+ lesions over four MRI scans at
`
`weeks 12, 16, 20 and 24. Kappos 2006 discloses that a 720 mg/day dosage
`
`significantly reduced the mean number of Gd+ lesions versus placebo. (Ex. 1003A
`
`2; Ex. 1045 ¶62). Kappos 2006 does not explicitly describe use of a
`
`therapeutically effective dosage of “about 480 mg/day” (Ex. 1045 ¶67).
`
`Joshi ‘999 claims treating a patient in need of treatment for MS with an
`
`effective amount of a pharmaceutical preparation wherein the only active
`
`ingredient is DMF (Ex. 1030 8:14-19), which is metabolized to MMF after
`
`administration (id. 3:33-34). Preferred preparations contain 10 to 300 mg DMF in
`
`the form of enteric-coated micro-tablets to reduce side effects, e.g., GI irritation,
`
`seen with conventional tablets (id. 4:46-48; 5:34-53). (Ex. 1005 ¶¶23, 32; Ex.
`
`1045 ¶¶64, 67). Joshi ‘999 does not explicitly describe using an effective amount
`
`of “about 480 mg/day” DMF.
`
`15
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`
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`Case No. IPR2015-01993
`Patent 8,399,514
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`ClinicalTrials discloses DMF as the active ingredient in BG-12 given orally
`
`and states dose reduction is appropriate for subjects unable to tolerate the dosage
`
`due to flushing episodes and GI disturbances (Ex. 1022 1-2) (Ex. 1005 ¶¶31-32;
`
`Ex. 1045 ¶¶63, 67).
`
`According to ICH Guideline, assessment of any dose-response should be an
`
`integral component of drug development studies as an inherent part of establishing
`
`the safety and effectiveness of the drug (Ex. 1045 ¶65). Choice of size of an
`
`individual point dose is often intertwined with frequency of dosing and dose-
`
`response studies should take time into account in a variety of other ways to
`
`administer the drug, e.g., orally or by injection. The study period at a given dosage
`
`should be long enough for the full clinical effect of the drug to be realized, and to
`
`determine whether any delay of the clinical effect is the result of pharmacokinetic,
`
`or pharmacodynamics factors. (Ex. 1004 7:28-30; 9-10, 18; 28-3; Ex. 1005 ¶37;
`
`Ex. 1045 ¶¶65, 67-68.) ICH Guideline Section IV provides general guidance and
`
`advice on dose-response information to support drug registration in Europe, Japan
`
`and USA (Ex. 1004 13:1-14:48; Ex. 1005 ¶24; Ex. 1045 ¶65).
`
`Based on the combined teachings of Kappos 2006, Joshi ‘999,
`
`ClinicalTrials, and ICH Guideline, POSA would have been motivated to treat a
`
`subject with MS with the claimed dosage of about 480 mg/day DMF and/or MMF
`
`16
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`Case No. IPR2015-01993
`Patent 8,399,514
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`with a reasonable expectation of success given the known efficacy of 240 mg DMF
`
`TID (720 mg/day, but not 120 mg DMF either QD (120 mg/day) or TID (360
`
`mg/day), as disclosed in Kappos 2006. POSA would have been further motivated
`
`by ClinicalTrials disclosure of reducing the amount of DMF to reduce side effects,
`
`e.g., flushing and GI disturbances. Knowing conventional assessment of dose-
`
`response is an inherent part of establishing the safety and effectiveness of a drug as
`
`disclosed in the ICH Guideline, POSA also would have been motivated to seek the
`
`claimed dosage in order to closely adhere to those guidelines. See e.g., Ex. 1005,
`
`¶¶26-34, Ex. 1045, ¶¶67-68.
`
`B.
`
`POSA Would Have Selected a Dosage of About 480 mg/day DMF
`
`1.
`
`ICH Guideline Suggests Conventional Dose-Response Study
`
`ICH Guideline is relied on for disclosing conventional assessment of dose-
`
`response as an inherent part of establishing the safety and effectiveness of a drug:
`
`“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” (Ex. 1004 5:5-7, emphasis
`
`added).
`
`Biogen argues that clinicians cannot, should not, and do not dose titrate for
`
`an individual MS patient because deviation from the recommended package label
`
`17
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`
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`Case No. IPR2015-01993
`Patent 8,399,514
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`exposes the patient to unnecessary adverse events. Opposition at 31. This
`
`argument is a red herring which tries to shift POSA’s focus from the Kappos 2006
`
`phase 2 trial to how a clinician would administer an FDA approved drug (see Ex.
`
`1045 ¶69). The FDA approved Tecfidera® on March 27, 2013 – almost seven
`
`years after Kappos 2006. Ex. 1066 at 1.
`
`In instituting this IPR, the PTAB found “Kappos 2006 differs from the
`
`subject matter of claims 1, 11, 15, and 20 of the ‘514 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’” and, “based on ICH, … that one
`
`skilled in the art would have been capable of determining effective dosages vis-à-
`
`vis non-effective dosages” (Decision at 13 and 25). Biogen has not shown
`
`otherwise. POSA would be well aware that dosages studied in a Phase 2 trial were
`
`designed to identify potential pharmacodynamically effective point doses for
`
`further evaluation in follow-up trials as suggested by ICH Guideline (Ex. 1045,
`
`¶¶69-72).
`
`2.
`
`ICH Guideline Emphasizes Dose-Response Function
`
`Biogen argues lack of motivation to add a fifth dosage of about 480 mg/day
`
`to Kappos 2006 or to perform an additional study using a dosage of about 480
`
`mg/day. Opposition. at 32.
`
`18
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`Case No. IPR2015-01993
`Patent 8,399,514
`
`Kappos 2006 demonstrated a point dose of 240 mg TID, but not 120 mg QD
`
`or TID, was efficacious versus placebo (Ex. 1003A 2; Ex. 2005). According to
`
`ICH Guideline, more than the minimum number of doses (at least two in addition
`
`to placebo) is generally desirable; a linear relationship can be derived from the
`
`response to two active doses (although more active doses would be more
`
`informative); and, study designs should emphasize elucidation of the dose-
`
`response function (Ex. 1004 13:46-14:6).
`
`Combining elimination of a point dose in Kappos 2006 with ICH
`
`Guideline’s suggestion to derive a drug’s dose-response
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