`
`Paper No. __
`
`
`
`
`
`For the Petitioner
`Lead counsel: Robert W. Hahl, Reg. No. 33,893
`Backup counsel: Robert Mihail, Reg. No. 66,021
`Backup counsel: John K. Pike, Reg. No. 41,253
`Neifeld IP Law, PC
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`
`Coalition For Affordable Drugs V LLC
`Petitioner
`v.
`
`Biogen MA Inc.
`Patent Owner
`____________
`
`Case: Unassigned
`Patent 8,399,514
`Title: TREATMENT FOR MULTIPLE SCLEROSIS
`____________
`
`
`
`
`Petition
`
`
`
`Mail Stop PATENT BOARD
`U.S. Patent Trial & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-14
`
`Page 1 of 71
`
`Biogen Exhibit 2031
`Mylan v. Biogen
`IPR2018-01403
`
`
`
`
`
`TABLE OF CONTENTS
`
`
`I. INTRODUCTION ............................................................................................. 1
`
`II. MANDATORY NOTICES ............................................................................ 1
`
`A. Real Party-In-Interest 37 C.F.R. § 42.8(b)(1) ............................................... 1
`
`B. Related Matters 37 C.F.R. § 42.8(b)(2)......................................................... 3
`
`C. Designation of Lead and Backup Counsel 37 C.F.R. § 42.8(b)(3) ............... 3
`
`D. Notice of Service Information (37 C.F.R. § 42.8(b)(4)) ............................... 3
`
`III. FEES 37 C.F.R. § 42.15(a) ............................................................................. 4
`
`IV. REQUIREMENTS UNDER 37 C.F.R. § 42.104 .......................................... 4
`
`A. Grounds for Standing 37 C.F.R. § 42.104(a) ................................................ 4
`
`B. Challenge and Precise Relief Requested 37 C.F.R. § 42.104(b) .................. 4
`
`V. UNPATENTABILITY OF THE ’514 PATENT ......................................... 8
`
`A. Background and History of the ‘514 Patent .................................................. 8
`
`B.
`
`C.
`
`Prosecution History of the ‘514 Patent ....................................................... 10
`
`The Effective Filing Date of U.S. 8,399,514 .............................................. 14
`
`D. Brief overview of the ‘514 Patent ............................................................... 14
`
`
`
`i
`
`Page 2 of 71
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`
`
`E.
`
`F.
`
`Person of Ordinary Skill in the Art ............................................................. 16
`
`Claim Construction ...................................................................................... 17
`
`VI. Overview of Prior Art Reviewed by Dr. Linberg ...................................... 18
`
`A.
`
`35 U.S.C. 325(d) .......................................................................................... 19
`
`VII. DETAILED EXPLANATION OF THE CHALLENGES .................... 21
`
`A. Ground 1: Claims 1-6, 8-16 and 20 are unpatentable under 35 U.S.C. §103
`
`as obvious over Kappos 2006 (Ex. 1003), ClinicalTrials NCT00168701 (Ex.
`
`1022), Joshi (Ex. 1030), and ICH Guideline E4 (Ex. 1004) ................................ 24
`
`B. Ground 2: Claim7 is unpatentable under 35 U.S.C. §103 as obvious over
`
`Kappos 2006 (Ex. 1003), ClinicalTrials NCT00168701 (Ex. 1022), Joshi (Ex.
`
`1030), ICH Guideline E4 (Ex. 1004) and Joshi 2002 (Ex. 1036). ....................... 54
`
`C. Ground 3: Claims 17-19 are unpatentable under 35 U.S.C. §103 as obvious
`
`over Kappos 2006 (Ex. 1003), ClinicalTrials NCT00168701 (Ex. 1022), Joshi
`
`(Ex. 1030), ICH Guideline E4 (Ex. 1004), and Begleiter (Ex. 1027). ................. 56
`
`VIII. CONCLUSION .......................................................................................... 59
`
`
`
`
`
`
`
`
`
`ii
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`Page 3 of 71
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`
`
`TABLE OF AUTHORITIES
`Cases
`
`Bettcher Indus., Inc. v. Bunzl USA, Inc., 661 F.3d 629 (Fed. Cir. 2011)…………56
`
`Biomarin v. Genzyme, IPR2013-00534, Paper 81, (PTAB 2015)...………....……23
`
`Biomarin v. Genzyme, IPR2013-00537, Paper 79, (PTAB 2015).……………..…22
`
`In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009)……………………………….22
`
`In re Montgomery, 677 F.3d 1375, 1382–83 (Fed. Cir. 2012)……………………24
`
`In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980)………………………...9
`
`In re Wyer, 655 F.2d 221, 227, 210 USPQ 790, 795 (CCPA 1981) ……………...5
`
`KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007) ……………13, 21, 22
`
`Macauto U.S.A. v. BOS GmbH & KG, IPR2012-00004, Paper 18, (PTAB 2013)..21
`
`PAR Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186 (Fed. Cir. 2014)………....56
`
`Statutes
`
`35 U.S.C. § 102 ........................................................................................... 4, 5, 6, 20
`
`35 U.S.C. § 103 ......................................................................................... 7, 8, 54, 56
`
`35 U.S.C. § 314(a).……………………………………………………………........8
`
`35 U.S.C. 325(d)………..……………………………………………………19, 20
`
`Rules
`
`37 C.F.R. § 42.8……………………………………………………...…………..1, 3
`
`37 C.F.R. § 42.15…………………………………………………………………..4
`
`
`
`iii
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`Page 4 of 71
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`
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`37 C.F.R. § 42.22…………………………………………………………………..8
`
`37 C.F.R. § 42.100…………………………………………………………………1
`
`37 C.F.R. § 42.104…………………………………………..…………………..4, 7
`
`Other Authorities
`
`MPEP § 716.07………………………………………………….………………...9
`
`MPEP § 2128.I.A.……………………………………………………..……..……5
`
`
`
`iv
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`Page 5 of 71
`
`
`
`LIST OF EXHIBITS
`
`Exhibit 1001
`
`US Patent No. 8,399,514, titled “Treatment for Multiple
`
`Sclerosis” to Lukashev et al. (‘514 patent)
`
`Exhibit 1002
`
`Wakkee M et al., “Drug evaluation: BG-12, an
`
`immunomodulatory dimethylfumarate.” Curr. Opin. Investig.
`
`Drugs. 2007 Nov; 8(11):955-62.
`
`Exhibit 1003
`
`Kappos et al., “Efficacy of a novel 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; pg. II/27 O108.
`
`Exhibit 1004
`
`International Conference on Harmonization of Technical
`
`Requirements for Registration of Pharmaceuticals for Human
`
`Use, ICH Harmonized Tripartite Guideline, Dose-Response
`
`Information to Support Drug Registration E4, Current Step 4
`
`version, dated 10 March 1994. Published in the Federal
`
`Register, 9 November 1994, Vol. 59, No. 216, p. 55972-55976
`
`Exhibit 1005
`
`Declaration of Dr. Steven E. Linberg.
`
`Exhibit 1006
`
`European Medicines Agency, Assessment Report, Tecfidera, 26
`
`November 2013.
`
`
`
`v
`
`Page 6 of 71
`
`
`
`Exhibit 1007
`
`“Preliminary Amendment Under 37 C.F.R. § 1.115, In re
`
`application of: LUKASHEV et al.”, Application No.
`
`13/372,426 that issued into US Patent No. 8,399,514.
`
`Exhibit 1008
`
`“Amendment and Reply Under 37 C.F.R. § 1.111, In re
`
`application of: LUKASHEV et al., Application No.
`
`13/372,426” that issued into US Patent No. 8,399,514.
`
`Exhibit 1009
`
`Office Action with mail date of 05/03/2012 for Application No.
`
`13/372,426 that issued into US Patent No. 8,399,514.
`
`Exhibit 1010
`
`Paper 178, Interference 106,023.
`
`Exhibit 1011
`
`PCT Application No. PCT/US2008/001602.
`
`Exhibit 1012
`
`Certified copy of US Provisional Application No. 60/888,921
`
`Exhibit 1013
`
`Assignment Record for US Patent No. 8,399,514 from
`
`USPTO’s Assignments on the Web.
`
`Exhibit 1014
`
`Paper 179, Interference 106,023.
`
`Exhibit 1015
`
`Unassigned.
`
`Exhibit 1016
`
` D. Werdenberg, et al., “Presystemic Metabolism and Intestinal
`
`Absorption of Antipsoriatic Fumaric Acid Esters”, 2003,
`
`BIOPHARMACEUTICS & DRUG DISPOSITION, Biopharm.
`
`Drug Dispos. 24: 259–273 (2003), Published online in Wiley
`
`
`
`vi
`
`Page 7 of 71
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`
`
`InterScience (www.interscience.wiley.com). DOI:
`
`10.1002/bdd.364.
`
`Exhibit 1017
`
`CV of Dr. Steven E. Linberg.
`
`Exhibit 1018
`
`US Application 13/372,426, as filed on February 13, 2012
`
`Exhibit 1019
`
`Nieboer et al., “Fumaric Acid Therapy in Psoriasis: A Double-
`
`Blind Comparison between Fumaric Acid Compound Therapy
`
`and Monotherapy with Dimethylfumaric Acid Ester”
`
`Dermatologica 1990; 181:33- 37.
`
`Exhibit 1020
`
`Declaration of Scott Bennett.
`
`Exhibit 1021
`
`Unassigned.
`
`Exhibit 1022
`
`Clinicaltrials NCT0016870, “View of NCT00168701 on
`
`2005_09_14”, from URL
`
`https://clinicaltrials.gov/archive/NCT00168701/2005_09_14.
`
`Exhibit 1023
`
`Unassigned.
`
`Exhibit 1024
`
`Declaration of Robert Mihail.
`
`Exhibit 1025
`
`Unassigned.
`
`Exhibit 1026
`
`Unassigned.
`
`Exhibit 1027
`
`Begleiter et al., “Dietary induction of NQO1 increases the
`
`antitumour activity of mitomycin C in human colon tumours in
`
`vivo”, 2004, British Journal of Cancer, 1624 – 1631.
`
`
`
`vii
`
`Page 8 of 71
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`
`
`Exhibit 1028
`
`Unassigned.
`
`Exhibit 1029
`
`Hartung et al., “The cost of multiple sclerosis drugs in the US
`
`and the pharmaceutical industry”, American Academy of
`
`Neurology, 2015
`
`Exhibit 1030
`
`US Patent 7,320,999 to Joshi et al.
`
`Exhibit 1031
`
`US Patent Application 2003/0018072 to Joshi et al.
`
`Exhibit 1032
`
`Unassigned.
`
`Exhibit 1033
`
`Unassigned.
`
`Exhibit 1034
`
`Unassigned.
`
`Exhibit 1035
`
`IPR2015-01136, Paper 23, Decision Denying Institution of
`
`Inter Partes Review.
`
`Exhibit 1036
`
`US Patent No. 6,436,992, titled “Use Of Fumaric Acid
`
`Derivatives” to Joshi et al.
`
`Exhibit 1037
`
`Unassigned.
`
`Exhibit 1038
`
`Unassigned.
`
`Exhibit 1039
`
`Unassigned.
`
`Exhibit 1040
`
`Current view of ClinicalTrials NCT00168701 on URL
`
`https://clinicaltrials.gov/show/NCT00168701.
`
`Exhibit 1041
`
`History of Changes and the ClinicalTrials.gov Archive Site on
`
`URL https://clinicaltrials.gov/ct2/archive/NCT00168701.
`
`
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`viii
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`Page 9 of 71
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`
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`Exhibit 1042
`
`History of ClinicalTrials NCT00168701 on URL
`
`https://clinicaltrials.gov/archive/NCT00168701
`
`Exhibit 1043
`
`ClinicalTrials.gov Background on URL
`
`.https://www.clinicaltrials.gov/ct2/about%ADsite/background
`
`Exhibit 1044
`
`Hendricks, Steve, “The Rise of Bib Generic: Why Knockoff
`
`Prescriptions Now Cost $1,200,” 08/08/2015, on URL
`
`http://www.truth-out.org/news/item/32182-the-rise-of-big-
`
`generic-why-knockoff-prescriptions-now-cost-1-200.
`
`
`
`ix
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`Page 10 of 71
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`
`
`I.
`
`
`
`INTRODUCTION
`Inter partes review is requested under 35 U.S.C. §§ 311-319 and 37 C.F.R.
`
`§§ 42.1-.80 & 42.100-123, for claims 1-20 of US patent 8,399,514, titled
`
`“Treatment for Multiple Sclerosis” (‘514 patent) (Ex. 1001). The '514 patent issued
`
`from 13/372,426, filed Feb. 13, 2012 (Ex. 1018), which is a continuation of
`
`12/526,296, §371(c) date Jan. 13, 2011 (now abandoned), which is the national
`
`stage of PCT/US2008/001602, filed Feb. 7, 2008 (Ex. 1011), which claims benefit
`
`of provisional 60/888,921, filed Feb. 8, 2007 (Ex. 1012). The ‘514 patent was
`
`assigned on 12/6/2010 from Lukashev, Matvey E., O’Neill, Gilmore to Biogen
`
`IDEC MA Inc., and on 03/23/2015 it was assigned from Biogen IDEC MA Inc. to
`
`Biogen MA Inc., the current assignee. Ex. 1013. For reasons provided herein,
`
`claims 1-20 of the ‘514 patent should be canceled as unpatentable.
`
`II. MANDATORY NOTICES
`
`A. Real Party-In-Interest 37 C.F.R. § 42.8(b)(1)
`
`Petitioner certifies that Coalition For Affordable Drugs V LLC (“CFAD”),
`
`Hayman Credes Master Fund, L.P. (“Credes”), Hayman Orange Fund SPC –
`
`Portfolio A (“HOF”), Hayman Capital Master Fund, L.P. (“HCMF”), Hayman
`
`Capital Management, L.P. (“HCM”), Hayman Offshore Management, Inc.
`
`(“HOM”), Hayman Investments, L.L.C. (“HI”), nXn Partners, LLC (“nXnP”), IP
`
`Navigation Group, LLC (“IPNav”), J Kyle Bass, and Erich Spangenberg are the
`
`
`
`1
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`Page 11 of 71
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`
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`real parties in interest (collectively, “RPI”). The RPI hereby certify the following
`
`information: CFAD is a wholly owned subsidiary of Credes. Credes is a limited
`
`partnership. HOF is a segregated portfolio company. HCMF is a limited
`
`partnership. HCM is the general partner and investment manager of Credes and
`
`HCMF. HCM is the investment manager of HOF. HOM is the administrative
`
`general partner of Credes and HCMF. HI is the general partner of HCM. J Kyle
`
`Bass is the sole member of HI and sole shareholder of HOM. CFAD, Credes, HOF
`
`and HCMF act, directly or indirectly, through HCM as the general partner and/or
`
`investment manager of Credes, HOF and HCMF. nXnP is a paid consultant to
`
`HCM. Erich Spangenberg is 98.5% member of nXnP. IPNav is a paid consultant to
`
`nXnP. Erich Spangenberg is the 98.5% member of IPNav. Other than HCM and J
`
`Kyle Bass in his capacity as the Chief Investment Officer of HCM and nXnP and
`
`Erich Spangenberg in his capacity as the Manager/CEO of nXnP, no other person
`
`(including any investor, limited partner, or member or any other person in any of
`
`CFAD, Credes, HOF, HCMF, HCM, HOM, HI, nXnP or IPNav) has authority to
`
`direct or control (i) the timing of, filing of, content of, or any decisions or other
`
`activities relating to this Petition or (ii) any timing, future filings, content of, or any
`
`decisions or other activities relating to the future proceedings related to this
`
`Petition. All of the costs associated with this Petition will be borne by HCM,
`
`CFAD, Credes, HOF and/or HCMF.
`
`
`
`2
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`Page 12 of 71
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`
`
`B. Related Matters 37 C.F.R. § 42.8(b)(2)
`Interference No 106,023 involves the challenged ‘514 patent. A non-
`
`institution decision in IPR2015-01136 involving the challenged ‘514 patent, by this
`
`petitioner, was entered September 2, 2015 (Paper 23, Ex. 1035); a Request for
`
`Rehearing is due Oct. 2, 2015. To the best of our knowledge there are no other
`
`matters relating to the ‘514 patent that would affect or be affected by this
`
`proceeding.
`
`C. Designation of Lead and Backup Counsel 37 C.F.R. § 42.8(b)(3)
`
`
`
`Pursuant to 37 C.F.R. §§ 42.8(b)(3) and 42.10(a), Petitioner hereby
`
`identifies its lead and backup counsel as shown below. A Power of Attorney is
`
`being filed concurrently herewith in accordance with 37 C.F.R. § 42.10(b).
`
`Lead Counsel for Petitioner: Robert W. Hahl, Reg. No. 33,893.
`
`Backup Counsel for Petitioner: Robert Mihail, Reg. No. 66,021 and John K. Pike,
`
`Reg. No. 41,253.
`
`D. Notice of Service Information (37 C.F.R. § 42.8(b)(4))
`Direct all correspondence to counsel at the below address. Petitioner
`
`consents to email service at: rhahl@neifeld.com and rmihail@neifeld.com and
`
`jkpike@neifeld.com and general@neifeld.com. Postal address for lead and backup
`
`counsel: Neifeld IP Law, PC, 4813-B Eisenhower Avenue, Alexandria, VA 22304.
`
`Tel: 1-703-415-0012. Fax: 1-703-415-0013.
`
`
`
`3
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`Page 13 of 71
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`
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`III. FEES 37 C.F.R. § 42.15(a)
`Petitioner authorizes the Director to charge the 37 C.F.R. 42.15(a) fee and
`
`
`
`any other fees due on this Petition to Deposit Account 502106. Fees total:
`
`$25,000.00.
`
`IV. REQUIREMENTS UNDER 37 C.F.R. § 42.104
`A. Grounds for Standing 37 C.F.R. § 42.104(a)
`
`Petitioner certifies that the ‘514 patent is available for inter partes review.
`
`Petitioner also certifies that it is not barred or estopped from challenging the ‘514
`
`patent on the Grounds identified in this Petition. 37 C.F.R. § 42.104(a)
`
`B. Challenge and Precise Relief Requested 37 C.F.R. § 42.104(b)
`
`1.
`
`Patents and Printed Publications 37 C.F.R. 42.104(b)(2)
`
`
`1. Kappos 2006 (Ex. 1003; See also Scott Bennett’s declaration (Ex. 1020)
`
`regarding Kappos 2006), “Efficacy of a novel single-agent fumarate, BG00012,
`
`in patients with relapsing-remitting multiple sclerosis: results of a phase 2
`
`study” by Kappos et al., J Neurol (May 2006) 253 [Suppl 2]: II/1–II/170 pg
`
`II/27 O108. Kappos 2006 is prior art under 35 U.S.C. § 102(b) (pre-AIA)
`
`because (1) it is an abstract published in the Journal of Neurology in May 2006
`
`and (2) because the ‘514 patent was accorded benefit of PCT/US2008/001602,
`
`7 February 2008, but not that of Provisional 60/888,921, filed Feb. 8, 2007. See
`
`Interference 106,023, Paper 178, page 2 (Ex. 1010) and Paper 179, page 5 (Ex.
`
`
`
`4
`
`Page 14 of 71
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`
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`1014). This date is more than one year prior to February 7, 2008, the earliest
`
`effective filing date for the claims of the ‘514 patent.
`
`2. ClinicalTrials NCT00168701 (Ex. 1022; See also Robert Mihail’s declaration
`
`(Ex. 1024, ¶¶2-11) regarding ClinicalTrials NCT00168701), “Effacacy [sic]
`
`and Safety of BG00012 in MS,” is prior art at least under 35 U.S.C. § 102(b)
`
`(pre-AIA) because it was published in 2005, which is more than one year prior
`
`to February 7, 2008. Ex. 1022 is an archival web page of the study marked as
`
`“NCT00168701.” The information on the webpage now marked as Ex. 1022
`
`was publicly available on September 14, 2005 and said information was not
`
`removed from that webpage since September 14, 2005. Ex. 1024, ¶11. An
`
`electronic publication, including an on-line database or Internet publication, is
`
`considered to be a “printed publication” within the meaning of 35 U.S.C.
`
`102(a)(1) and pre-AIA 35 U.S.C. 102(a) and (b), provided the publication was
`
`accessible to persons concerned with the art to which the document relates. See
`
`In re Wyer, 655 F.2d 221, 227, 210 USPQ 790, 795 (CCPA 1981). Prior art
`
`disclosures on the Internet or on an on-line database are considered to be
`
`publicly available as of the date the item was publicly posted. MPEP §
`
`2128.II.A.
`
`3. Joshi (Ex. 1030), US 7,320,999 to Joshi et al., “DIMETHYL FUMARATE
`
`FOR THE TREATMENT OF MULTIPLE SCLEROSIS” is prior art at least
`
`
`
`5
`
`Page 15 of 71
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`
`
`under 35 U.S.C. § 102(e) (pre-AIA) because it issued from Application No.
`
`10/197,077, filed by another in the US on Jul. 17, 2002, which is a Division of
`
`Application No. 09/831,620, filed as PCT/EP99/08215 on Oct. 29, 1999, now
`
`US Patent No. 6,509,376.
`
`4. ICH Guideline E4 (Ex. 1004), “ICH-E4; INTERNATIONAL CONFERENCE
`
`ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR
`
`REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE - ICH
`
`HARMONISED TRIPARTITE GUIDELINE, DOSE-RESPONSE
`
`INFORMATION TO SUPPORT DRUG REGISTRATION E4 (Current Step 4
`
`version dated 10 March 1994).” The ICH Guideline E4 is prior art under 35
`
`U.S.C. § 102(b) (pre-AIA) because it was published in the Federal Register
`
`on November 9, 1994, which is more than one year prior to February 7, 2008,
`
`the earliest effective filing date for the claims of the ‘514 patent.
`
`5. Joshi 2002 (Ex. 1036), U.S. Patent 6,436,992 to Joshi et al. “USE OF
`
`FUMARIC ACID DERIVATIVES” is prior art at least under 35 U.S.C. §
`
`102(b) (pre-AIA) because it was published August 20, 2002.
`
`6. Begleiter (Ex. 1027), “Dietary induction of NQO1 increases the antitumour
`
`activity of mitomycin C in human colon tumours in vivo” by Beglieter et al.
`
`British Journal of Cancer (2004) 91, 1624 – 1631 is prior art at least under 35
`
`U.S.C. § 102(b) (pre-AIA) because it was published in 2004.
`
`
`
`6
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`Page 16 of 71
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`
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`2.
`
`Specific Statutory Grounds for Challenge 42.104(b)(2)
`
`
`Ground 1: Claims 1-6, 8-16 and 20 are unpatentable under 35 U.S.C. §103 as
`
`obvious over Kappos 2006 (Ex. 1003), ClinicalTrials NCT00168701 (Ex. 1022),
`
`Joshi (Ex. 1030), and ICH Guideline E4 (Ex. 1004).
`
`
`
`Kappos 2006 (Ex. 1003) discloses the results of a double-blind Phase II
`
`clinical trial for treating multiple sclerosis with “BG00012” administered orally at
`
`three dose levels.
`
`ClinicalTrials NCT00168701 (Ex. 1022) discloses a dose-ranging Phase II
`
`clinical trial protocol using “DMF [dimethyl fumarate] the active ingredient in
`
`BG00012”. The protocol states that intolerance of BG00012 as determined by
`
`flushing episodes and gastrointestinal (G.I.) disturbances may be a problem for
`
`patients, and dose reductions are specified.
`
`Joshi (Ex. 1030) is a U.S. patent disclosing that DMF is therapeutically
`
`effective against autoimmune diseases including multiple sclerosis, it causes G.I.
`
`irritation, and that DMF is a pro-drug that is converted to MMF as metabolized in
`
`the body.
`
`ICH Guideline E4 (Ex. 1004) teaches that dosing studies are conducted as
`
`standard procedure in drug development in order to establish proper dose ranges.
`
`
`
`7
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`Page 17 of 71
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`
`
`Ground 2: Claim7 is unpatentable under 35 U.S.C. §103 as obvious over Kappos
`
`2006 (Ex. 1003), ClinicalTrials NCT00168701 (Ex. 1022), Joshi (Ex. 1030), ICH
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`Guideline E4 (Ex. 1004) and Joshi 2002 (Ex. 1036).
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`Joshi 2002 (Ex. 1036) teaches monomethyl fumarate useful in treating multiple
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`sclerosis.
`
`Ground 3: Claims 17-19 are unpatentable under 35 U.S.C. §103 as obvious over
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`Kappos 2006 (Ex. 1003), ClinicalTrials NCT00168701 (Ex. 1022), Joshi (Ex.
`
`1030), ICH Guideline E4 (Ex. 1004), and Begleiter (Ex. 1027).
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`Begleiter (Ex. 1027) teaches level of NQO1 activity increase in DMF treated cells.
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`This Petition is supported by the Declaration of Dr. Steven E. Linberg (Ex.
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`1005, Ex. 1017), which shows there is a reasonable likelihood the Petitioner will
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`prevail with respect to at least one of the challenged claims, and that each of the
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`challenged claims is unpatentable, as cited below. 35 U.S.C. § 314(a). Petitioner
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`requests cancellation of claims 1-20 of the ‘514 patent. 37 C.F.R. § 42.22.
`
`V. UNPATENTABILITY OF THE ’514 PATENT
`A. Background and History of the ‘514 Patent
`The ‘514 patent is an example of evergreening, a business strategy by which
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`companies with patents that are about to expire retain their monopolies for longer
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`than would normally be permitted under law by taking out new patents, e.g.,
`
`claiming associated delivery systems or new drug mixtures. Evergreening is one
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`reason why MS drug prices are so high; see Hartung et al. (Ex. 1029) and
`8
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`Page 18 of 71
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`
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`Hendricks, “The Rise of Big Generic: Why Knockoff Prescriptions Now Cost
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`$1,200” (Ex. 1044). The challenged ‘514 patent is the second Biogen patent which
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`claims a method for treating multiple sclerosis using DMF. The first one was Joshi
`
`et al. (US Patent No. 7,320,999, Ex. 1030) “DIMETHYL FUMARATE FOR THE
`
`TREATMENT OF MULTIPLE SCLEROSIS,” Application No. 10/197,077, filed
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`July 17, 2002, published on January 23, 2003 as US Publication No. 2003/0018072
`
`(Ex. 1031), priority DE 198 53 487, November 19, 1998. Claim 1 of Joshi reads:
`
`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, claim 1, emphasis added)
`The phrase “effective amount” is functional language. The actual amount of DMF
`
`that is effective for treating MS is not disclosed, but its therapeutic activity in MS
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`was established by this Joshi patent. When a reference anticipates or makes
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`obvious all claim elements, the reference is presumed to be operable. The burden is
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`then on applicant to provide facts rebutting the presumption of operability. In re
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`Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). See also MPEP § 716.07.
`
`The challenged ‘514 patent claims a method for treating multiple sclerosis
`
`with “about 480 mg/day” of DMF. So the functional language in claim 1 of Joshi
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`above is replaced by a specific amount of DMF in the ‘514 patent. This is
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`Page 19 of 71
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`
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`astonishing, not because 480 mg/day is a novel dose level (480 mg/day of DMF
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`had been previously used to treat psoriasis: “Dosage DMFAE-EC: 120-480
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`mg/day,” Ex. 1019, page 3, Table 1) but because by allowing the ‘514 patent, the
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`USPTO essentially held that determining the lowest effective dose of DMF was
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`inventive even after treating MS with “an effective amount” of DMF had been
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`claimed in a U.S. patent. Biogen argued that a person of ordinary skill in the art
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`(POSITA) was not motivated to find the lowest effective dose of DMF for treating
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`MS even in view of Joshi. That was error.
`
`B. Prosecution History of the ‘514 Patent
`In a Preliminary Amendment (Ex. 1007), the ‘514 patent applicants relied on
`
`a Rule 132 Declaration by Dawson pertaining to a Phase II clinical trial published
`
`by Kappos et al. (Kappos 2006 Ex. 1003) and a Rule 132 Declaration by Rudick.
`
`On May 3, 2012 (Ex. 1009) the examiner rejected all claims over Schimrigk et al.:
`
`…Merely determining the optimal conditions for practicing a prior art
`process, in the absence of unexpected results, does not constitute a
`patentable inventive contribution. (Ex. 1009, 7:8–20)
` It is Applicant's discovery, subsequent to the filing of the instant
`application, that the majority of embodiments described in the
`specification are inoperative that is unexpected. The fact that dimethyl
`fumarate, methyl ethyl fumarate and diethyl fumarate can be
`successfully employed to treat MS was not unexpected as of the filing
`date of the instant application. (Ex. 1009, 8:9–13)
`
`
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`10
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`Page 20 of 71
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`
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`On August 3, 2012, applicants asserted that Kappos 2006 suggested that the
`
`amount of DMF “required” for relapsing remitting multiple sclerosis (RRMS)
`
`activity is 720 mg/day, e.g., “(b) The 720 mg/day dose was expected to be required
`
`for clinical effectiveness” (Ex. 1008, page 16). Kappos 2006 disclosed a dose-
`
`ranging study using BG00012, at three dose levels: 120 mg per day, 360 mg per
`
`day and 720 mg per day. Kappos 2006 found that only the 720 mg per day dose
`
`was effective, thus producing only a single dose-response data point. Applicants
`
`argued that a POSITA would not test a lower dose than 720 mg/day, even while
`
`conceding that there were good reasons to try (“side effects associated with
`
`chronic, lifelong treatment are generally dose-related, so the 480 mg/day dose
`
`naturally would be expected to have fewer side effects in the long run.” (Ex. 1008,
`
`7:8-9). Why, then, wouldn’t a POSITA try a lower dose? According to the
`
`applicants, simply because the 720 mg/day dose had worked.
`
`In light of those results, a person of ordinary skill in the art would
`have been motivated to treat a patient having MS by administering
`720 mg/day DMF, not a DMF dose less than 720 mg/day (e.g., 480
`mg/day). (Ex. 1008, 8:16–9:2)
`Applicants also asserted that it was surprising to find that the clinical effects
`
`of taking 480 mg per day are similar to the clinical effects of taking 720 mg
`
`per day (“The 480 mg/day dose having similar efficacy as the 720 mg/day
`
`
`
`11
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`Page 21 of 71
`
`
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`dose is unexpected based on results from a Phase 2 study”)1 Ex. 1008, 15:7-
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`8. This statement means only that the dose-response relationship is rather
`
`constant between 480 mg and 720 mg/day, e.g., a line with zero slope
`
`(horizontal). One cannot draw a dose-response line or curve based on a
`
`single data point since the slope of a line through one point is arbitrary, but
`
`Kappos 2006 demonstrated only one dose that gave any response (720
`
`mg/day) since none of the lower doses seemed to be effective, and (in
`
`retrospect), because 480 mg/day and 600 mg/day were not tested in that
`
`particular trial. If one of the lower doses tested by Kappos 2006 had actually
`
`been effective, that result would have provided a second data point, hence a
`
`
`1 It will be noted that in a report from the European Medicines Agency (“Agency”)
`
`concerning assessment of Tecfidera (DMF) for marketing authorization, the
`
`Agency noted “considerable imbalances” in the baseline for the 360 mg dosing
`
`group studied in Kappos 2006, and requested that the data for the 360 mg dosing
`
`group be reanalyzed. In doing so, the Agency found that “when correcting for the
`
`baseline number of Gd-enhancing lesions in the statistical models as a covariate,
`
`the effect of the 120 mg TID [360 mg daily] dosing regimen also reached
`
`statistical significance for the various MRI endpoints, at least in one of the
`
`requested models” (Ex. 1006, page 34 (emphasis added) and page 79).
`
`
`
`12
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`Page 22 of 71
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`
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`better dose-response curve. But Kappos 2006 did not include 480 mg/day or
`
`600 mg/day – so, of course – a POSITA would have tested to find another
`
`effective dose. While Drs. Rudick and Dawson never denied this truth, they
`
`never admitted it either. Instead they pointed out that the dose-response
`
`behavior of DMF in RRMS was still uncharacterized (e.g., Rudick ¶9, “the
`
`effects seen for the different doses of BG-12 were not clearly dose-
`
`proportional,” and Dawson ¶14, “the Phase 2 results do not demonstrate a
`
`linear dose response between the DMF dose and the efficacy”), meaning
`
`only that the clinical effect of 480 mg per day could not be estimated from
`
`the results of Kappos 2006. But determining the dose-response behavior of a
`
`compound that is already known to be therapeutically effective is “the
`
`product not of innovation but of ordinary skill and common sense.” KSR,
`
`550 U.S. at 421. In fact it is a standard part of developing new drugs in
`
`Europe, Japan and the United States. Ex. 1004. Biogen asserted that its later
`
`dose-ranging study was inventive because Kappos 2006 had provided “no
`
`expectation as to whether the 480 mg/day dose would be efficacious when
`
`compared to placebo (and certainly no expectation the 480 mg/day dose
`
`would have similar efficacy as the 720 mg/day dose.”) (Ex. 1008, 15:7–
`
`16:9), really meaning only that Kappos 2006 did not happen to test 480
`
`mg/day. (“It is all too common to discover, at the end of a parallel dose-
`
`
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`13
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`Page 23 of 71
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`
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`response study, that all doses were too high (on the plateau of the dose-
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`response curve), or that doses did not go high enough.” Ex. 1004, 10:39-41.)
`
`Drs. Rudick and Dawson did not admit that dose-ranging studies are routine,
`
`empirical trials, nor did they give any reason why a POSITA would not have
`
`tested a lower dose of DMF, as a routine part of drug development, nor did
`
`they allege that a POSITA would have assumed that Kappos 2006 had
`
`already found the minimum effective dose. Finally, throughout prosecution
`
`the applicants and Biogen’s experts made no distinction between the
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`therapeutic properties of DMF (claims 1 – 6 and 8-20) versus those of MMF
`
`(claim 7).
`
`C. The Effective Filing Date of U.S. 8,399,514
`
`The ‘514 patent is involved in Interference 106,023, which was Redeclared
`
`(Paper 179) and accorded benefit of PCT/US2008/001602, 7 February 2008, but
`
`not that of Provisional 60/888,921, filed Feb. 8, 2007. See Interference 106,023,
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`Paper 178, page 2 (Ex. 1010) and Paper 179, page 5 (Ex. 1014).
`
`D. Brief overview of the ‘514 Patent
` The ‘514 patent teaches that dimethylfumarate (DMF) and
`
`monomethylfumarate (MMF) have essentially the same biological activity, “FIG. 1
`
`demonstrates that DMF and MMF are activators of Nrf2 at concentrations within
`
`clinical exposure range (cells in culture).” Ex. 1001, col. 4:65-67. “FIG. 3 shows
`
`
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`14
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`Page 24 of 71
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`
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`evidence of Nrf2 activation by DMF and MMF in vivo. FIG. 4 shows evidence of
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`Nrf2 activation by DMF and MMF in vivo.” Ex. 1001, col. 5:2-5. There is nothing
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`in the ‘514 patent which defines or explains that the therapeutic properties of MMF
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`are different from the therapeutic properties of DMF. Ex. 1005, ¶17.
`
`Figure 1 of the ‘514 patent shows the expression level of NQO1 is elevated
`
`at all concentrations of DMF tested and is proportional to the DMF concentration.
`
`The ‘514 patent states that “[t]he results shown in FIG. 1, demonstrate that DMF
`
`and MMF are potent activators of Nrf2 at concentrations within clinical exposure
`
`range.” Ex. 1001, col. 2:12-14. The ‘514 patent asserts that Nrf2 controls the
`
`expression level of NQO1 at doses described in the Examples. The ‘514 patent
`
`states that “genes under the control of Nrf2 include…For example, expression
`
`levels of endogenous or exogenously introduced NQO1 may be determined as
`
`described in the Examples.” Ex. 1001, col. 14:38-44. Ex. 1005, ¶18.
`
`The effective amounts of DMF and MMF are the same, per the ‘514 patent:
`
`For DMF or MMF, an effective amount can range from 1 mg/kg to 50
`mg/kg (e.g., from 2.5 mg/kg to 20 mg/kg or from 2.5 mg/kg to 15
`mg/kg). Effective doses will also vary, as recognized by those skilled
`in the art, dependent on route of administration, excipient usage, and
`the possibility of co-usage with other therapeutic treatments including
`use of other therapeutic agents. 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 day, 200 mg to about 800 mg per day
`
`
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`15
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`Page 25 of 71
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`
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`(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. The dosage may be determined by a
`physician and adjusted, as necessary, to suit observed effects of the
`treatment. Ex. 1001, col. 18:52-67; Ex. 1005, ¶19.
`Dr. Linberg notes that Example 3 of the ‘514 patent tested the same dose (15
`
`mg/kg) twice a day, for both DMF and MMF: “Each treat
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