For the Patent Owner
`Backup counsel: Robert W. Hahl, Reg. No. 33,893
`Backup counsel: Robert Mihail, Reg. No. 66,021
`Neifeld IP Law, PC
`
`
`
`Paper No. __
`
`
`
`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: IPR2015-01136
`Patent 8,399,514
`Title: TREATMENT FOR MULTIPLE SCLEROSIS
`____________
`
`
`
`
`First Amended Petition
`
`
`
`Mail Stop PATENT BOARD
`U.S. Patent Trial & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-14
`
`Page 1 of 63
`
`Biogen Exhibit 2002
`Coalition v. Biogen
`IPR2015-01993
`
`
`Backup counsel: Robert W. Hahl, Reg. No. 33,893
`Backup counsel: Robert Mihail, Reg. No. 66,021
`Neifeld IP Law, PC
`
`
`
`Paper No. __
`
`
`
`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: IPR2015-01136
`Patent 8,399,514
`Title: TREATMENT FOR MULTIPLE SCLEROSIS
`____________
`
`
`
`
`First Amended Petition
`
`
`
`Mail Stop PATENT BOARD
`U.S. Patent Trial & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-14
`
`Page 1 of 63
`
`Biogen Exhibit 2002
`Coalition v. Biogen
`IPR2015-01993
`
`
`
`
`
`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) ............................................................................. 3
`
`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 ......................................... 7
`
`A.
`
`Prosecution History of the ‘514 Patent ......................................................... 7
`
`B.
`
`The Effective Filing Date of U.S. 8,399,514 .............................................. 10
`
`C. Brief overview of the ‘514 Patent ............................................................... 11
`
`D.
`
`Person of Ordinary Skill in the Art ............................................................. 13
`
`
`
`i
`
`Page 2 of 63
`
`
`
`E. Claim Construction ...................................................................................... 14
`
`F. Overview of Prior Art Reviewed by Dr. Linberg ....................................... 15
`
`VI. DETAILED EXPLANATION OF THE CHALLENGES ........................ 16
`
`A. Ground 1: Claims 1-20 would have been obvious over Kappos 2005 (Ex.
`
`1003A) or ClinicalTrials NCT00168701 (Ex. 1022A) or ‘514 Patent admission
`
`of prior art in view of ICH Guideline E4 (Ex. 1004A) ........................................ 16
`
`VII. CONCLUSION .......................................................................................... 51
`
`
`
`
`
`
`
`
`
`ii
`
`Page 3 of 63
`
`
`
`TABLE OF AUTHORITIES
`Cases
`
`Bettcher Indus., Inc. v. Bunzl USA, Inc., 661 F.3d 629 (Fed. Cir. 2011)…………43
`
`KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007) .................................. 17
`
`PAR Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186 (Fed. Cir. 2014)………....43
`
`Statutes
`
`35 U.S.C. § 102 ......................................................................................................4, 5
`
`35 U.S.C. § 103 .......................................................................................................... 6
`
`Rules
`
`37 C.F.R. § 42.8……………………………………………………...…………..1, 3
`
`37 C.F.R. § 42.15…………………………………………………………………..4
`
`37 C.F.R. § 42.22…………………………………………………………………..7
`
`37 C.F.R. § 42.100…………………………………………………………………1
`
`37 C.F.R. § 42.104…………………………………………..…………………..4, 6
`
`
`
`
`
`
`
`iii
`
`Page 4 of 63
`
`
`
`LIST OF EXHIBITS
`
`Exhibit 1001A
`
`US Patent No. 8,399,514, titled “Treatment for Multiple
`
`Sclerosis” to Lukashev et al. (‘514 patent)
`
`Exhibit 1002
`
`Unassigned
`
`Exhibit 1003A
`
`Kappos et al., “A randomised, placebo-controlled phase II trial
`
`of a novel oral single-agent fumarate therapy, BG00012, in
`
`patients with relapsing-remitting multiple sclerosis”, 2005, J
`
`Neurol (2005) 252 [Suppl 2]: II/95–II/170, pII/148, P574.
`
`Exhibit 1004A
`
`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.
`
`Exhibit 1005A
`
`Declaration of Dr. Steven E. Linberg.
`
`Exhibit 1006
`
`Unassigned
`
`Exhibit 1007A
`
`“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 8,399,514.
`
`
`
`iv
`
`Page 5 of 63
`
`
`
`Exhibit 1008A
`
`“Amendment and Reply Under 37 C.F.R. § 1.111, In re
`
`application of: LUKASHEV et al., Appl. No. 13/372,426” that
`
`issued into US Patent 8,399,514.
`
`Exhibit 1009A
`
`Office Action with mail date of 05/03/2012 for Application No.
`
`13/372,426 that issued into US Patent 8,399,514.
`
`Exhibit 1010
`
`Unassigned
`
`Exhibit 1011A
`
`PCT Application No. PCT/US2008/001602.
`
`Exhibit 1012A
`
`Certified copy of US Provisional Application No. 601888,921
`
`Exhibit 1013A
`
`Assignment Record for US Patent No. 8,399,514 from
`
`USPTO’s Assignments on the Web.
`
`Exhibit 1014A
`
`IFW of PCT/US2008/001602.
`
`Exhibit 1015A
`
`Priority document transmitted to the International Bureau, Rule
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`17 .1 (a) or (b)" for PCT/US2008/001602; received by the
`
`International Bureau on March 26, 2008; and identified as
`
`Certified Copy of US Provisional 60/888,921. This document is
`
`a copy of the certified copy of the priority document present in
`
`the IFW of the parent application, 12526296.
`
`Exhibit 1016A
`
` D. Werdenberg, et al., “Presystemic Metabolism and Intestinal
`
`Absorption of Antipsoriatic Fumaric Acid Esters”, 2003,
`
`BIOPHARMACEUTICS & DRUG DISPOSITION, Biopharm.
`
`
`
`v
`
`Page 6 of 63
`
`
`
`Drug Dispos. 24: 259–273 (2003), Published online in Wiley
`
`InterScience (www.interscience.wiley.com). DOI:
`
`10.1002/bdd.364.
`
`Exhibit 1017A
`
`CV of Dr. Steven E. Linberg
`
`Exhibit 1018A
`
`US Application 13/372,426, as filed on February 13, 2012
`
`Exhibit 1019A
`
`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 1020A
`
`Declaration of Scott Bennett
`
`Exhibit 1021A
`
`“BG 12 BG 00012, BG 12/Oral Fumarate, FAG-201, Second-
`
`Generation Fumarate Derivative – Fumapharm/ Biogen Idec”,
`
`2005, Drugs R D 2005; 6 (4): 229-230.
`
`Exhibit 1022A
`
`Clinicaltrials NCT0016870, “View of NCT00168701 on
`
`2005_09_14”, from URL
`
`https://clinicaltrials.gov/archive/NCT00168701/2005_09_14
`
`Exhibit 1023A
`
`Fumapharm AG - Galenical Development (2005) from URL
`
`http://web.archive.org/web/20050803080203/http://www.fumap
`
`harm.ch/EN/Research/Galenical_Development/index.php[4/30/
`
`2015 10:21:25 AM]
`
`vi
`
`
`
`Page 7 of 63
`
`
`
`Exhibit 1024A Declaration of Robert Mihail
`
`Exhibit 1025A Declaration of Chris Butler
`
`Exhibit 1026A
`
`Talalay et al., “Identification of a common chemical signal
`
`regulating the induction of enzymes that protect against
`
`chemical carcinogenesis”, November 1998, Proc. Nati. Acad.
`
`Sci. USA, Vol. 85, pp. 8261-8265, Medical Sciences.
`
`Exhibit 1027A
`
`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 63
`
`
`
`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. 1001A). The '514 patent
`
`issued from 13/372,426, filed Feb. 13, 2012 (Ex. 1018A), 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. 1011A), which claims
`
`benefit of provisional 60/888,921, filed Feb. 8, 2007 (Ex. 1012A). 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. 1013A. This petition shows that there is
`
`a reasonable likelihood the petitioner will prevail on at least one challenged claim,
`
`based on one or more patents or printed publications. 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)
`
`
`
`Pursuant to 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”),
`
`
`
`1
`
`Page 9 of 63
`
`
`
`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 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
`
`
`
`2
`
`Page 10 of 63
`
`
`
`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.
`
`B.
` Related Matters 37 C.F.R. § 42.8(b)(2)
`Interference No 106,023 was declared on April 13, 2005, involving the’514
`
`patent. To the best of Petitioner’s knowledge there are no other matters, such as
`
`pending litigations, related to the ‘514 patent that would affect, or be affected by, a
`
`decision in 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
`Neifeld IP Law, PC, 4813-B
`Eisenhower Avenue, Alexandria, VA
`22304
`Tel: 1-703-415-0012 Ext. 103
`Fax: 1-703-415-0013
`Email: rhahl@neifeld.com
`
`
`Backup Counsel for Petitioner
`Robert Mihail, Reg. No. 66,021
`Neifeld IP Law, PC, 4813-B
`Eisenhower Avenue, Alexandria, VA
`22304
`Tel: 1-703-415-0012 Ext. 107
`Fax: 1-703-415-0013
`Email: rmihail@neifeld.com
`
`
`
`D. Notice of Service Information (37 C.F.R. § 42.8(b)(4))
`Please direct all correspondence to counsel at the above address. Petitioner
`
`consents to email service at: rhahl@neifeld.com; and rmihail@neifeld.com.
`
`III. FEES 37 C.F.R. § 42.15(a)
`
`3
`
`
`
`Page 11 of 63
`
`
`
`
`
`Petitioner authorizes the Director to charge the fee, 37 C.F.R. 42.15(a) and
`
`any other fees associated with this Petition to Deposit Account 502106.
`
`
`
`The fees are: $ 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)
`
`Petitioner relies on the following patents and printed publications:
`
`
`
`1. Kappos 2005 (Ex. 1003A), (Ex. 1020A): J Neurol (2005) 252 [Suppl 2]: p2; “A
`
`randomised, placebo-controlled phase II trial of a novel oral single agent
`
`fumarate therapy, BG00012, in patients with relapsing-remitting multiple
`
`sclerosis,” L. Kappos, D. Miller, R. Gold, E. Havrdova, C. Polman, V.
`
`Limmroth, G. O’Neill, R. Kappos 2005 is prior art at least under 35 U.S.C. §
`
`102(b) (pre-AIA) because it represents a conference poster presented on June
`
`22, 2005 in Vienna, Austria, and it was received and date-stamped on July 6,
`
`2005, as a printed publication held in the collection at the University of
`
`Maryland Health Sciences and Human Services Library, Baltimore, MD. (Ex.
`
`
`
`4
`
`Page 12 of 63
`
`
`
`1020A) These dates are more than one year prior to February 8, 2007, the
`
`earliest effective filing date for the claims of the ‘514 patent.
`
`2. ICH Guideline E4 (Ex. 1004A), (Ex. 1024A): 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). ICH Guideline E4 is prior art at
`
`least under 35 U.S.C. § 102(b) (pre-AIA) because it was published in 1994,
`
`which is more than one year prior to February 8, 2007, the earliest effective
`
`filing date for the claims of the ‘514 patent. “This Guideline has been
`
`developed by the appropriate ICH Expert Working Group and has been subject
`
`to consultation by the regulatory parties, in accordance with the ICH Process.
`
`At Step 4 of the Process the final draft is recommended for adoption to the
`
`regulatory bodies of the European Union, Japan and USA.” (Title page)
`
`3. ClinicalTrials NCT00168701 (Ex. 1022A) (Ex. 1025A) “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 8, 2007, the earliest effective filing date for the claims of the ‘514
`
`patent.
`
`
`
`5
`
`Page 13 of 63
`
`
`
`
`
`2.
`
`Specific Statutory Grounds for Challenge 42.104(b)(2)
`
`
`Ground 1: Claims 1-20 are unpatentable under 35 U.S.C. §103 as obvious over
`
`any one of Kappos 2005 (Ex. 1003A) or ClinicalTrials NCT00168701 (Ex.
`
`1022A) or ‘514 Patent admission of prior art (“Fumaric acid esters, such as DMF,
`
`have been proposed for treatment of MS”) in view of ICH Guideline E4 (Ex.
`
`1004A).
`
`
`
`None of these Grounds are redundant. Kappos 2005 is a printed publication,
`
`indexed and catalogued at a library. Kappos 2005 discloses treating multiple
`
`sclerosis patients with DMF, as BG00012. It does not disclose that DMF causes
`
`G.I. complaints, and does not refer to monomethyl fumarate (MMF). ClinicalTrials
`
`NCT00168701 discloses that BG00012 contains dimethyfumarate (DMF) as the
`
`sole active agent, that patient tolerance for BG00012 is a major issue, and dose
`
`reductions are specified. The reference may be challenged as not a patent or
`
`printed publication, and it does not refer to MMF. Claim 7 is limited to a
`
`composition consisting essentially of monomethylfumarate (MMF). The
`
`“admission of prior art” in the ‘514 Patent discloses that “fumaric acid esters”
`
`(which include DMF and MMF) have therapeutic activity for multiple sclerosis.
`
`The ICH Guideline E4 provides information to the pharmaceutical industry
`
`regarding drug registration with an emphasis on dosing determinations.
`
`
`
`6
`
`Page 14 of 63
`
`
`
`Petition is supported by the Declaration of Dr. Steven E. Linberg (Ex.
`
`1005A) showing that there is a reasonable likelihood the Petitioner will prevail
`
`with respect to at least one of the challenged claims, and that each of the
`
`challenged claims is unpatentable for reasons cited in this Petition. See 35 U.S.C. §
`
`314(a). Petitioner requests cancellation of claims 1-20 of the ‘514 patent. 37 C.F.R.
`
`§ 42.22.
`
`V. UNPATENTABILITY OF THE ’514 PATENT
`A. Prosecution History of the ‘514 Patent
`The ‘514 patent issued from 13/372,426, filed Feb. 13, 2012. During
`
`prosecution, in a Preliminary Amendment (Ex. 1007A), the applicants relied on a
`
`Rule 132 Declaration by Dawson with five attachments, pertaining to a phase 2
`
`clinical trial published by Kappos et al. from 2006 to 2008 (collectively “Kappos
`
`2006”) and a Rule 132 Declaration by Rudick. On May 3, 2012 (Ex. 1009A) 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. 1009A, p7:8-20)
`
`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
`
`
`
`7
`
`Page 15 of 63
`
`
`
`successfully employed to treat MS was not unexpected as of the filing
`date of the instant application. (Ex. 1009A, p8:9-13)
`
`On August 3, 2012 (Ex. 1008A), applicants responded that Kappos 2006
`
`suggests the amount of DMF “required” for RRMS activity is 720 mg/day, e.g.,
`
`“(b) The 720 mg/day dose was expected to be required for clinical effectiveness”
`
`(Ex. 1008A, p16). Kappos 2006 reports a dose-ranging study using BG00012
`
`taken once per day (120 mg) or three times per day (doses of 360 mg, or 720 mg).
`
`It was found that only the 720 mg per day dose was effective. Applicants argued
`
`that a Person of ordinary skill in the art (POSITA) would not try to test a lower
`
`dose, even while conceding that there was a reason 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.
`
`1008A, p7:7-9) simply because 720 mg per day had been effective:
`
`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. 1008A, p8:16 – p9:2)
`
`
`
`The applicants also argued 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 dose is unexpected based on results from a Phase 2 study”) Ex.
`8
`
`
`
`Page 16 of 63
`
`
`
`1008A, p15:7-8. But what this statement means is only that the dose-
`
`response is flat in that range, i.e., a line with zero slope (horizontal). Of
`
`course one cannot mathematically determine a line, or the slope of a line,
`
`through one single data point because then its slope would be arbitrary. But
`
`Kappos 2006 gave only one dose-response data point – at three 240 mg
`
`doses per day – since none of the lower doses tested was effective – and 480
`
`mg/day and 600 mg/day were never tested. If one of the lower doses actually
`
`tested happened to be effective, then Kappos 2006 would have provided two
`
`data points and defined a dose-response relationship – but it didn’t. Thus a
`
`POSITA certainly would have tried to find another effective dose. While
`
`Drs. Ridick and Dawson never said otherwise, they didn’t admit it either.
`
`They merely pointed out that the dose-response behavior of DMF on RRMS
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`was still undetermined (e.g., Rudick ¶9, “the effects seen for the different
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`doses of BG-12 were not clearly dose-proportional,” and Dawson ¶14, “the
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`Phase 2 results do not demonstrate a linear dose response between the DMF
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`dose and the efficacy”), i.e., the clinical response expected from 480 mg per
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`day could not be projected. But projecting the response to a drug dose, after
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`that drug’s clinical efficacy has already been demonstrated is not inventive,
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`it is routine. It is a standard part of registering new drugs for sale (Ex.
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`1004A). Yet applicants argued that their next, routine dose-ranging study,
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`9
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`Page 17 of 63
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`was inventive because “there is no expectation as to whether the 480 mg/day
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`dose would be efficacious when compared to placebo (and certainly no
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`expectation the 480 mg/day dose would have similar efficacy as the 720
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`mg/day dose) (Ex. 1008A, p15:7 to p16:9) The phrase “there is no
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`expectation” means only that Kappos 2006 did not provide at least two dose-
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`response data points from which to draw a line, which is not unusual. But
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`Dr. Rudick failed to say so, or to say why a POSITA would not try to
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`determine the low end of the dose-response curve, or why a POSITA would
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`think that Kappos 2006 had somehow already determined the minimum
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`effective dose.
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`Throughout prosecution, the applicants and experts made no
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`distinction between the therapeutic properties of DMF (claims 1 – 6 and 8-
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`20) versus those of MMF (claim 7).
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`B. The Effective Filing Date of U.S. 8,399,514
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`No inventor is named in U.S. Provisional 60/888,921, filed Feb. 8, 2007; a
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`certified copy of which is Ex. 1012A. The Image File Wrapper (IFW) for the
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`US/RO filing of the PCT/US2008/001602 is Ex. 1014A. What the International
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`Bureau (IB) received is Ex. 1015A. The IFW for 60/888,921 is unavailable on
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`PAIR. The ‘921 Provisional’s cover sheet does not identify an inventor. Ex.
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`1015A, p3. No Application Data Sheet (ADS) was filed with the ‘921 provisional
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`10
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`Page 18 of 63
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`
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`when it was filed. Ex. 1015A, pp46-48. The filers knew that no inventor was
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`named, because they entered ".." in the Provisional’s cover sheet in the fields for
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`“INVENTOR(s)/ APPLICANT(s) LAST NAME, MIDDLE INITIAL,
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`RESIDENCE (CITY AND EITHER STATE OR FOREIGN COUNTRY).” Ex.
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`1015A, p3. The applicable pre-AIA version of 37 CFR 1.41(a)(2) specifies that the
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`inventorship of a provisional is the inventorship set forth in the provisional
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`application cover sheet. Continuity of inventorship is required for entitlement to
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`benefit under 35 U.S.C. §119(e). The ‘514 patent is not entitled to benefit of the
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`Provisional’s filing date because there is no continuity of inventorship. Under 37
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`CFR 1.41(a)(2), inventors could have been named during pendency of the
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`provisional application. No evidence indicates such a correction was made. (Ex.
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`1012A, April 6, 2015) If the ‘514 patent is not entitled to benefit under 119(e) to
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`the date of the US Provisional 60/888,921, February 8, 2007, then the earliest
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`effective filing date of the ‘514 patent is February 7, 2008.
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`C. Brief overview of the ‘514 Patent
` The ‘514 patent teaches that dimethylfumarate (DMF) and
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`monomethylfumarate (MMF) have essentially the same biological activity, “FIG. 1
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`demonstrates that DMF and MMF are activators of Nrf2 at concentrations within
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`clinical exposure range (cells in culture).” Ex. 1001A, 4:65-67. “FIG. 3 shows
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`evidence of Nrf2 activation by DMF and MMF in vivo. FIG. 4 shows evidence of
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`11
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`Page 19 of 63
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`
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`Nrf2 activation by DMF and MMF in vivo.” Ex. 1001A, 5:2-5. There is nothing in
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`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. 1005A, ¶17.
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`FIG 1 of the ‘514 patent shows, the expression level of NQO1 is elevated at
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`all concentrations of DMF tested, which expression level is proportional to DMF
`
`concentration. The specification of the ‘514 patent also states that “[t]he results
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`shown in FIG. 1, demonstrate that DMF and MMF are potent activators of Nrf2 at
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`concentrations within clinical exposure range.” Ex. 1001A, 2:12-14. The ‘514
`
`specification teaches 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. 1001A,
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`14:38-44. Ex. 1005A, ¶18.
`
`Dr. Linberg attests that the ‘514 patent teaches that the effective amounts of
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`DMF and MMF are the same:
`
`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 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,
`12
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`
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`Page 20 of 63
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`
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`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. 1001A, 18:52-67; Ex. 1005A, ¶19.
`
`Dr. Linberg notes, Example 3 of the ‘514 patent tested the same dose
`
`
`
`per body weight (15 mg/kg), twice a day, for both DMF and MMF: “Each
`
`treatment group consisted of 8 animals: vehicle alone as a negative control, 5
`
`mg/kg body weight DMF twice a day, 15 mg/kg body weight DMF twice a
`
`day, 15 mg/kg body weight MMF twice a day.” Ex. 1001A, 21:6-10,
`
`emphasis added. Ex. 1005A, ¶20.
`
`D. Person of Ordinary Skill in the Art
`
`
`
`The level of skill in the art and field of the invention at the time of the
`
`invention may be derived from a review of the relevant prior art. Petitioner
`
`submits an expert declaration from Dr. Steven E. Linberg, who has over 35 years
`
`in academic clinical research and commercial drug development including strategy
`
`of overall development programs, individual clinical trial design, execution and
`
`reporting, and regulatory interactions with the FDA. Ex. 1005A. Dr. Linberg
`
`attests that the field of the ‘514 patent is treating a disease with an orally
`
`administered drug. A person of ordinary skill in the art at the time of the alleged
`
`invention of the ‘514 patent (“POSITA”) would most likely have held an advanced
`
`degree, such as a Ph.D. in one of the life sciences, M.D., a D.O., or a Pharm.D.
`13
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`
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`Page 21 of 63
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`
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`Additionally, POSITA would have had some experience with clinical trials. Ex.
`
`1005A, ¶¶3, 8, 9.
`
`E. Claim Construction
`
`
`
`Other than the terms construed below, Petitioner contends that all of the
`
`terms in the challenged claims should be given their plain and ordinary meaning.
`
`
`
`“Excipients” - Dr. Linberg attests that the ‘514 patent defines the term
`
`“excipient” or “excipients”: “As used herein, the phrase ‘pharmaceutically
`
`acceptable excipient’ refers to any and all solvents, dispersion media, coatings,
`
`antibacterial and antifungal agents, isotonic and absorption delaying agents, and
`
`the like, that are compatible with pharmaceutical administration.” Ex. 1001A,
`
`19:6-10. Dr. Linberg attests that the term “excipients” means “any and all solvents,
`
`dispersion media, coatings, antibacterial and antifungal agents, isotonic and
`
`absorption delaying agents, and the like, that are compatible with pharmaceutical
`
`administration.” Ex. 1005A, ¶21.
`
`
`
`
`
`“Consisting essentially of” - Except for claim 20, which uses the
`
`transitional phrase “comprising,” all other claims in the ‘514 patent recites
`
`compositions “consisting essentially of…[active ingredient(s)]…” Dr. Linberg has
`
`been instructed that a claim reciting a thing “consisting essentially of” specified
`
`ingredients limits the scope of the claim to the specified ingredients plus those
`
`
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`14
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`Page 22 of 63
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`
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`ingredients which do not materially affect the basic and novel characteristic(s) of
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`that thing. Ex. 1005A, ¶22.
`
`F. Overview of Prior Art Reviewed by Dr. Linberg
`Once it became known that DMF is therapeutically active for treating
`
`RRMS, as taught by Kappos 2005 or ClinicalTrials NCT00168701 or ‘514 Patent
`
`admission of prior art (“Fumaric acid esters, such as DMF, have been proposed for
`
`treatment of MS”), it would have been standard procedure in drug development to
`
`determine the appropriate dosing range of DMF or MMF including its minimum
`
`effective dose, in accordance with government guidance: ICH Guideline E4. Ex.
`
`1005A, ¶23.
`
`Dr. Linberg has also reviewed the document “Drugs R&D, 2005, 6(4):229-
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`30” (Ex. 1021A) cited in the ‘514 patent where it admits that fumaric acid esters,
`
`such as DMF, were known to be therapeutically active (“Fumaric acid esters, such
`
`as DMF, have been proposed for treatment of MS…Drugs R&D, 2005,6(4):229-
`
`30).” Ex 1001A, 5:6-8. Drugs R&D reports the following entry in Table II: “Nov
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`2004 Phase II in Multiple sclerosis in Europe (PO)” Ex. 1021A, p2. In Dr.
`
`Linberg’s opinion, this table entry indicates to a POSITA that a phase 2 clinical
`
`trial using the oral BG00012 composition was conducted on MS patients beginning
`
`in 2004. The fact that this was a phase 2 trial indicates that DMF was believed to
`
`have therapeutic activity against MS at that time. Also, ClinicalTrials
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`15
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`Page 23 of 63
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`
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`NCT00168701 titled “Effacacy [sic] and Safety of BG00012 in MS” (Ex. 1022A)
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`disclosed in 2005 that “DMF, the active ingredient in BG00012, is an
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`immunomodulator demonstrating…possible therapeutic efficacy in MS (Schimrigk
`
`et al, 2001).” The Drug R&D 2005 (Ex. 1021A) article states that “Fumapharm
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`AG has developed a second-generation fumarate (fumaric acid) derivative, BG 12
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`[BG 00012, FAG-201, BG 12/Oral Fumarate], for the oral treatment of psoriasis”
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`(Abstract). Ex. 1005A, ¶24.
`
`Dr. Linberg has also reviewed the document, Fumapharm AG - Galenical
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`Development (Ex. 1023A), which is an internet archived webpage of Fumapharm
`
`(Aug 3, 2005), indicating development of “enteric coated microtablets in capsules”
`
`of a “second-generation product” identified as a fumaric acid derivative
`
`“monosubstance.” Even though the product BG00012 is not mentioned by name in
`
`Ex. 1023A, in Dr. Linberg’s opinion it appears that BG00012 is the “second-
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`generation” product discussed on the webpage. Ex. 1005A, ¶25.
`
`VI. DETAILED EXPLANATION OF THE CHALLENGES
`
`A. Ground 1: Claims 1-20 would have been obvious over Kappos
`2005 (Ex. 1003A) or ClinicalTrials NCT00168701 (Ex. 1022A) or ‘514
`Patent admission of prior art in view of ICH Guideline E4 (Ex. 1004A)
`The rationale to support a conclusion that a claim would have been obvious
`
`
`
`is that all claimed elements were known in the prior art and one skilled in the art
`
`could have combined the elements as claimed by known methods with no change
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`
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`16
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`Page 24 of 63
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`
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`in their respective function, and the combination yielded no more than predictable
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`results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc.,
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`550 U.S. 398, 416 (2007) (citing United States v. Adams, 383 U.S. 39, 40 (1966);
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`Anderson's-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57 (1969); and
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`Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976)).
`
`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, wherein the therapeutically effective amount of dimethyl fumarate,
`monomethyl fumarate, or a combination thereof is about 480 mg per day.
`
`
`
`The first element of claim 1 requires, “[a] method of
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