Trials@uspto.

gov
571-272-7822

Paper 20
Entered: 22 March 2016

UNITED STATES PATENT AND TRADEMARK OFFICE

__________
BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________
COALITION FOR AFFORDABLE DRUGS V LLC;
HAYMAN CREDES MASTER FUND, L.P.;
HAYMAN ORANGE FUND SPC PORTFOLIO A;
HAYMAN CAPITAL MASTER FUND, L.P.;
HAYMAN CAPITAL MANAGEMENT, L.P.;
HAYMAN OFFSHORE MANAGEMENT, INC.;
HAYMAN INVESTMENTS, LLC;
NXN PARTNERS, LLC;
IP NAVIGATION GROUP, LLC;
J KYLE BASS, and ERICH SPANGENBERG,
Petitioners,
v.
BIOGEN MA INC.,
Patent Owner.
__________
Case IPR2015-01993
Patent 8,399,514 B2
__________
Before FRED E. McKELVEY, SALLY GARDNER LANE, and
DEBORAH KATZ, Administrative Patent Judges.
McKELVEY, Administrative Patent Judge.
DECISION
Institution of Inter Partes Review
37 C.F.R. 42.108

IPR2015-01993
Patent 8,399,514 B2

I. Introduction
A. Background
A second petition seeking to institute an inter partes review in
connection with U.S. Patent No. 8,399,514 B2 (514 patent) is before the
Board. Paper 1.
A first petition seeking to institute an inter partes review was denied.
Coalition for Affordable Drugs V LLC v. Biogen MA Inc., IPR2015-01136,
2015 WL 5169256 (Paper 23) (PTAB Sept. 2, 2015), rehg denied,
IPR2015-01136 (Paper 29) (PTAB Oct. 23, 2015).
The 514 patent is also involved in Biogen MA Inc. v. Forward
Pharma, Interference 106,023 (PTAB Declared Apr. 13, 2015).
Patent Owner timely filed a Preliminary Response. Paper 11.
Petitioner was invited to file a Reply. Paper 13.
Petitioner timely filed the Reply.1 Paper 17.
B. The Parties
Petitioner is:
(1) Coalition for Affordable Drugs V LLC,
(2) Hayman Credes Master Fund, L.P.,

The Reply is styled REPLY TO PATENT OWNERS PRELIMINARY

RESPONSE IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
OF U.S. PATENT 8,399,514 UNDER 35 U.S.C. 311-319. In the future
the style of any paper filed in this IPR shall not exceed one line. A more
appropriate style would have been REPLY TO PRELIMINARY
RESPONSE. Use of a single line renders entry of papers into Board data
records much easier. Failure to adhere to the one-line rule established in this
IPR may result in a paper being expunged.
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Patent 8,399,514 B2
(3) Hayman Orange Fund SPC Portfolio A,
(4) Hayman Capital Master Fund, L.P.,
(5) Hayman Capital Management, L.P.,
(6) Hayman Offshore Management, Inc.,
(7) Hayman Investment, LLC,
(8) NXN Partners, LLC,
(9) IP Navigation Group, LLC,
(10) J. Kyle Bass, and
(11) Erich Spangenberg.
Paper 1, pages 12.
Patent Owner is Biogen MA Inc. Paper 11, page 1.
C. Abbreviations
BG00012 or BG12

Dimethyl fumarate

DMF

Dimethyl fumarate

ICH

International Conference on Harmonisation

MMF

Monomethyl fumarate

MRI

Magnetic resonance imaging

RRMS

Relapsing-remitting multiple sclerosis

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Patent 8,399,514 B2
D. Evidence Relied Upon2
The following evidence is relied upon in support of the Petition:
Name

Exhibit
No.

Description

Date

Efficacy of a Novel Oral

Single-Agent Fumarate,
BG00012, in Patients with
Kappos 2006
1003
May 2006
Relapsing-Remitting Multiple
Sclerosis: Results of a Phase
2 Study, J. NEUROL (2006)
253 (SUPPL 2); II/1II/170,
page II27
Kappos 2006 is prior art under 35 U.S.C. 102(b) based on the filing
date of Biogens PCT application (7 February 2008). If Biogen is entitled to
a benefit date of its Provisional Application (8 February 2007), Kappos 2006
is prior art under 35 U.S.C. 102(a).
Further discussion of Kappos 2006 occurs later in this opinion.
Double-Blind, PlaceboControlled, Dose-Ranging
Study to Determine the
Clinical Trials
1022
14 Sept. 2005
Effacacy and Safety of
BG00012 in Subjects with
Relapsing-Remitting Multiple
Sclerosis,
CLINICALTRIALS.GOV
ARCHIVE

Clinical Trials is prior art under 35 U.S.C. 102(b).

Because the application maturing into the 514 patent was filed before
the enactment of the Leahy-Smith America Invents Act (AIA), Pub. L.
No. 112-29, 125 Stat. 284 (2011), we apply the pre-AIA version of 35 U.S.C.
102, 103, 112, and 119.
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Patent 8,399,514 B2

Name

Exhibit
No.

Description

Date

22 Jan. 2008
Joshi 999
1030
U.S. Patent 7,320,999 B2
filed
17 July 2002
Joshi 999 is prior art under 35 U.S.C. 102(a) having issued prior to
Biogens PCT filing date (7 February 2008). If Biogen is entitled to a
benefit date of its Provisional Application (8 February 2007), then Joshi
999 is prior art under 35 U.S.C. 102(e) based on its filing date (17 July
2002).
ICH Harmonised Tripartite
ICH Guideline
1004
Guideline, DOSE-RESPONSE
10 Mar. 1994
INFORMATION TO SUPPORT
DRUG REGISTRATION E4
Joshi 992
1036
U.S. Patent 6,436,992 B1
20 Aug. 2002
Dietary Induction of NQOI
Increases the Antitumour
Begleiter
1027
2004
Activity of Mitomycin C in
Human Colon Tumours in
vivo,
91 BRITISH J. CANCER 1624
1631
ICH Guideline, Joshi 992, and Begleiter are prior art under 35 U.S.C.
102(b).
E. Grounds of Unpatentability
Claims 120 appear in the 514 patent. Ex. 1001, col. 27:58 through
col. 30:27.
The following grounds of unpatentability are urged in the Petition.

IPR2015-01993
Patent 8,399,514 B2

Statutory
Basis
Ground 1

103(a)

Ground 2

103(a)

Ground 3

103(a)

Prior Art
Relied On
Kappos 2006
ClinicalTrials,
Joshi 999, and
ICH Guideline
Kappos 2006,
ClinicalTrials,
Joshi 999,
ICH Guideline, and
Joshi 992
Kappos 2006,
ClinicalTrials,
Joshi 999,
ICH Guideline and
Begleiter

Claims

16, 816, and 20

1719

F. Kappos 2006
The application maturing into the 514 patent was filed on
13 February 2012. Ex. 1001, page 1.
Biogen claims benefit of Provisional Application 60/888,921, filed
8 February 2007.
The Petition has not challenged Patent Owners 7 February 2008
claim to priority based on Patent Owners PCT application. Paper 1, page 4.
The Petition alleges that Patent Owner is not entitled to benefit of its
Provisional Application based on Patent Owner having not been accorded
benefit in Interference 106,023. Id.
Patent Owner was accorded benefit of its Provisional Application at
the time Interference 106,023 was declared. Interference 106,023, Paper 1,

IPR2015-01993
Patent 8,399,514 B2

page 4. There came a time in Interference 106,023 when the Board

determined that Patent Owner was not entitled to claim benefit of its
Provisional Application filing date of 8 February 2007. Interference
106,023, Paper 171. Subsequent to the Boards determination, Biogen was
authorized to file a motion to revive its abandoned application 12/526,296
for the purpose of entry of an amendment to make a specific reference to its
Provisional Application. Interference 106,023, Paper 197. The motion to
revive was timely filed. Interference 106,023, Paper 122. Upon
consideration of the motion to revive, the Board ordered that application
12/526,296 be revived and further ordered that an amendment making a
specific reference to Biogens Provisional Application be entered.
Interference 106,023, Paper 611. In ordering revival and entry of the
amendment, the Board did not determine on the merits whether Biogen is
entitled to the benefit of its Provisional Application 60/888,921 under
35 U.S.C. 119(e)(1)in other words, the Board did not determine in
Interference 106,023 whether the invention claimed in the 514 patent is
disclosed in the Provisional Application in the manner required by the first
paragraph of 35 U.S.C. 112.
The prior art date of Kappos 2006 is May of 2006. As noted earlier in
this opinion, Kappos 2006 is prior art under 35 U.S.C. 102(b) if Biogen is
not entitled to benefit of the 7 February 2007 filing date of its Provisional
Application. Kappos 2006 is prior art under 35 U.S.C. 102(a) if Biogen is
entitled to benefit of the 8 February 2007 filing date of its Provisional
Applicationless than one year after May of 2006.

IPR2015-01993
Patent 8,399,514 B2

In its Preliminary Response, Patent Owner does not assert that it is

entitled to benefit of its Provisional Application.
At this stage, Kappos 2006 will be treated as prior art under 35 U.S.C.
102(b), without prejudice to Patent Owner establishing its right to a benefit
date as of the filing date of its Provisional Application. The mere fact that
Petitioner has not challenged the sufficiency of the PCT application does not
establish that Patent Owner is entitled to benefit of its Provisional
Application. There was no need for Petitioner to challenge benefit of the
PCT because Kappos 2006 is prior art under 35 U.S.C. 102(b) as to the
PCT application.
Should Patent Owner elect to seek benefit of its Provisional
Application, it is noted that the written description portion of the
Specification of the 514 patent contains the following:
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.
Ex. 1001, page 24, col. 18:5864 (italics added).
Atofina v. Great Lakes Chemical Corp., 441 F.3d 991, 1000 (Fed. Cir.
2006), states that a disclosure of a range of 150 to 350 C does not constitute
a specific disclosure of the endpoints of that range, i.e., 150C and 350 C;
the disclosure is only that of a range, not a specific temperature in that range

IPR2015-01993
Patent 8,399,514 B2

and the disclosure of a range is not a disclosure of end points of the range
any more than it is of each of the intermediate points.
Since the description of 480 mg in the 514 patent is an end point, in
the event Patent Owner elects to seek benefit of its Provisional Application,
it should address why benefit should be accorded in light of Atofina.
II. Analysis
A. ChallengeClaims 1, 11, 15, and 20
According to Petitioner, claims 16, 816, and 20 are unpatentable
under 35 U.S.C. 103(a) over a combination of (1) Kappos 2006,
(2) ClinicalTrials, (3) Joshi 999, and (4) ICH Guideline.
B. Claims 1, 11, 15, and 20
The invention can be readily understood by reference to independent
claims 1, 11, 15, and 20, all reproduced below (indentation added; principal
limitation in dispute italicized):
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,

IPR2015-01993
Patent 8,399,514 B2

wherein the therapeutically effective amount of

dimethyl fumarate, monomethyl fumarate, or a
combination thereof is about 480 mg per day.
Ex. 1001, col. 27:5967.
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.
Claim 15
A method of treating a subject in need of treatment
for multiple sclerosis comprising
orally administering to the subject [a] 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.
Claim 20
A method of treating a subject in need of treatment
for multiple sclerosis comprising

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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.
C. Kappos 2006
Kappos 2006 is a 27 page document. Ex. 1003. The only relevant
parts of Kappos 2006 are (1) page 1 of 27 identifying the publication date of
Kappos 2006 and (2) article number O108 in column 2 of page 27 of 27.
The remaining parts of Kappos (1) have not been relied upon by
Petitioner, (2) sua sponte are excluded from evidence, (3) will not be
considered and (4) are not considered to be part of the record before the
Board.
Petitioner is directed to forthwith refile Exhibit 1003 as Exhibit
1003A containing only pages 1 and 27. Upon filing of Exhibit 1003A,
Exhibit 1003 will be expunged.
The relevant description in Kappos 2006 is generally self-explanatory
and reads as follows (some indentation added):
Objective: To determine the efficacy of three dose levels
of BG00012, a novel oral fumarate preparation, on brain
lesion activity as measured by magnetic resonance
imaging (MRI) in patients with relapsing-remitting
multiple sclerosis (RRMS).
Methods: This was a randomised, double-blind,
placebo-controlled clinical trial of BG00012 in patients
with RRMS. Men and women 18 to 55 years of age were
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eligible for the study if they had a diagnosis of RRMS

and an Expanded Disability Status Scale (EDSS) score
between 0.0 and 5.0. In addition, patients must have had
either 1 relapse within 12 months prior to
randomisation or gadolinium-enhancing (Gd+) lesions on
cranial MRI at screening. Patients were assigned to four
treatment groups and received BG00012 capsules 120 mg
by mouth (PO)
[1] once daily (120 mg/day),
[2] 120 mg three times daily (360 mg/day),
[3] 240 mg three times daily (720 mg/day), or
[4] placebo for 24 weeks.
The treatment period was followed by a 24-week
dose-blinded safety-extension period during which all
patients received BG00012. The primary end point was
the total number of Gd+ lesions over four MRI scans at
weeks 12, 16, 20, and 24 (calculated as the sum of the
four scans).
Secondary end points included the
cumulative number of new Gd+ lesions from week 4 to
week 24 and the number of new/enlarging
T2-hyperintense lesions at week 24. Additional end
points included the number of new T1-hypointense
lesions at week 24, relapse rate, and disability
progression as measured by EDSS.
Results: A total of 257 patients were enrolled in
the study; 64 patients each were randomly assigned to
receive one of the three BG00012 doses and 65 patients
to placebo. Approximately 90% of patients completed
the 24-week treatment period. BG00012 (720 mg/day)
significantly reduced the mean number of new Gd+
lesions (the primary end point) compared with placebo.
In addition, BG00012 reduced the cumulative number of
new Gd+ lesions, the number of new/enlarging
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Patent 8,399,514 B2

T2-hyperintense lesions, and the number of new

T1-hypointense lesions compared with placebo.
Conclusion: BG00012 significantly reduces brain
lesion activity, in a dose-dependent manner, as measured
by MRI in patients with RRMS over 24 weeks of
treatment.
This study was sponsored by Biogen Idec and
Fumapharm AG.
Ex. 1003, page 27, col. 2.
BG00012 and BG12 are designations for dimethyl
fumarate (also referred to the record as DMF). See Linberg
Testimony, Ex. 1005, 23, last three lines referring to Ex. 1002,
page 1 and Ex. 1022, page 1.
Kappos 2006 differs from the subject matter of claims 1, 11, 15,
and 20 of the 514 patent in that Kappos 2006 does not explicitly
describe the use of a therapeutically effective amount of dimethyl
fumarate that is about 480 mg per day.
D. Joshi 999
Joshi 999 (Ex. 1030) relates to the use of dialkyl fumarates,
including dimethyl fumarate (col. 6:1617 and 60; col. 8:19), for preparing
pharmaceutical preparations for use in transplantation medicine or the
therapy of autoimmune diseases, including multiple sclerosis (col. 1:29;
col. 4:45; and col. 8:15), and pharmaceutical preparations in the form of
micro-tablets or micro-pellets containing dialkyl fumarates.
Joshi 999 claim 1 reads [indentation added]:
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Patent 8,399,514 B2

A method of treating multiple sclerosis comprising

treating a patient in need of treatment for multiple
sclerosis
with an amount of a pharmaceutical preparation
effective for treating said multiple sclerosis,
wherein the only active ingredient for the
treatment of multiple sclerosis present in said
pharmaceutical preparation is dimethyl fumarate.
Ex. 1030, col. 8:1419.
Claim 2 reads:
The method of claim 1, wherein 10 to 300 mg of
dimethyl fumarate is present in said pharmaceutical
preparation.
Ex. 1030, col. 8:2022.
Claim 9 reads:
The method of claim 1, wherein 120 mg of
dimethyl fumarate is present in said pharmaceutical
preparation.
Ex. 1030, col. 8:3839.
Claim 18 reads:
The method of claim 1, wherein the
pharmaceutical preparation comprises one or more
excipients.
Ex. 1030, col. 8:6263.

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According to Joshi 999:
The dialkyl fumarates used according to the
invention may be used alone or as a mixture of several
compounds, optionally in combination with the
customary carriers and excipients. The amounts to be
used are selected in such a manner that the preparations
obtained contain the active ingredient in an amount
corresponding to 10 to 300 mg of fumaric acid.
Preferred preparations according to the invention
contain a total amount of 10 to 300 mg of dimethyl
fumarate and/or diethyl fumarate.
Ex. 1030, col. 4:3948 (italics added).
Joshi 999 differs from the subject matter of claims 1, 11, 15,
and 20 of the 514 patent in that Joshi 999 does not describe the use
of a therapeutically effective amount of dimethyl fumarate that is
about 480 mg per day.
E. ICH Guideline
ICH Guideline (Ex. 1004) describes guidelines for determining
appropriate dosages of pharmaceutical products.
ICH means International Conference on Harmonisation.
According to ICH:
Knowledge of the relationships among dose, drugconcentration in blood, and clinical response
(effectiveness and undesirable effects) is important for
the safe and effective use of drugs in individual patients.
This information can 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

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Patent 8,399,514 B2

would be unlikely to provide added benefit or would

produce unacceptable side effects. . . .
Historically, drugs have often been initially
marketed at what were later recognized as excessive
doses (i.e., doses well onto the plateau of the doseresponse curve for the desired effect), sometimes with
adverse consequences (e.g. hypokalemia and other
metabolic disturbances with thiazide-type diuretics in
hypertension). This situation has been improved by
attempts to find the smallest dose with a discernible
useful effect or a maximum dose beyond which no further
beneficial effects is seen, but practical study designs do
not exist to allow for precise determination of these doses.
Further, expanding knowledge indicates that the concepts
of minimum effective dose and maximum useful dose do
not adequately account for individual differences and do
not allow a comparison, at various doses, of both
beneficial and undesirable effects. Any given dose
provides a mixture of desirable and undesirable effects,
with no single dose necessarily optimal for all patients.
Ex. 1004, page 5 of 14 (italics added).
Further according to ICH:
In adjusting the dose in an individual patient after
observing the response to an initial dose, what would be
most helpful is knowledge of the shape of individual
dose-response curves, which is usually not the same as
the population (group) average dose-response curve.
Study designs that allow estimation of individual doseresponse curves could therefore be useful in guiding
titration, although experience with such designs and their
analysis is very limited.

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In utilizing dose-response information, it is

important to identify, to the extent possible, factors that
lead to differences in pharmacokinetics of drugs among
individuals, including demographic factors (e.g. age,
gender, race), other diseases (e.g. renal or hepatic
failure), diet, concurrent therapies, or individual
characteristics (e.g. weight, body habitus, other drugs,
metabolic differences).
Ex. 1004, page 6 of 14 (italics added).
The choice of the size of an individual dose is often
intertwined with the frequency of dosing. Ex. 1004, page 7 of 14.
ICH teaches that:
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.
Ex. 1004, page 7 of 14; Ex. 1005, 32.
Following up on discussion on page 7 of 15, second paragraph, ICH
further teaches:
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. A formally planned interim
analysis (or other multi-stage design) might detect such a
problem and allow study of the proper dose range.
Ex. 1004, page 10 of 27; Ex. 1005, 32.
Pages 13 of 14 and 14 of 14 describe guidance and advice for
determining dosages.

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F. ClinicalTrials
ClinicalTrials addresses a proposed study of a Double-Blind,
Placebo-Controlled, Dose-Range Study to Determine the Effacacy and
Safety of BG00012 in Subjects with Relapsing-Remitting Multiple
Sclerosis. Ex. 1022, page 1 of 7.
As noted earlier, BG00012 is dimethyl fumarate. Ex. 1022, page 1
of 7; Ex. 1005, 28.
In Part 1 of the study, the described dose ranges to be tested are
essentially the same as the dosages described as having been tested by
Kappos 2006. Ex. 1022, page 2 of 7; Ex. 1003, page 27 of 27; Ex. 1005,
31.
In Part 2, ClinicalTrials notes that [d]ose reduction will be allowed
for subjects who are unable to tolerate investigational drug. Ex. 1022,
page 2 of 7; Ex. 1005, 31.
G. Dr. Steven E. Linberg
Petitioner relies on the direct Declaration testimony of Dr. Steven E.
Linberg. Ex. 1005.
With respect to differences between (1) the subject matter of claim 1
of the 514 patent vis--vis (2) Joshi 999 and Kappos 2006, Dr. Linberg
testifies:
In my opinion, the ICH Guideline E4 would have
instructed a POSITA [person of skill in the art] as
follows: Assessment of dose-response should be an
integral component of drug development with studies
designed to assess dose-response [being] an inherent part
of establishing the safety and effectiveness of the drug.
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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, 7[ of 14]:2732. 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, 10[ of
14]:3941. In my opinion, 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.
Kappos 2006 . . . [does] not disclose doses between 360
mg/day and 720 mg/day. However, in my opinion,
Kappos 2006 . . . disclose[s] that single dosage forms
were readily available in 120 mg units (120 mg by
mouth once daily), making dose ranges of 480 mg daily
and 600 mg daily readily apparent intervals for further
testing. Further, ClinicalTrials . . . indicates that side
effects such as gastrointestinal distress were known and
were enough of a concern, that dosing could be reduced
for subjects who are unable to tolerate investigational
drug (Ex. 1022, page 2). Joshi also discloses unwanted
side effects from the administration of the drug (By
administration of the dialkyl fumarates in the form of
micro-tablets, which is preferred, gastrointestinal
irritations and side effects, which are reduced already
when conventional tablets are administered but is still
observed, may be further reduced vis-a-vis fumaric acid
derivatives and salts. Ex. 1030, col. 5:2933.) Because
side effects are always a concern in drug development, as
they were for DMF, and because doses in multiples of
120 mg were readily available, a POSITA, in my opinion,
would have been motivated to develop a method of
treating a subject in need of treatment for multiple
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sclerosis by administering dimethyl fumarate at about

480 mg per day (as well as 600 mg per day) in order to
identify an appropriate dose of DMF that minimized side
effects. It would have been apparent to a POSITA that
the teaching of Kappos 2006 in view of at least
ClinicalTrials . . . , Joshi, and ICHGuideline E4 would
have enabled just such a development of a method such
as described at alternative dosing levels with a reasonable
expectation of success because the intervals were readily
available for a standard process of drug development.
Ex. 1005, 32.
H. Discussion
1. Case for Likelihood of Obviousness
Consistent with applicable precedent, a claimed range within a range
described by the prior art is typically prima facie obvious. In re Boesch,
617 F.2d 272, 275 (CCPA 1980) (where ranges overlap, a prima facie case
of obviousness is made out). The Federal Circuit has consistently followed
Boesch. See, e.g., In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (a
prima facie case of obviousness typically exists when the ranges of a
claimed composition overlap the ranges disclosed in the prior art); In re
Harris, 409 F.3d 1339, 1341 (Fed. Cir. 2005) (a prima facie case of
obviousness arises when the ranges of a claimed composition are completely
encompassed by the prior art); In re Huang, 100 F.3d 135, 139 (Fed. Cir.
1996) (same).
In the case before us, Patent Owners range of about 480 mg per
day squarely falls within the combined ranges described by Kappos 2006
(720 mg/day on the high end) and Joshi 999 (10 to 300 mg/day on the low
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end, it being noted that Joshi 999 claim 1 calls for a broader amount of a
pharmaceutical preparation effective for treating . . . multiple
sclerosis . . . .). The combined effective ranges described by Kappos
2006 and Joshi 999 are consistent with Patent Owners statement in its
Specification that an effective dose of DMF or MMR . . . can be from about
0.1 to 1 g [1000 mg] per [d]ay. Ex. 1001, page 24, col. 18:5960.
The ICH Guideline provides convincing evidence of how a person of
ordinary skill in the art likely would go about determining an appropriate
dosage for a particular person having multiple sclerosis.
For example, if a dose is too high for a particular individual, one
skilled in the art likely would have tested lower dosages for that individual
in an attempt to find a most appropriate dose to achieve a result, all the while
minimizing side-effects.
Petitioner has made out a sufficient case to establish a reasonable
likelihood of success as to each of the independent claims.
2. Preliminary Response
The Preliminary Response asserts numerous reasons why an
inter partes review should not be instituted.
(a) Non-merits Arguments
In determining whether to institute an inter partes review, the
Director may take into account whether, and reject the petition . . . because,
the same or substantially the same prior art or arguments previously were
presented to the Office. 35 U.S.C. 325(d).

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According to Patent Owner, the prior art and arguments here are
the same as those made in IPR2015-01136 involving the same parties.
Paper 11, pages 514. An inter partes review was not instituted in
IPR2015-01136. Coalition for Affordable Drugs V LLC v. Biogen MA Inc.,
IPR2015-01136, 2015 WL 5169256 (PTAB Sept. 2, 2015), rehg denied,
IPR2015-01136 (Paper 29) (PTAB Oct. 23, 2015).
In IPR2015-01136, Petitioner did not cite or rely on (1) the two Joshi
patents relied upon in this IPR or (2) Kappos 2006.
Kappos 2006 has a highly relevant and significant teaching not
present in Kappos 2005 (Ex. 1003A of IPR2015-01136). Compare the
(1) Results in Kappos 2006, which states that BG00012 at 720 mg/day
significantly reduced Gd+ lesions, with (2) the Results in Kappos 2005
detailing only what a paper based on tests might reveal.
We have taken into account the differences in prior art cited and relied
upon in IPR2015-01136 vis--vis the different prior art cited and relied upon
in this IPR. In view of those differences, and because we find the prior art
cited and relied upon in this IPR to be considerably more persuasive, we see
no reason for not instituting an inter partes review in this IPR.
In support of its position, Patent Owner cites numerous decisions in
other IPRs. Whether an inter partes review is instituted in a particular IPR
based on alleged obviousness manifestly depends on the precise facts.
Cf. In re Jones, 958 F.2d 347, 350 (Fed. Cir. 1992). Accordingly, institution
or non-institution decisions in other IPRs based on different facts are of little
help in resolving whether to institute in the IPR before us.

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According to Patent Owner, [t]he Boards practice is to prevent
petitioners from using failed institution attempts as how-to guide(s) in
preparing later challenges. Paper 11, page 15. We are unaware of any
established per se rule of this Board declining to institute based on so-called
how-to guide(s). While it may be true that some cases determined that it
was inappropriate to institute based on a second petition, 325(d) gives the
Director discretion to consider the merits of a second petition, apart from
any refusal to institute on the basis of a first petition. As noted earlier,
because the prior art here is significantly different from that in IPR201501136, we find that it is appropriate to institute an inter partes review in this
proceeding.
We have considered all the remaining non-merits arguments presented
by Patent Owner, but find them unpersuasive on the issue of whether an
inter parties review should be ordered in this IPR.
(b) Merits Arguments
According to Patent Owner, one skilled in the art would have had no
reason to select a dose of 480 mg/day. Paper 11, page 20.
Further according to Patent Owner, the [P]etition presents no
evidence that one of ordinary skill based on the asserted prior art, would
have had a reasonable expectation that a dose of about 480 mg/day of DMF
would [have been] therapeutically effective or useful in treating MS as
claimed. Id. See also Paper 11, page 25.
Still further according to Patent Owner, one of ordinary skill would
not have been motivated to add a dose of about 480 mg/day to an already

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Patent 8,399,514 B2
well-designed [Kappos 2006] Phase II study. Paper 11, page 21, last
sentence.
Patent Owner also maintains that gastrointestinal side-effects would
have provided no reason to select a dose of 480 mg/day. Paper 11, page 22.
KSR International Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007)
instructs:
Often, it will be necessary . . . to look to interrelated
teachings of multiple patents; the effects of demands
known to the design community or present in the
marketplace; and the background knowledge possessed
by a person having ordinary skill in the art, all in order to
determine whether there was an apparent reason to
combine the known elements in the fashion claimed by
the patent at issue. To facilitate review, this analysis
should be made explicit. See In re Kahn, 441, F.3d 977,
988 (C.A.Fed.2006) ([R]ejections on obviousness
grounds cannot be sustained by mere conclusory
statements; instead, there must be some articulated
reasoning with some rational underpinning to support the
legal conclusion of obviousness). As . . . [Supreme
Court] precedents make clear, however, the analysis need
not seek out precise teachings directed to the specific
subject matter of the challenged claim, for a court can
take account of the inferences and creative steps that a
person of ordinary skill in the art would employ.
In re OFarrell, 853 F.2d 894, 90304 (Fed. Cir. 1988), further
instructs that obviousness does not require absolute predictability of
success; all that is required is a reasonable expectation of success.
Patent Owners selection argument does not undermine a reasonable
likelihood of success on the part of Petitioner. Petitioner has not made any
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Patent 8,399,514 B2

selection; rather, it is Patent Owner who selected 480 mg/day from broad
dosage ranges described in the prior art. Based on the public domain prior
art before us, absent an unexpected result, a person having ordinary skill in
the art was free to use any dosage that would be effective in treating multiple
sclerosis. Further, based on ICH, we find that one skilled in the art would
have been capable of determining effective dosages vis--vis non-effective
dosages.
Joshi 999 teaches that a dosage of range of 10 to 300 mg/day is
effective. See, e.g., claim 2 of the Joshi 999 patent. Ex. 1030, page 7,
col. 8:2022. Kappos 2006 teaches that a dosage of 720 mg/day is effective.
Not apparent is why dosages between 300 mg/day and 720 mg/day
reasonably would not also have been expected to be effective, a fact Patent
Owner is in somewhat of a poor position to challenge given its assertion in
the 514 patent that dosages from 0.1 g/day to 1000 g/day constitute an
effective dosage. ClinicalTrials reveals that one skilled in the art would
have recognized that a [d]ose reduction will be allowed for subjects who
are unable to tolerate [an] investigational drug. Ex. 1022, page 2. Hence,
on this record there was ample reason for one skilled in the art to have
looked into dosages below 720 mg/day.
(c) Unexpected Results
Patent Owner argues that Petitioner did not attempt to rebut the
claimed inventions unexpected results established during prosecution.
Paper 11, page 30. The unexpected results are said to have been established

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Patent 8,399,514 B2

via ex parte Rule 132 Declarations of Dr. Katherine Dawson (Ex. 1 of

Ex. 1007) and Dr. Richard Rudick (Ex. 2011). Id. at 31.
We disagree that Petitioner made no attempt to rebut the ex parte
evidence asserting unexpected results. Paper 1, pages 1114.
Apart from the fact that there was a rebuttal in the Petition, there are
at least two additional reasons why Patent Owners fail to rebut argument
is not persuasive.
First, the unexpected results evidence was presented in an ex parte
examination. The results of that examination are not binding on Petitioner.
See Keystone Bridge Co. v. Phoenix Iron Co., 95 U.S. 274, 279 (1877)
(patents are procured ex parte; the public is not bound by decision of the
Patent Office to issue the patent); Sze v. Bloch, 458 F.2d 137, 140 (CCPA
1972) (decision during ex parte examination cannot be binding in
subsequent inter partes case involving same application in which decision
was made); Switzer v. Sockman, 333 F.2d 935, 7678 (CCPA 1964) (same).
Second, Petitioner has not had a chance to cross-examine Dr. Dawson
or Dr. Rudick. Whether unexpected results have been established is a
question of fact. In re Harris, 409 F.3d 1339, 1341 (Fed. Cir. 2005)
(whether an invention produces an unexpected result is a question of fact);
In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (same). At this stage of
the proceeding, resolution of whether the Dawson/Rudick showing
establishes unexpected results is a disputed question of fact, best resolved at
trialwhich could include cross-examination if Patent Owner places the
Dawson/Rudick testimony in evidence as part of its opposition on the merits.

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Patent 8,399,514 B2

Because the Petition establishes a prima facie case of obviousness, it

follows that Petitioner has made out a case that there is a reasonable
likelihood that . . . [it] would prevail with respect to . . . claims [1, 11, 15,
and 20] challenged in the petition. 35 U.S.C. 314(a).
I. Remaining Claims and Challenges
Patent Owner does not separately address on the merits Grounds 2
and 3 or dependent claims involved in Ground 1.
We have considered the arguments made in, and evidence presented
with, the Petition and find, for the reasons given, that those arguments and
evidence support a finding that Petitioner has made out a case that there is a
reasonable likelihood that . . . [it] would prevail with respect to . . . [the
remaining] claims [on Grounds 1, 2, and 3 as] challenged in the petition.
35 U.S.C. 314(a).
III. ORDER
Upon consideration of the Petition (Paper 1), the Preliminary
Response (Paper 11), and Reply to the Preliminary Response (Paper 17), and
for the reasons given, it is
ORDERED that pursuant to 35 U.S.C. 314(a), an inter partes
review trial is hereby instituted on the following grounds.
Ground 1: claims 16, 816, and 20 of the 514 patent as
unpatentable under 103(a) over Kappos 2006, ClinicalTrials, Joshi 999,
and ICH Guideline.

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Patent 8,399,514 B2
Ground 2: claim 7 of the 514 patent as unpatentable under
103(a) over Kappos 2006, ClinicalTrials, Joshi 999, ICH Guideline, and
Joshi 992.
Ground 3: claims 1719 of the 514 patent as unpatentable
under 103(a) over Kappos 2006, ClinicalTrials, Joshi 999, ICH Guideline,
and Begleiter.
FURTHER ORDERED that inter partes review of the 514
patent is hereby instituted commencing on the date of this DECISION.
35 U.S.C. 314(a).
FURTHER ORDERED that notice is hereby given of the
institution of an inter partes review trial. 35 U.S.C. 314(c); 37 C.F.R.
42.4.
FURTHER ORDERED that the trial is limited to the grounds
and claims identified above.

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Patent 8,399,514 B2

PETITIONER:
Robert W. Hahl
Robert Mihail
John K. Pike
NEIFELD IP LAW
rhahl@neifeld.com
rmihail@neifeld.com
jkpike@neifeld.com
general@neifeld.com
James T. Carmichael
Carmichael IP, PLLC
jim@carmichaelip.com
PATENT OWNER:
Michael Flibbert
Maureen D. Queler
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP
michael.flibbert@finnegan.com
maureen.queler@finnegan.com

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