-
For the Patent Owner Paper No. __ Backup counsel: Robert W.
Hahl, Reg. No. 33,893 Backup counsel: Robert Mihail, Reg. No.
66,021 Neifeld IP Law, PC
UNITED STATES PATENT AND TRADEMARK OFFICE ____________
BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________
Coalition For Affordable Drugs V LLC Petitioner
v.
Biogen MA Inc. Patent Owner
____________
Case: 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
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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
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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
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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
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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.
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v
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.
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vi
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 Double-
Blind Comparison between Fumaric Acid Compound Therapy
and Monotherapy with Dimethylfumaric Acid Ester
Dermatologica 1990; 181:33- 37
Exhibit 1020 Declaration of Scott Bennett
Exhibit 1021 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 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]
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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.
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I. INTRODUCTION Inter partes review is requested under 35 U.S.C.
311-319 and 37 C.F.R.
42.1-.80 & 42.100-123, for claims 1-20 of US patent
8,399,514, titled
Treatment for Multiple Sclerosis (514 patent) (Ex. 1001). The
'514 patent issued
from 13/372,426, filed Feb. 13, 2012 (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),
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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
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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 Backup 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: [email protected]
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: [email protected]
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: [email protected]; and
[email protected].
III. FEES 37 C.F.R. 42.15(a)
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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 relapsing-
remitting 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.
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5
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, 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 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.
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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
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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.,
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8
(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
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9
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
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10
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 dose-
response 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 8-
20) 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
pre-
AIA version of 37 CFR 1.41(a)(2) specifies that the inventorship
of a provisional is
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11
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
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12
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
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13
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.
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14
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, 19:6-
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. 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
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15
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):229-
30 (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):229-
30). 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
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16
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
second-
generation 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)).
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17
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,
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,
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
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18
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
-
19
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
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20
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
-
21
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
-
22
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
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23
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.
Claim 3 depends on claim 1 and incorporates all its limitations.
Claim 3
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, 1:28-
2:3. 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,
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24
involving gastralgia, but also nausea, vomiting and diarrhea.)
EX. 1019, p35, 2:6-
10, 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
-
25
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.
Claim 4: The method of claim 3, wherein the therapeutically
effective amount is administered in separate administrations of 2
equal doses. Claim 4 depends on claim 3 and incorporates all its
limitations. Claim 4
further requires, the therapeutically effective amount is
administered in separate
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.
-
26
Claim 5: The method of claim 3, wherein the therapeutically
effective amount is administered in separate administrations of 3
equal doses. Claim 5 depends on claim 3 and incorporates all its
limitations. Claim 5
further requires, the therapeutically effective amount is
administered in separate
administrations of 3 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,
1:28-2:3.
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.
Claim 6 depends on claim 1 and incorporates all its limitations.
Claim 6
further requires, the pharmaceutical composition consists
essentially of dimethyl
fumarate and one or more pharmaceutically acceptable excipients.
Kappos 2005
-
27
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
NCT00168701 or admitted prior art, in view of ICH Guideline
E4.
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 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
-
28
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.
Claim 8 depends on claim 1 and incorporates all its limitations.
Claim 8
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,
-
29
placebo-controlled, phase II study being conducted at 45
clinical centers in
EuropeEligible 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. 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.
Claim 9: The method of claim 6, wherein the therapeutically
effective amount is administered to the subject in 2 equal doses.
Claim 9 depends on claim 6 and incorporates all its limitations.
Claim 9
further requires, the therapeutically effective amount is
administered in separate
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
-
30
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
ClinicalTrials NCT00168701 or admitted prior art, in view of ICH
Guideline E4.
Claim 10: The method of claim 9, wherein the therapeutically
effective amount is administered to the subject for at least 12
weeks. Claim 10 depends on claim 9 and incorporates all its
limitations. Claim 10
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
NCT0016870 or admitted prior art, in view of ICH Guideline
E4.
Claim 11: A method of treating a subject in need of treatment
for multiple sclerosis consisting essentially of orally
administering to the subject about 480 mg per day of dimethyl
fumarate, monomethyl fumarate, or a combination thereof. 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
-
31
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 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. 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
-
32
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
-
33
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
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
-
34
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, 60.
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
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
that a POSITA would have had reason to conduct dose-ranging
studies due to the
-
35
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. 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.
Claim 12 depends on claim 11 and incorporates all its
limitations. Claim 12
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.
-
36
Claim 13: The method of claim 12, wherein the dimethyl fumarate
is administered in separate administrations of 2 equal doses.
Claim 13 depends on claim 12 and incorporates all its
limitations. Claim 13
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
ClinicalTrials NCT00168701 or admitted prior art, in view of ICH
Guideline E4.
Claim 14: The method of claim 12, wherein the dimethyl fumarate
is administered in separate administrations of 3 equal doses.
Claim 14 depends on claim 12 and incorporates all its
limitations. Claim 14
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
ClinicalTrials NCT00168701 or admitted prior art, in view of ICH
Guideline E4.
Claim 15: A method of treating a subject in need of treatment
for multiple 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
-
37
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, Dose-
Ranging 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.
-
38
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
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
-
39
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 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, 73.
Kappos 2005 teaches BG00012, which is a composition containing
DMF as
the sole active agent (patients randomized to receive BG00012
120 mg PO once
-
40
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, as disclosed
by Kappos
2005. 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
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, 74.
The third element of claim 15 requires, (b) one or more
pharmaceutically
acceptable excipients. DMF is poorly tolerated by patients (Ex.
1019, p35, 2:6-
-
41
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,
-
42
p1:7-10. Ex. 1005, 76. Therefore, claim 15 is obvious over
Kappos 2005 or
ClinicalTrials NCT00168701 or admitted prior art, in view of ICH
Guideline E4.
Claim 16: The method of claim 15, wherein the dimethyl fumarate
is administered in separate administrations of 2 equal doses. Claim
16 depends on claim 15 and incorporates all its limitations. Claim
16
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
NCT00168701 or admitted prior art, in view of ICH Guideline
E4.
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 effective amount of dimethyl fumarate,
monomethyl fumarate, or a 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
-
43
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)).
Claim 17 depends on claim 1 and incorporates all its
limitations. Claim 17
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
-
44
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
NCT00168701 or admitted prior art, in view of ICH Guideline
E4.
-
45
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.
Claim 18 depends on claim 11 and incorporates all its
limitations. Claim 18
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
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, 89. Therefore, claim 18 is obvious over Kappos 2005 or
ClinicalTrials
NCT00168701 or admitted prior art, in view of ICH Guideline
E4.
-
46
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.
Claim 19 depends on claim 15 and incorporates all its
limitations. Claim 19
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
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, 90, 91. Therefore, claim 19 is obvious over Kappos 2005 or
ClinicalTrials
NCT00168701 or admitted prior art, in view of ICH Guideline
E4.
Claim 20: A method of treating a subject in need of treatment
for multiple sclerosis comprising treating the subject in need
thereof with a therapeutically effective amount of dimethyl
fumarate, monomethyl fumarate, or a combination thereof, wherein
the therapeutically effective amount of dimethyl fumarate,
monomethyl fumarate, or a combination thereof is about 480 mg per
day.
-
47
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
-
48
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.
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
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
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
-
49
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
-
50
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.