Kyle Bass, Biogen IPR Petition, Patent '514

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: IPR Unassigned
Patent 8,399,514
Title: TREATMENT FOR MULTIPLE SCLEROSIS
____________
PETITION FOR INTER PARTES REVIEW OF

U.S. PATENT NO. 8,399,514
UNDER 35 U.S.C. 312 AND 37 C.F.R. 42.104
Mail Stop PATENT BOARD

U.S. Patent Trial & Trademark Office
P.O. Box 1450
Alexandria, VA 22313-14
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
E.
Claim Construction......................................................................................13
F.
Overview of Prior Art Reviewed by Dr. Linberg .......................................14
VI. DETAILED EXPLANATION OF THE CHALLENGES........................16

A.
Ground 1: Claims 1-20 would have been obvious over Kappos 2005 (Ex.
1003) or ClinicalTrials NCT00168701 (Ex. 1022) or 514 Patent admission of

prior art in view of ICH Guideline E4 (Ex. 1004) ................................................16
VII.
CONCLUSION ..........................................................................................51
ii
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) ..................................16
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..3, 4
37 C.F.R. 42.22..7
37 C.F.R. 42.1001
37 C.F.R. 42.104....4, 6
iii
LIST OF EXHIBITS
Exhibit 1001
US Patent No. 8,399,514, titled Treatment for Multiple

Sclerosis to Lukashev et al. (514 patent)
Exhibit 1002
Unassigned
Exhibit 1003
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/95II/170, pII/148, P574.
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.
Exhibit 1005
Declaration of Dr. Steven E. Linberg.
Exhibit 1006
Unassigned
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 8,399,514.
iv
Exhibit 1008
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 1009
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 1011
PCT Application No. PCT/US2008/001602.
Exhibit 1012
Certified copy of US Provisional Application No. 601888,921
Exhibit 1013
Assignment Record for US Patent No. 8,399,514 from

USPTOs Assignments on the Web.
Exhibit 1014
IFW of PCT/US2008/001602.
Exhibit 1015
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 1016
D. Werdenberg, et al., Presystemic Metabolism and Intestinal

Absorption of Antipsoriatic Fumaric Acid Esters, 2003,
BIOPHARMACEUTICS & DRUG DISPOSITION, Biopharm.
v
Drug Dispos. 24: 259273 (2003), Published online in Wiley

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 DoubleBlind 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
BG 12 BG 00012, BG 12/Oral Fumarate, FAG-201, SecondGeneration Fumarate Derivative Fumapharm/ Biogen Idec,
2005, Drugs R D 2005; 6 (4): 229-230.
Exhibit 1022
Clinicaltrials NCT0016870, View of NCT00168701 on

2005_09_14, from URL
https://clinicaltrials.gov/archive/NCT00168701/2005_09_14
Exhibit 1023
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
Exhibit 1024
Declaration of Robert Mihail
Exhibit 1025
Declaration of Chris Butler
Exhibit 1026
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 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
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 (Ex1018), 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 (Ex1011), which claims benefit
of provisional 60/888,921, filed Feb. 8, 2007 (Ex1012). The 514 patent was
assigned on 12/6/2010 from Lukashev, Matvey E.; ONeill, 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. 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),
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
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 the514

patent. To the best of Petitioners 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
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 the514 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. 1003), (Ex. 1020): J Neurol (2005) 252 [Suppl 2]: II/95
II/170, pII148, P574; A randomised, placebo-controlled phase II trial of a
novel oral single agent fumarate therapy, BG00012, in patients with relapsingremitting multiple sclerosis, L. Kappos, D. Miller, R. Gold, E. Havrdova, C.
Polman, V. Limmroth, G. ONeill, 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.
1020) 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. 1004), (Ex. 1024): ICH-E4; INTERNATIONAL
CONFERENCE ON HARMONISATION OF TECHNICAL
REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR
HUMAN USE - ICH HARMONISED TRIPARTITE GUIDELINE, DOSERESPONSE 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 1022) (Ex.1025) 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.
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. 1003) or ClinicalTrials NCT00168701 (Ex. 1022) 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. 1004).
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 monomethylfumarate (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.
Petition is supported by the Declaration of Dr. Steven E. Linberg (Ex 1005)
showing that there is a reasonable likelihood the Petitioner will prevail with respect
6
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. 1007), 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. 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, p5:8-20)
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, p6:9-13)
On August 3, 2012 (Ex. 1008), applicants responded that Kappos 2006
suggests the amount of DMF required for RRMS activity is 720 mg/day, e.g.,
7
(b) The 720 mg/day dose was expected to be required for clinical effectiveness
(Ex. 1008, 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. 1008,
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. 1008, 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.
1008, 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
8
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 didnt. Thus a POSITA
certainly would have tried to find another effective dose. While Drs. Ridick
and Dawson never said otherwise, they didnt admit it either. They merely
pointed out that the dose-response behavior of DMF on RRMS was still
undetermined (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), i.e., the clinical response expected from 480 mg per day could
not be projected. But projecting the response to a drug dose, after that drugs
clinical efficacy has already been demonstrated is not inventive, it is routine.
It is a standard part of registering new drugs for sale (Ex. 1004). Yet
applicants argued that their next, routine dose-ranging study, was inventive
because there is 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, p15:7 to p16:9) The phrase there is no expectation means only that
9
Kappos 2006 did not provide at least two dose-response data points from
which to draw a line, which is not unusual. But Dr. Rudick failed to say so,
or to say why a POSITA would not try to determine the low end of the doseresponse curve, or why a POSITA would think that Kappos 2006 had
somehow already determined the minimum effective dose.
Throughout prosecution, the applicants and experts made no
distinction between the therapeutic properties of DMF (claims 1 6 and 820) versus those of MMF (claim 7).
B.
The Effective Filing Date of U.S. 8,399,514
No inventor is named in U.S. Provisional 60/888,921, filed Feb. 8, 2007; a

certified copy of which is Ex. 1012. The Image File Wrapper (IFW) for the US/RO
filing of the PCT/US2008/001602 is Ex. 1014. What the International Bureau (IB)
received is Ex. 1015. The IFW for 60/888,921 is unavailable on PAIR. The 921
Provisionals cover sheet does not identify an inventor. Ex. 1015, p3. No
Application Data Sheet (ADS) was filed with the 921 provisional when it was
filed. Ex. 1015, pp46-48. The filers knew that no inventor was named, because
they entered ".." in the Provisionals cover sheet in the fields for INVENTOR(s)/
APPLICANT(s) LAST NAME, MIDDLE INITIAL, RESIDENCE (CITY AND
EITHER STATE OR FOREIGN COUNTRY). Ex. 1015, p3. The applicable preAIA version of 37 CFR 1.41(a)(2) specifies that the inventorship of a provisional is
10
the inventorship set forth in the provisional application cover sheet. Continuity of
inventorship is required for entitlement to benefit under 35 U.S.C. 119(e). The
514 patent is not entitled to benefit of the Provisionals filing date because there is
no continuity of inventorship. Under 37 CFR 1.41(a)(2), inventors could have
been named during pendency of the provisional application. No evidence indicates
such a correction was made. (Ex. 1012, April 6, 2015) If the 514 patent is not
entitled to benefit under 119(e) to the date of the US Provisional 60/888,921,
February 8, 2007, then the earliest effective filing date of the 514 patent is
February 7, 2008.
C. 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, 4:65-67. FIG. 3 shows
evidence of Nrf2 activation by DMF and MMF in vivo. FIG. 4 shows evidence of
Nrf2 activation by DMF and MMF in vivo. Ex. 1001, 5:2-5. There is nothing in
the 514 patent which defines or explains that the therapeutic properties of MMF
are different from the therapeutic properties of DMF. Ex. 1005, 17.
FIG 1 of the 514 patent shows, the expression level of NQO1 is elevated at
all concentrations of DMF tested, which expression level is proportional to DMF
11
concentration. The specification of the 514 patent also 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, 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 includeFor example, expression levels of endogenous or exogenously
introduced NQO1 may be determined as described in the Examples. Ex. 1001,
14:38-44. Ex. 1005, 18.
Dr. Linberg attests that the 514 patent teaches that the effective amounts of
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,
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, 18:52-67; Ex. 1005, 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
12
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. 1001, 21:6-10, emphasis
added. Ex. 1005, 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. 1005 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. Additionally,
POSITA would have had some experience with clinical trials. Ex. 1005, 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.
13
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. 1001, 19:610. 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. 1005, 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
ingredients which do not materially affect the basic and novel characteristic(s) of
that thing. Ex. 1005, 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
14
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.
1005, 23.
Dr. Linberg has also reviewed the document Drugs R&D, 2005, 6(4):22930 (Ex. 1021) 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 MSDrugs R&D, 2005,6(4):22930). Ex 1001, col. 5:6-8. Drugs R&D reports the following entry in Table II:
Nov 2004 Phase II in Multiple sclerosis in Europe (PO) Ex. 1021, p230. In Dr.
Linbergs 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
NCT00168701 titled Effacacy [sic] and Safety of BG00012 in MS (Ex. 1022)
disclosed in 2005 that DMF, the active ingredient in BG00012, is an
immunomodulator demonstratingpossible therapeutic efficacy in MS (Schimrigk
et al, 2001). The Drug R&D 2005 (Ex. 1021) article states that Fumapharm AG
has developed a second-generation fumarate (fumaric acid) derivative, BG 12 [BG
15
00012, FAG-201, BG 12/Oral Fumarate], for the oral treatment of psoriasis

(Abstract). Ex. 1005, 24.
Dr. Linberg has also reviewed the document, Fumapharm AG - Galenical
Development (Ex. 1023), 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. 1023, in Dr. Linbergs opinion it appears that BG00012 is the secondgeneration product discussed on the webpage. Ex. 1005, 25.
VI. DETAILED EXPLANATION OF THE CHALLENGES
A. Ground 1: Claims 1-20 would have been obvious over Kappos
2005 (Ex. 1003) or ClinicalTrials NCT00168701 (Ex. 1022) or 514
Patent admission of prior art in view of ICH Guideline E4 (Ex. 1004)
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
in their respective function, and the combination yielded no more than predictable
results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc.,
550 U.S. 398, 416 (2007) (citing United States v. Adams, 383 U.S. 39, 40 (1966);
Anderson's-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57 (1969); and
Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976)).
16
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 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 and
defines a method of treating a subject in need of treatment for MS with an oral
pharmaceutical composition. Kappos 2005 discloses A randomized, placebocontrolled phase II trial of a novel oral single agent fumarate therapy, BG00012, in
patients with relapsing-remitting multiple sclerosis. Ex. 1003, P574, pII/148, 1:13. ClinicalTrials NCT00168701 discloses Double-Blind, Placebo-Controlled,
Dose-Ranging Study to Determine the Effacacy [sic] and Safety of BG00012 in
Subjects with Relapsing-Remitting Multiple Sclerosis Ex. 1022, p1 Ex. 1005,
26;
The second element of claim 1 requires, (a) a therapeutically effective
amount of dimethyl fumarate, monomethyl fumarate, or a combination thereof.
Kappos 2005 discloses a pilot study that orally administered to patients what
appears to be a therapeutically effective amount of fumaric acid esters, indicated
by a significantly reduced the number of gadolinium-enhancing (Gd+) lesions in
17
patients with RRMS. Ex. 1003, pII/148, P574, 1:13-16. ClinicalTrials

NCT00168701 teaches the efficacy data in the pilot MS study of BG00012
support a proof of concept study in MS. Ex. 1022, p1-2. ClinicalTrials
NCT00168701 also teaches that DMF is the active ingredient in BG00012. Ex.
1022, p1. Dr. Linberg attests that DMF is an abbreviation for dimethylfumarate
and MMF is an abbreviation for monomethyfumarate. The 514 patent cites to
prior art clinical studies on MS patients which indicated that [f]umaric acid esters,
such as DMF have been proposed for treatment of MS. Ex. 1001, 5:6-7. Dr
Linberg attests that fumaric acid esters refer principally to DMF or MMF. Thus,
the 514 Patent admits that a POSITA believed that DMF and MMF were
therapeutically active for MS. Ex. 1005, 27.
Kappos 2005 discloses BG00012 contains DMF as the sole active
ingredient. The objective is [t]o determine the efficacy and safety of a novel
single-agent oral fumarate therapy, BG00012, in patients with relapsing-remitting
multiple sclerosis (RRMS). Ex. 1003, pII/148 1:1-3. Kappos 2005 discloses that
this phase II study was designed to evaluate the efficacy of three doses of
BG00012 on brain lesion activity in MS patients. Ex.1003, pII/148, P574, 1:17-20
Kappos 2005 also discloses that this phase II study is a dose-ranging study. Ex.
1003, pII/148, P574, 2:16-17. Dr. Linberg attests, the Kappos 2005 dose-ranging
study would not have been undertaken unless BG00012 had previously been
18
determined to be therapeutically active in treating patients with MS. Ex. 1005,

28.
Dr. Linberg attests that ClinicalTrials NCT00168701 discloses: Effacacy
[sic] and Safety of BG00012 in MS. and teaches the efficacy data in the pilot MS
study of BG00012 support a proof of concept study in MS. Ex. 1022, p1-2. Ex.
1005, 29.
Furthermore, DMF is known to be metabolically converted to MMF rapidly
by hydrolysis in the intestinal tissue. Ex. 1016, p1, 1:6 - 2:1-12. Dr. Linberg attests
that Kappos 2005 or ClinicalTrials NCT00168701 or the 514 patent admissions
each teach a POSITA that DMF and MMF are therapeutically active on RRMS.
Ex. 1005, 30.
The third element of claim 1 requires, b) one or more pharmaceutically
acceptable excipients. Dr. Linberg attests that DMF is poorly tolerated by
patients (Ex. 1005 citing to Ex. 1019, p35, 2:6-10, and p36, Table 2) and it would
be obvious to use excipients to reduce G.I. complaints. Dr. Linberg further attests
that MMF is also poorly tolerated in patients and therefore a POSITA would have
been motivated to use excipients to reduce G.I. complaints. Ex. 1005, 31.
The fourth element of claim 1 requires, wherein the therapeutically
effective amount of dimethyl fumarate, monomethyl fumarate, or a combination
thereof is about 480 mg per day. Kappos 2005 discloses a dose-ranging study in
19
which [e]ligible patients were randomized to receive BG00012 120 mg PO once

daily (120 mg/day), 120 mg PO three times daily (360 mg/day), 240mg PO three
times daily (720 mg/day), or placebo. Ex. 1003, pII/148, P574, 1:28 to 2:1-3.
ClinicalTrials NCT00168701 teaches a dose-ranging study with the same doses of
DMF and further acknowledges that if DMF is not well tolerated by patients, lower
doses can alleviate the problem. Dose reduction will be allowed for subjects who
are unable to tolerate investigational drug. Ex. 1022, p2, 24-25; Ex. 1005, 32.
Dr. Linberg attests that the ICH Guideline E4 would have instructed a
POSITA as follows: Assessment of dose-response should be an integral
component of drug development with studies designed to assess dose-response an
inherent part of establishing the safety and effectiveness of the drug. If
development of dose-response information is built into the development process it
can usually be accomplished with no loss of time and minimal extra effort
compared to development plans that ignore dose-response. Ex. 1004, p3:27-32.
ICH Guideline E4 also would have instructed that: It is all too common to
discover, at the end of a parallel dose-response study, that all doses were too high
(on the plateau of the dose-response curve), or that doses did not go high enough.
Ex. 1004, p6:39-41. The ICH Guideline E4 instructed a POSITA to perform dosing
studies as a standard procedure in drug development in order to allow study of the
proper dose range in phase III. Because Kappos 2005 did not test doses between
20
360 mg/day and 720 mg/day, because side effects are always a concern in drug
development, as they were for DMF, and because doses in multiples of 120 mg and
240 mg were readily available, a POSITA would have conducted clinical trials by
administering BG00012 at a total daily dose equivalent to 480 mg/day DMF as
well as 600 mg/day, as a standard process of drug development. Ex. 1005, 33.
Kappos 2005 and ClinicalTrials NCT00168701 disclose BG00012, which is
a composition dosing 120 mg or 240 mg dimethylfumarate as the sole active
ingredient (patients randomized to receive BG00012 120 mg PO once daily (120
mg/day), 120 mg PO three times daily (360 mg/day), 240mg PO three times daily
(720 mg/day), Ex. 1003, pII/148, P574, 2:1-3. Dr. Linberg attests, a POSITA
would have designed additional dose-ranging studies using doses of 240 mg, 480
mg and 600 mg in multiples of 120 mg or 240 mg, because BG00012 was already
conveniently formulated to achieve such doses. Ex. 1005, 34.
Dr. Linberg explains that a POSITA would have had reason to modify the
clinical trial design of Kappos 2005 or ClinicalTrials NCT00168701 in view of the
ICH Guideline E4, as part of a group of dosing studies, because the purpose of the
ICH Guideline E4 is to provide instructions to help identify an appropriate
starting dose, the best way to adjust dosage to the needs of a particular patient, and
a dose beyond which increases would be unlikely to provide added benefit or
would produce unacceptable side effects. Ex. 1004, p1:7-10. Dr. Linberg attests
21
that a POSITA would have had reason to conduct dose-ranging studies due to the
admittedly known therapeutic activity of DMF, in view of the ICH Guideline E4,
because the purpose of the ICH Guideline E4 is to provide instructions to help
identify an appropriate starting dose, the best way to adjust dosage to the needs of
a particular patient, and a dose beyond which increases would be unlikely to
provide added benefit or would produce unacceptable side effects. Ex. 1004,
p1:7-10. Ex. 1005, 35.
In sum, a POSITA would have been motivated to conduct routine
experiments at a range of doses, including 480 mg/day, by orally administering
that dose and a 600 mg/day dosage strength to subjects in need of treatment for
MS. Ex. 1005, 36. Thus, claim 1 is obvious over Kappos 2005 or ClinicalTrials
NCT00168701 or admitted prior art, in view of ICH Guideline E4.
Claim 2: The method of claim 1, wherein the pharmaceutical composition is
administered in the form of a tablet, a suspension, or a capsule.
Claim 2 depends on claim 1 and incorporates all its limitations. Claim 2
further requires, the pharmaceutical composition is administered in the form of a
tablet, a suspension, or a capsule. Kappos 2005 discloses administering BG00012
orally to MS patients using formulations with dosing strengths of 120 mg or 240
mg DMF. Ex. 1003, pII/148, P574, 2:1-3 ClinicalTrials NCT00168701 also
discloses the same formulations of DMF: Effacacy [sic] and Safety of BG00012
in MS, wherein the efficacy data in the pilot MS study of BG00012 support a
22
proof of concept study in MS. Ex. 1022, p1-2. In Dr. Linbergs opinion, it would
have been obvious to a POSITA to administer DMF as a tablet or capsule in
general, and particularly in view of Kappos 2005 or ClinicalTrials NCT00168701.
Ex. 1005, 37. Thus claim 2 is obvious over Kappos 2005 or ClinicalTrials
NCT00168701 or admitted prior art in view of ICH Guideline E4.
Claim 3: The method of claim 1, wherein the therapeutically effective amount
is administered in separate administrations of 2, 3, 4, or 6 equal doses.
further requires, the therapeutically effective amount is administered in separate
administrations of 2, 3, 4, or 6 equal doses. Kappos 2005 discloses a dose-ranging
study in which [e]ligible patients were randomized to receive BG00012 120 mg
PO once daily (120 mg/day), 120 mg PO three times daily (360 mg/day), 240mg
PO three times daily (720 mg/day), or placebo. Ex. 1003, pII/148, P574, 1:282:3. ClinicalTrials NCT00168701 also discloses a dose-ranging study of BG00012
with the same doses. Both Kappos 2005 and ClinicalTrials NCT00168701 disclose
at least one dose or three equal doses. Routine dosing experiments would have
shown that administration of 2, 4 or 6 equal doses are therapeutically effective. Ex.
1005, 39.
Furthermore, Dr. Linberg attests that DMF is known to cause gastrointestinal
discomfort (The gastrointestinal complaints, on the other hand, presented a real
problem. More than half the patients were troubled by serious stomach complaints,
23
involving gastralgia, but also nausea, vomiting and diarrhea.) EX. 1019, p35, 2:610, and p36, Table 2) and so dividing the daily dose into smaller equal doses taken
separately, throughout the day, would have been expected to reduce gastric distress,
because smaller doses expose the G. I. tract to less DMF at one time. The ICH
Guideline E4 teaches that [t]he choice of the size of an individual dose is often
intertwined with the frequency of dosing. In general, when the dose interval is long
compared to the half-life of the drug, attention should be directed to the
pharmacodynamic basis for the chosen dosing interval. For example, there might
be a comparison of the long dose-interval regimen with the same dose in a more
divided regimen, looking, where this is feasible, for persistence of desired effect
throughout the dose-interval and for adverse effects associated with blood level
peaks. Ex. 1004, p3:9-15. Attempting to find the optimal individual dose, dosing
frequency and total daily dose are a normal part of drug development. Ex. 1005,
40.
Administering therapeutically effective amounts of DMF to a subject, in a
number of equal doses throughout the day, would necessarily smooth out peak
blood levels of the biologically active metabolite, MMF. Dr. Linberg attests, a
POSITA would have known that DMF is therapeutically active for MS, and thus
would have been motivated to use multiples of a 120 mg or 240 mg to perform
dosing studies, since BG00012 includes both 120 mg and 240 mg dosage strengths
24
of DMF, as disclosed by Kappos 2005. Dr. Linberg also explains that since claim 3
recites every dosing interval from 2 equal doses to 6 equal doses, there is no
critical dosing interval. In sum, it was obvious to a POSITA to administer the
therapeutically effective amount of about 480 mg/day DMF in separate
administrations of 2 or 4 equal doses Ex. 1005, 41, 42. Thus claim 3 is obvious
over Kappos 2005 or ClinicalTrials NCT00168701 or admitted prior art, in view of
ICH Guideline E4.
is administered in separate administrations of 2 equal doses.
administrations of 2 equal doses. As shown with respect to claim 3, it would have
been obvious to a POSITA to administer 480 mg/day in 2 equal doses based on the
ready availability of 240 mg BG00012. It would have been obvious, in light of
ICH Guideline E4, to administer 480 mg/day in two equal doses, because the
alternative of taking 120 mg doses four times per day would be expected to
decrease patient compliance. In sum, it was obvious to a POSITA to administer
480 mg/day of DMF in separate administrations of 2 equal doses. Ex. 1005, 43.
Thus claim 4 is obvious over Kappos 2005 or ClinicalTrials NCT00168701 or
admitted prior art, in view of ICH Guideline E4.
25

is administered in separate administrations of 3 equal doses.
administrations of 3 equal doses. Kappos 2005 discloses a dose-ranging study in
times daily (720 mg/day), or placebo. Ex. 1003, pII/148, P574, 1:28-2:3.
ClinicalTrials NCT00168701 also discloses a dose-ranging study of BG00012 with
the same dosing. Dr. Linberg attests that both of these studies disclose using three
equal doses, and if the desired dose is 480 mg a POSITA would have known how
to provide equal doses of appropriate strength. In sum, it was obvious to a POSITA
to administer 480 mg/day of DMF in separate administrations of three equal doses.
Ex. 1005, 44.
Thus claim 5 is obvious over Kappos 2005 or ClinicalTrials NCT00168701
or admitted prior art, in view of ICH Guideline E4.
Claim 6: The method of claim 1, wherein the pharmaceutical
composition consists essentially of dimethyl fumarate and one or more
pharmaceutically acceptable excipients.
further requires, the pharmaceutical composition consists essentially of dimethyl
fumarate and one or more pharmaceutically acceptable excipients. Kappos 2005
26
teaches A randomized, placebo-controlled phase II trial of a novel oral single

agent fumarate therapy, BG00012, in patients with relapsing-remitting multiple
sclerosis. Ex. 1003, pII/148, P574, 1:1-3. ClinicalTrials NCT00168701 discloses
Double-Blind, Placebo-Controlled, Dose-Ranging Study to Determine the
Effacacy [sic] and Safety of BG00012 in Subjects with Relapsing-Remitting
Multiple Sclerosis Ex. 1022, p1. DMF is the only active ingredient in BG00012.
DMF is poorly tolerated by patients (Ex. 1019, p35, 2:6-10, and p36, Table 2) and
it would have been obvious to use excipients to reduce G.I. complaints. Ex. 1005,
46.
In sum, claim 6 is obvious in view of Kappos 2005 or ClinicalTrials
Claim 7: The method of claim 1, wherein the pharmaceutical
composition consists essentially of monomethyl fumarate and one or more
pharmaceutically acceptable excipients.
Claim 7 depends on claim 1 and incorporates all its limitations. Claim 7 further
requires, the pharmaceutical composition consists essentially of monomethyl
fumarate. Kappos 2005 teaches A randomized, placebo-controlled phase II trial
of a novel oral single agent fumarate therapy, BG00012, in patients with relapsingremitting multiple sclerosis. Ex. 1003, pII/148, P574, 1:1-3. ClinicalTrials
NCT00168701 discloses Double-Blind, Placebo-Controlled, Dose-Ranging Study
to Determine the Effacacy [sic] and Safety of BG00012 in Subjects with
27
Relapsing-Remitting Multiple Sclerosis Ex. 1022, p1. The therapeutically active

compound in BG00012 is dimethylfumarate, not monomethylfumarate. However,
DMF is known to be metabolically converted to MMF rapidly by hydrolysis in the
intestinal tissue. Ex. 1016, p1, 1:6 - 2:1-12. In view of the foregoing, a POSITA
would find it obvious to modify the BG00012 of Kappos, which contains DMF as
the sole active ingredient, and administer a composition in which
monomethylfumarate is the sole active ingredient instead, since the therapeutic
efficacy of each is essentially the same. Ex. 1005, 48.
The second element of claim 7 is one or more pharmaceutically acceptable
excipients. DMF is poorly tolerated by patients (Ex. 1019, p35, 2:6-10, and p36,
Table 2) and it would be obvious to use excipients to reduce G.I. complaints. MMF
is also poorly tolerated in patients and therefore a POSITA would have been
motivated to use excipients to reduce G.I. complaints. Ex. 1005, 49.
Therefore, claim 7 of the 514 patent is obvious over Kappos 2005 or
ClinicalTrials NCT00168701 or admitted prior art in view of ICH Guideline E4.
Claim 8: The method of claim 1, wherein the pharmaceutical composition is
administered to the subject for at least 12 weeks.
further requires wherein the pharmaceutical composition is administered to the
subject for at least 12 weeks. Kappos 2005 discloses the following information
about its dose-ranging study: Design: This is a randomized, double-blind,
28
placebo-controlled, phase II study being conducted at 45 clinical centers in

EuropeEligible patients were randomized to receive BG00012 120 mg PO once
times daily (720 mg/day), or placebo. The study consists of 2 phases: a 24-week
double-blind treatment phase followed by a 24-week, blinded, safety-extension
phase in which all patients will receive some level of BG00012. Ex. 1003,
pII/148, P574, 1:21 to 2:5. ClinicalTrials NCT00168701 discloses the following
about its dose-ranging study, The primary endpoint for the primary objective is
the total number of Gd-enhancing lesions over four scans at Weeks 12, 16, 20, and
24 (calculated as the sum of these four MRI scans). Ex. 1022, p3. BG00012 refers
to formulations containing DMF as the only active ingredient. In light of Kappos
2005 or ClinicalTrials NCT00168701, it would have been obvious to a POSITA to
administer DMF to the subject for at least 12 weeks. Ex. 1005, 51, 52. In sum,
claim 8 of the 514 patent would have been obvious over Kappos 2005 or
ClinicalTrials NCT00168701 or admitted prior art, in view of ICH Guideline E4.
is administered to the subject in 2 equal doses.
administrations of 2 equal doses. As shown above with respect to claim 4, it
would have been obvious to a POSITA to administer 480 mg/day in 2 equal doses
29
based on the ready availability of 240 mg BG00012. It would have been obvious,
in light of ICH Guideline E4, to administer 480 mg/day in two equal doses,
because the alternative of taking 120 mg doses four times per day would be
expected to decrease patient compliance. In sum, it was obvious to a POSITA to
administer 480 mg/day of DMF in separate administrations of 2 equal doses Ex.
1005, 53, 54. Thus claim 9 of the 514 patent is obvious over Kappos 2005 or
Claim 10: The method of claim 9, wherein the therapeutically effective
amount is administered to the subject for at least 12 weeks.
further requires wherein the pharmaceutical composition is administered to the
subject for at least 12 weeks. As shown in regard to claim 8, it was obvious to
administer DMF to the subject for at least 12 weeks. Ex. 1005, 55. In sum, claim
10 of the 514 patent would have been obvious over Kappos 2005 or ClinicalTrials
sclerosis consisting essentially of orally administering to the subject about 480
mg per day of dimethyl fumarate, monomethyl fumarate, or a combination
thereof.
The first element of independent claim 11 requires, [a] method for treating
a subject in need of treatment for multiple sclerosis consisting essentially of orally
administering to the subject and defines a method of treating a subject in need of
30
treatment for MS by administering an oral composition. Claim 11 does not recite

therapeutically effective but the broadest reasonable interpretation of treating a
subject in need of treatment for multiple sclerosis requires a therapeutically
effective dose. Ex. 1005, 56.
Kappos 2005 discloses A randomized, placebo-controlled phase II trial of a
novel oral single agent fumarate therapy, BG00012, in patients with relapsingremitting multiple sclerosis. Ex. 1003, P574, pII/148, 1:1-3. ClinicalTrials
NCT00168701 discloses Double-Blind, Placebo-Controlled, Dose-Ranging Study
to Determine the Effacacy [sic] and Safety of BG00012 in Subjects with
Relapsing-Remitting Multiple Sclerosis Ex. 1022, p1. The 514 patent cites to
prior art clinical studies on MS patients which indicated that [f]umaric acid esters,
such as DMF have been proposed for treatment of MS. Ex. 1001, 5:6-7. Fumaric
acid esters refers principally to DMF or MMF. Thus, the 514 Patent admits a
POSITA believed that DMF and MMF were therapeutically active for MS. Ex.
1005, 57.
Kappos 2005 discloses that the single agent in BG00012 is DMF. The
objective is [t]o determine the efficacy and safety of a novel single-agent oral
fumarate therapy, BG00012, in patients with relapsing-remitting multiple sclerosis
(RRMS). Ex. 1003, pII/148 1:1-3. Kappos 2005 discloses that this phase II study
was designed to evaluate the efficacy of three doses of BG00012 on brain lesion
31
activity in MS patients. Ex.1003, pII/148, P574, 1:17-20. Kappos 2005 also

discloses that this phase II study is a dose-ranging study. Ex. 1003, pII/148,
P574, 2:16-17. Dr. Linberg attests that the Kappos 2005 dose-ranging study would
not have been undertaken unless BG00012 had previously been determined to be
therapeutically active in treating patients with MS, based on the pilot study data
mentioned in Kappos 2005 where a mixture of fumaric acid esters significantly
reduced the number and volume of gadolinium-enhancing (Gd+) lesions in patients
with RRMS. ClinicalTrials NCT00168701 teaches the efficacy data in the pilot
MS study of BG00012 support a proof of concept study in MS. Ex. 1022, p1-2.
The 514 patent cites to prior art clinical studies on MS patients which indicated
that [f]umaric acid esters, such as DMF have been proposed for treatment of MS.
Ex. 1001, 5:6-7. Fumaric acid esters refers principally to DMF and MMF. Thus,
the 514 Patent admits a POSITA believed that DMF or MMF were therapeutically
active for MS. Dr. Linberg attests that Kappos 2005 and ClinicalTrials
NCT00168701 and the 514 patent admissions each teach a POSITA that DMF is
therapeutically active on RRMS. Ex. 1005, 58.
The second element of claim 11 requires administering to the subject about
480 mg per day of dimethyl fumarate, monomethyl fumarate, or a combination
thereof. Kappos 2005 discloses a dose-ranging study in which [e]ligible patients
were randomized to receive BG00012 120 mg PO once daily (120 mg/day), 120
32
mg PO three times daily (360 mg/day), 240mg PO three times daily (720 mg/day),
or placebo. Ex. 1003, pII/148, P574, 1:28 to 2:1-3. ClinicalTrials NCT00168701
teaches a dose-ranging study with the same doses of DMF. It acknowledges that
DMF is not well tolerated by patients, and that lower doses can alleviate the
problem. Dose reduction will be allowed for subjects who are unable to tolerate
investigational drug. Ex. 1022, p29-25; Ex. 1005, 59.
Dr. Linberg attests that the ICH Guideline E4 would have instructed a
POSITA as follows: Assessment of dose-response should be an integral
component of drug development with studies designed to assess dose-response an
inherent part of establishing the safety and effectiveness of the drug. If
Ex. 1004, p6:39-41. The ICH Guideline E4 instructed a POSITA to perform dosing
33
Kappos 2005 and ClinicalTrials NCT00168701 disclose BG00012, which is
a composition dosing 120 mg or 240 mg dimethylfumarate as the sole active
ingredient (patients randomized to receive BG00012 120 mg PO once daily (120
mg/day), 120 mg PO three times daily (360 mg/day), 240mg PO three times daily
(720 mg/day), Ex. 1003, pII/148, P574, 2:1-3. Dr. Linberg attests, a POSITA
would have designed additional dose-ranging studies using doses between 240 mg
and 600 mg in multiples of 120 mg or 240 mg, because BG00012 is conveniently
formulated to achieve such doses. Ex. 1005, 61.
Dr. Linberg explains that a POSITA would have had reason to modify the
34
p1:7-10. In sum, a POSITA would have been motivated to conduct routine
experiments at a range of doses, including 480 mg/day, by orally administering
that dose and a 600 mg/day dosage strength to subjects in need of treatment for
MS. Ex. 1005, 62, 63. Therefore claim 11 of the 514 patent is obvious over
Kappos 2005 or ClinicalTrials NCT00168701 or admitted prior art, in view of ICH
Guideline E4.
Claim 12: The method of claim 11, wherein about 480 mg of dimethyl
fumarate per day is administered to the subject.
further requires, wherein about 480 mg of dimethyl fumarate per day is
administered to the subject. As shown with regard to claim 11, it would have been
obvious to conduct routine experiments to determine the dose-response of DMF,
and thereby reveal that 480 mg per day is a therapeutically effective amount. Ex.
1005, 64. In sum, claim 12 of the 514 patent would have been obvious over
Kappos 2005 or ClinicalTrials NCT00168701 or admitted prior art, in view of ICH
Guideline E4.
35
Claim 13: The method of claim 12, wherein the dimethyl fumarate is
administered in separate administrations of 2 equal doses.
further requires, wherein the dimethyl fumarate is administered in separate
administrations of 2 equal doses. As shown with regard to claim 4, it would have
been obvious to administer 480 mg/day DMF in separate administrations of 2
equal doses. Ex. 1005, 66. Thus, claim 13 is obvious over Kappos 2005 or
further requires, wherein the dimethyl fumarate is administered in separate
administrations of 3 equal doses. As shown in regard to claim 5, it would have
been obvious to administer 480 mg/day DMF in separate administrations of 3
equal doses. Ex. 1005, 68. Thus claim 3 is obvious over Kappos 2005 or
sclerosis comprising orally administering to the subject pharmaceutical
composition consisting essentially of (a) a therapeutically effective amount of
dimethyl fumarate and (b) one or more pharmaceutically acceptable
excipients, wherein the therapeutically effective amount of dimethyl fumarate
is about 480 mg per day.
The first element of independent claim 15 requires [a] method of treating a
subject in need of treatment for multiple sclerosis comprising orally administering
36
to the subject pharmaceutical composition consisting essentially of and defines a

method of treating a subject in need of treatment for MS by administering an oral
composition. Kappos 2005 teaches A randomized, placebo-controlled phase II
trial of a novel oral single agent fumarate therapy, BG00012, in patients with
relapsing-remitting multiple sclerosis. Ex. 1003, P574, pII/148, 1:1-3.
ClinicalTrials NCT00168701 discloses Double-Blind, Placebo-Controlled, DoseRanging Study to Determine the Effacacy [sic] and Safety of BG00012 in Subjects
with Relapsing-Remitting Multiple Sclerosis Ex. 1022, p1; Ex. 1005, 70.
The second element of claim 15 requires, (a) a therapeutically effective
amount of dimethyl fumarate. Kappos 2005 discloses a pilot study that orally
administered to patients a therapeutically active amount of fumaric acid esters,
which significantly reduced the number of gadolinium-enhancing (Gd+) lesions in
patients with RRMS. Ex. 1003, pII/148, P574, 1:13-16. ClinicalTrials
NCT00168701 teaches the efficacy data in the pilot MS study of BG00012
support a proof of concept study in MS. Ex. 1022, p1-2. DMF is an abbreviation
for dimethylfumarate. The 514 patent cites to prior art clinical studies on MS
patients which indicated that [f]umaric acid esters, such as DMF have been
proposed for treatment of MS. Ex. 1001, 5:6-7. Fumaric acid esters refers
principally to DMF and MMF. Thus, the 514 Patent admits a POSITA believed
that DMF and MMF were therapeutically active for MS. Ex. 1005, 71.
37
activity in MS patients. Ex.1003, pII/148, P574, 1:17-20 Kappos 2005 discloses
that this phase II study is a dose-ranging study. Ex. 1003, pII/148, P574, 2:16-17
Dr. Linberg attests, the Kappos 2005 dose-ranging study would not have been
undertaken unless BG00012 had previously been determined to be therapeutically
active in treating patients with MS. ClinicalTrials NCT00168701 discloses:
Effacacy [sic] and Safety of BG00012 in MS. Ex. 1022, p1. Dr. Linberg attests
that Kappos 2005 and ClinicalTrials NCT00168701 and the 514 patent admissions
each teach a POSITA that DMF is therapeutically active on RRMS. Ex. 1005, 72.
Kappos 2005 discloses a dose-ranging study in which [e]ligible patients
were randomized to receive BG00012 120 mg PO once daily (120 mg/day), 120
mg PO three times daily (360 mg/day), 240mg PO three times daily (720 mg/day),
or placebo. Ex. 1003, pII/148, P574, 1:28 to 2:1-3. ClinicalTrials NCT00168701
teaches a dose-ranging study with the same doses of DMF. It acknowledges that
DMF is not well tolerated by patients, and that lower doses can alleviate the
problem. Dose reduction will be allowed for subjects who are unable to tolerate
38
investigational drug. Ex. 1022, p29-25 The ICH Guideline E4 would have
instructed a POSITA as follows: Assessment of dose-response should be an
integral component of drug development with studies designed to assess doseresponse an inherent part of establishing the safety and effectiveness of the drug. If
Ex. 1004, p6:39-41 The ICH Guideline E4 instructed a POSITA to perform dosing
Kappos 2005 teaches BG00012, which is a composition containing DMF as
the sole active agent (patients randomized to receive BG00012 120 mg PO once
39
times daily (720 mg/day)). Ex. 1003, pII/148, P574, 2:1-3. Dr. Linberg attests, a
POSITA would have designed additional dose-ranging studies using doses between
240 mg and 600 mg in multiples of 120 mg or 240 mg, as disclosed by Kappos
2005. Dr. Linberg explains that a POSITA would have had reason to modify the
p1:7-10. Ex. 1005, 74.
The third element of claim 15 requires, (b) one or more pharmaceutically
acceptable excipients. DMF is poorly tolerated by patients (Ex. 1019, p35, 2:640
10, and p36, Table 2) and it would be obvious to use excipients to reduce G.I.
complaints. MMF is also poorly tolerated in patients and therefore a POSITA
would have been motivated to use excipients to reduce G.I. complaints. Ex. 1005,
75.
The fourth element of claim 15 requires, wherein the therapeutically
effective amount of dimethyl fumarate is about 480 mg per day. As shown above
with respect to the second element of claim 15, in light of the ICH Guideline E4
instructions to perform initial dosing studies to allow study of the proper dose
range and because Kappos 2005 did not test intermediate dosages, a POSITA
would have conducted clinical trials by administering BG00012 at a total daily
dose equivalent to 480 mg DMF/per day, as well as 600 mg/day. Thus, a POSITA
would have designed additional dose-ranging studies using doses between 240 mg
and 600 mg in multiples of 120 mg or 240 mg, as disclosed by Kappos 2005. A
POSITA would have had reason to consider the clinical trial design of Kappos
2005 in view of the ICH Guideline E4, to be just a part of usual dose ranging
studies because the purpose of the ICH Guideline E4 is to provide instructions to
help identify an appropriate starting dose, the best way to adjust dosage to the
needs of a particular patient, and a dose beyond which increases would be unlikely
to provide added benefit or would produce unacceptable side effects. Ex. 1004,
41
p1:7-10. Ex. 1005, 76. Therefore, claim 15 is obvious over Kappos 2005 or
further requires wherein the dimethyl fumarate is administered in separate
administrations of 2 equal doses. ICH Guideline E4 teaches Adjustment of drug
exposure levels might be made on the basis of reliable information on drug taking
compliance. Ex. 1004, p10:30-31. Dr. Linberg attests, it would have been
obvious, in light of ICH Guideline E4, to administer 480 mg/day DMF in two
equal doses because the alternative of taking 120 mg four times per day would be
expected to decrease patient compliance. In sum, a POSITA would have had
reason to administer the DMF in separate administrations of 2 equal doses. Ex.
1005, 78, 79. Therefore, claim 16 is obvious over Kappos 2005 or ClinicalTrials
Claim 17: The method of claim 1, wherein the expression level of NQO1 in the
subject is elevated after administering to the subject the therapeutically
combination thereof.
Claims 17, 18 and 19 fail to add any narrowing limitations. They recite an
intended effect of administering the drug (i.e, the expression level of NQO1 is
elevated), but there is only one claimed disease (MS), one claimed dose (about 480
42
mg/day), and two claimed drugs (DMF or MMF) which both have essentially the
same therapeutic properties according the 514 Patent, as explained in the section
Brief overview of the 514 Patent above. Therefore claims 17, 18, and 19
involve an issue of inherency. In short, administering 480 mg/day of DMF or
MMF must elevate NQO1 as claimed. [I]nherency may supply a missing claim
limitation in an obviousness analysis. PAR Pharm., Inc. v. TWI Pharm., Inc., 773
F.3d 1186, 119495 (Fed. Cir. 2014) (citations omitted). The Federal Circuit has
cautioned, however, that the use of inherency doctrine must be carefully
circumscribed in the context of obviousness. Id. at 1195. Inherency may not be
established by probabilities or possibilities. Bettcher Indus., Inc. v. Bunzl USA,
Inc., 661 F.3d 629, 639 (Fed. Cir. 2011) (citing In re Oelrich, 666 F.2d 578, 581
(CCPA 1981)).
further requires wherein the expression level of NQO1 in the subject is elevated
after administering to the subject the therapeutically effective amount of dimethyl
fumarate, monomethyl fumarate, or a combination thereof. Ex. 1005, 81.
Dr. Linberg attests that an elevated expression of NQO1 is an inherent
property of administering 480 mg/day of DMF to the subject and that the
expression level of NQO1 is necessarily elevated as a result of administering 480
mg/day DMF to the subject. Ex. 1005, 82. Dr. Linberg discloses the following
43
facts underlying his conclusion. First, 480 mg is the only amount of dimethyl
fumarate, monomethyl fumarate or a combination thereof permitted under claim
1, whether it is therapeutically effective or not. Second, an elevated expression
of NQO1 is necessarily present as disclosed in multiple previous studies. Ex.
1005, 82-84, citing to Talalay that teaches that DMF is a moderately potent
inducer of NQO1, (Ex. 1026, p8263, 1:13-16, Table 3) and to Begleiter that
teaches that NQO1 activity increases after either in vitro or in vivo treatment with
DMF. Ex. 1027, p1626, 1:61 2:1-3, 2:11-14.
Furthermore, the 514 patent admits in claim 18 that the expression level of
NQO1 in the subject is elevated after administering to the subject about 480 mg
per day of dimethyl fumarate, monomethyl fumarate, or a combination thereof.
(emphasis added). Ex. 1005, 85.
In sum, it would have been obvious for a POSITA to combine the teachings
of Kappos2005 or ClinicalTrials NCT00168701 or admitted prior art in the 514
Patent, and treat a subject in need of treatment for MS by orally administering a
composition consisting essentially of 480 mg per day of DMF, and one or more
excipients, wherein the expression level of NQO1 in the subject is necessarily
elevated after administering to the subject said pharmaceutical composition. Ex.
1005, 86. Therefore, claim 17 is obvious over Kappos 2005 or ClinicalTrials
44
Claim 18: The method of claim 11, wherein the expression level of NQO1 in
the subject is elevated after administering to the subject about 480 mg per day
of dimethyl fumarate, monomethyl fumarate, or a combination thereof.
further requires, wherein the expression level of NQOl in the subject is elevated
after administering to the subject about 480 mg per day of dimethyl fumarate,
monomethyl fumarate, or a combination thereof. The motivation to administer
480 mg/day is shown above with respect to claim 11 and the increase of expression
levels of NQO1 are shown as inherent for the same reasons as set forth above in
claim 17. An elevated expression of NQO1 is an inherent property of
administering 480 mg/day of DMF to the subject and the expression level of
NQO1 is necessarily elevated as a result of administering 480 mg/day DMF to the
subject. Ex. 1005, 87, 88.
In sum, it would have been obvious for a POSITA to combine the teachings
of Kappos2005 or ClinicalTrials NCT00168701 or admitted prior art in the 514
elevated after administering to the subject said pharmaceutical composition Ex.
1005, 89. Therefore, claim 18 is obvious over Kappos 2005 or ClinicalTrials
45
Claim 19: The method of claim 15, wherein the expression level of NQO1 in
the subject is elevated after administering to the subject the therapeutically
effective amount of dimethyl fumarate.
further requires, wherein the expression level of NQO1 in the subject is elevated
after administering to the subject the therapeutically effective amount of dimethyl
fumarate. Dr. Linberg attests that an elevated expression of NQO1 is an
inherent property of administering 480 mg/day of DMF to the subject and that
the expression level of NQO1 is necessarily elevated as a result of administering
480 mg/day DMF to the subject for the same reasons as set forth above in claim
17. In sum, it would have been obvious for a POSITA to combine the teachings of
Kappos2005 or ClinicalTrials NCT00168701 or admitted prior art in the 514
elevated after administering to the subject said pharmaceutical composition Ex.
1005, 90, 91. Therefore, claim 19 is obvious over Kappos 2005 or ClinicalTrials
sclerosis comprising treating the subject in need thereof with a therapeutically
combination thereof, wherein the therapeutically effective amount of dimethyl
fumarate, monomethyl fumarate, or a combination thereof is about 480 mg
per day.
46
The first element of independent claim 20 requires A method of treating a

subject in need of treatment for multiple sclerosis comprising treating the subject
in need thereof and defines a method of treating a subject in need of treatment for
MS by administering an oral pharmaceutical composition. Kappos 2005 teaches A
randomized, placebo-controlled phase II trial of a novel oral single agent fumarate
therapy, BG00012, in patients with relapsing-remitting multiple sclerosis. Ex.
1003, P574, pII/148, 1:1-3. ClinicalTrials NCT00168701 discloses Double-Blind,
Placebo-Controlled, Dose-Ranging Study to Determine the Effacacy [sic] and
Safety of BG00012 in Subjects with Relapsing-Remitting Multiple Sclerosis Ex.
1022, p1; Ex. 1005, 92.
The second element of claim 20 requires, a therapeutically effective amount
of dimethyl fumarate, monomethyl fumarate, or a combination thereof. Kappos
2005 discloses a pilot study that orally administered a therapeutically active
amount of fumaric acid esters, which significantly reduced the number of
gadolinium-enhancing (Gd+) lesions in patients with RRMS. Ex. 1003, pII/148,
P574, 1:13-16. ClinicalTrials NCT00168701 teaches the efficacy data in the pilot
MS study of BG00012 support a proof of concept study in MS. Ex. 1022, p1-2.
DMF is an abbreviation for dimethylfumarate. The 514 patent cites to prior art
clinical studies on MS patients which indicated that [f]umaric acid esters, such as
DMF have been proposed for treatment of MS. Ex. 1001, 5:6-7. Fumaric acid
47
esters refers principally to DMF or MMF. Thus, the 514 Patent admits a POSITA
believed that DMF or MMF were therapeutically active for MS. Ex. 1005, 93.
activity in MS patients. Ex.1003, pII/148, P574, 1:17-20. Kappos 2005 discloses
that this phase II study is a dose-ranging study. Ex. 1003, pII/148, P574, 2:16-17.
Dr. Linberg attests, the Kappos 2005 dose-ranging study would not have been
undertaken unless BG00012 had previously been determined to be therapeutically
active in treating patients with MS. ClinicalTrials NCT00168701 discloses:
Effacacy [sic] and Safety of BG00012 in MS. Ex. 1022, p1. Dr. Linberg attests
that Kappos 2005 and ClinicalTrials NCT00168701 and the 514 patent admissions
each teach a POSITA that DMF is therapeutically active on RRMS. Ex. 1005, 94.
The third element of claim 20 requires, wherein the therapeutically
effective amount of dimethyl fumarate, monomethyl fumarate, or a combination
thereof is about 480 mg per day. Kappos 2005 discloses a dose-ranging study in
48
times daily (720 mg/day), or placebo. Ex. 1003, pII/148, P574, 1:28 to 2:1-3.
ClinicalTrials NCT00168701 teaches a dose-ranging study with the same doses of
DMF. It acknowledges that DMF is not well tolerated by patients, and that lower
doses can alleviate the problem. Dose reduction will be allowed for subjects who
are unable to tolerate investigational drug. Ex. 1022, p29-25. The ICH Guideline
E4 would have instructed a POSITA as follows: Assessment of dose-response
should be an integral component of drug development with studies designed to
assess dose-response an inherent part of establishing the safety and effectiveness of
the drug. If development of dose-response information is built into the
development process it can usually be accomplished with no loss of time and
minimal extra effort compared to development plans that ignore dose-response.
Ex. 1004, p3:27-32. ICH Guideline E4 also would have instructed that: It is all
too common to discover, at the end of a parallel dose-response study, that all doses
were too high (on the plateau of the dose-response curve), or that doses did not go
high enough. Ex. 1004, p6:39-41. The ICH Guideline E4 instructed a POSITA to
perform dosing studies as a standard procedure in drug development in order to
allow study of the proper dose range in phase III. Because Kappos 2005 did not
test doses between 360 mg/day and 720 mg/day, because side effects are always a
concern in drug development, as they were for DMF, and because doses in
multiples of 120 mg and 240 mg were readily available, a POSITA would have
49
conducted clinical trials by administering BG00012 at a total daily dose equivalent

to 480 mg/day DMF as well as 600 mg/day, as a standard process of drug
development. Ex. 1005, 95.
Kappos 2005 teaches BG00012, which contains DMF as the sole active
agent, and teaches that patients [were] randomized to receive BG00012 120 mg
PO once daily (120 mg/day), 120 mg PO three times daily (360 mg/day), 240mg
PO three times daily (720 mg/day), Ex. 1003, pII/148, P574, 2:1-3. Dr. Linberg
attests, a POSITA would have designed additional dose-ranging studies using doses
between 240 mg and 600 mg in multiples of 120 mg or 240 mg. Dr. Linberg
explains that a POSITA would have had reason to modify the clinical trial design
of Kappos 2005 in view of the ICH Guideline E4, because the purpose of the ICH
Guideline E4 is to provide instructions to help identify an appropriate starting
dose, the best way to adjust dosage to the needs of a particular patient, and a dose
beyond which increases would be unlikely to provide added benefit or would
produce unacceptable side effects. Ex. 1004, p1:7-10. Dr. Linberg further attests
50
p1:7-10. Ex. 1005, 96. In sum, claim 20 is obvious over Kappos 2005 or
ClinicalTrials Identifier: NCT00168701 (Ex. 1022) or admitted prior art, in view of
ICH Guideline.
VII. CONCLUSION
For the foregoing reasons, the petitioner respectfully requests that a trial be
instituted and that claims 1-20 of the 514 patent be canceled.
/RobertHahl#33,893/
Lead Counsel for the Petitioner
Tel: 1-703-415-0012 Ext. 103
Backup Counsel for Petitioner
Robert Mihail, Reg. No. 66,021
Tel: 1-703-415-0012 Ext. 107
Email: rmihail@neifeld.com
Fax for lead and backup counsel for the Petitioner: 1-703-415-0013
Postal address for lead and backup counsel:
Neifeld IP Law, PC, 4813-B Eisenhower Avenue, Alexandria, VA 22304
51
42.6(e) CERTIFICATE OF SERVICE

I certify that this document was served or simultaneously is being served on
each opposing party with the filing of this document. I certify that the following
exhibits being filed along with this document, if any, have been or simultaneously
are being served on each opposing party:
Exhibit Description
Number
1001
US Patent No. 8,399,514, titled Treatment for Multiple Sclerosis to
Lukashev et al. (514 patent)
1002
Unassigned
1003
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/95II/170, pII/148, P574.
1004
1005
1006
1007
1008
1009
1010
1011
1012
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.
Declaration of Dr. Steven E. Linberg.
Unassigned
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.
Amendment and Reply Under 37 C.ER. 1.111, In re application of:
LUKASHEV et al., Appl. No. 13/372,426 that issued into US Patent
8,399,514.
Office Action with mail date of 05/03/2012 for Application No.
13/372,426 that issued into US Patent 8,399,514
Unassigned
PCT Application No. PCTIUS2008/001602
Certified copy of US Provisional Application No. 601888,921
52
1013
1014
1015
1016
Assignment Record for US Patent No. 8,399,514 from USPTOs

Assignments on the Web
IFW of PCT/US2008/001602
Certified Copy of US Provisional 60/888,921 as received by the
International Bureau on March 26, 2008
D. Werdenberg, et al., Presystemic Metabolism and Intestinal
Absorption of Antipsoriatic Fumaric Acid Esters, 2003,
BIOPHARMACEUTICS & DRUG DISPOSITION, Biopharm. Drug
Dispos. 24: 259273 (2003), Published online in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/bdd.364.
1017
1018
CV of Dr. Steven E. Linberg

US Application 13/372,426, as filed on February 13, 2012
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
Declaration of Scott Bennett
BG 12 BG 00012, BG 12/Oral Fumarate, FAG-201, SecondGeneration Fumarate Derivative Fumapharm/ Biogen Idec, 2005,
Drugs R D 2005; 6 (4): 229-230
View of NCT00168701 on 2005_09_14, from URL
https://clinicaltrials.gov/archive/NCT00168701/2005_09_14
Galenic development, Fumapharm AG archival page located at
http://web.archive.org/web/20050803080203/http://www.fumapharm.c
h/EN/Research/Galenical_Development/index.php
Declaration of Robert Mihail
Declaration of Christopher Butler
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.
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.
1020
1021
1022
1023
1024
1025
1026
1027
53
42.6(e)(4) (iii)(A) The date and manner of service:

Manner of service: Priority Mail Express and email to the following firm of record
as listed on PAIR:
Jones Day
222 East 41st St.
New York, NY 10017
Date of Service: 5/1/2015
/RobertHahl#33,893/
Lead Counsel for the Petitioner
Neifeld IP Law, PC
4813-B Eisenhower Avenue
Alexandria, VA 22304
Tel: 1-703-415-0012 Ext. 103
Fax: 1-703-415-0013
54

Kyle Bass, Biogen IPR Petition, Patent &#39;514

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For the Patent Owner

Backup counsel: Robert W. Hahl, Reg. No. 33,893

UNITED STATES PATENT AND TRADEMARK OFFICE

Coalition For Affordable Drugs V LLC

PETITION FOR INTER PARTES REVIEW OF

Mail Stop PATENT BOARD

MANDATORY NOTICES ............................................................................1

Real Party-In-Interest 37 C.F.R. 42.8(b)(1) ...............................................1

Related Matters 37 C.F.R. 42.8(b)(2).........................................................3

Designation of Lead and Backup Counsel 37 C.F.R. 42.8(b)(3) ...............3

Notice of Service Information (37 C.F.R. 42.8(b)(4)) ...............................3

III. FEES 37 C.F.R. 42.15(a) .............................................................................3

Grounds for Standing 37 C.F.R. 42.104(a) ................................................4

Challenge and Precise Relief Requested 37 C.F.R. 42.104(b) ..................4

UNPATENTABILITY OF THE 514 PATENT .........................................7

Prosecution History of the 514 Patent .........................................................7

The Effective Filing Date of U.S. 8,399,514 ..............................................10

Brief overview of the 514 Patent ...............................................................11

Person of Ordinary Skill in the Art .............................................................13

Overview of Prior Art Reviewed by Dr. Linberg .......................................14

VI. DETAILED EXPLANATION OF THE CHALLENGES........................16

1003) or ClinicalTrials NCT00168701 (Ex. 1022) or 514 Patent admission of

US Patent No. 8,399,514, titled Treatment for Multiple

Kappos et al., A randomised, placebo-controlled phase II trial

International Conference on Harmonization of Technical

Declaration of Dr. Steven E. Linberg.

Preliminary Amendment Under 37 C.F.R. 1.115, In re

Amendment and Reply Under 37 C.F.R. 1.111, In re

Office Action with mail date of 05/03/2012 for Application No.

PCT Application No. PCT/US2008/001602.

Certified copy of US Provisional Application No. 601888,921

Assignment Record for US Patent No. 8,399,514 from

Priority document transmitted to the International Bureau, Rule

D. Werdenberg, et al., Presystemic Metabolism and Intestinal

Drug Dispos. 24: 259273 (2003), Published online in Wiley

CV of Dr. Steven E. Linberg

US Application 13/372,426, as filed on February 13, 2012

Declaration of Scott Bennett

Clinicaltrials NCT0016870, View of NCT00168701 on

Fumapharm AG - Galenical Development (2005) from URL

Declaration of Robert Mihail

Declaration of Chris Butler

Talalay et al., Identification of a common chemical signal

Begleiter et al., Dietary induction of NQO1 increases the

42.1-.80 & 42.100-123, for claims 1-20 of US patent 8,399,514, titled

Hayman Offshore Management, Inc. (HOM), Hayman Investments, L.L.C.

Related Matters 37 C.F.R. 42.8(b)(2)

Interference No 106,023 was declared on April 13, 2005, involving the514

Backup Counsel for Petitioner

D. Notice of Service Information (37 C.F.R. 42.8(b)(4))

Challenge and Precise Relief Requested 37 C.F.R. 42.104(b)

Patents and Printed Publications 37 C.F.R. 42.104(b)(2)

Petitioner relies on the following patents and printed publications:

Specific Statutory Grounds for Challenge 42.104(b)(2)

It is Applicant's discovery, subsequent to the filing of the instant

The Effective Filing Date of U.S. 8,399,514

No inventor is named in U.S. Provisional 60/888,921, filed Feb. 8, 2007; a

treatment group consisted of 8 animals: vehicle alone as a negative control, 5

Person of Ordinary Skill in the Art

Overview of Prior Art Reviewed by Dr. Linberg

Once it became known that DMF is therapeutically active for treating

treatment of MS), it would have been standard procedure in drug development to

00012, FAG-201, BG 12/Oral Fumarate], for the oral treatment of psoriasis

Claim 1: A method of treating a subject in need of treatment for multiple

Kyle Bass, Biogen IPR Petition, Patent '514

Kyle Bass, Biogen IPR Petition, Patent '514