Kyle Bass, Biogen IPR Petition, Patent '514

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

iv

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 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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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 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.

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.

1

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

3

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.

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

7

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.,

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

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

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

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

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

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.

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

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

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)).

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

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

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

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,

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


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


administrations of 3 equal doses. Kappos 2005 discloses a dose-ranging study in



times daily (720 mg/day), or placebo. Ex. 1003, pII/148, P574, 1:28-2:3.

ClinicalTrials NCT00168701 also discloses a dose-ranging study of BG00012 with

the same dosing. Dr. Linberg attests that both of these studies disclose using three

equal doses, and if the desired dose is 480 mg a POSITA would have known how

to provide equal doses of appropriate strength. In sum, it was obvious to a POSITA

to administer 480 mg/day of DMF in separate administrations of three equal doses.

Ex. 1005, 44.

Thus claim 5 is obvious over Kappos 2005 or ClinicalTrials NCT00168701

or admitted prior art, in view of ICH Guideline E4.

Claim 6: The method of claim 1, wherein the pharmaceutical composition consists essentially of dimethyl fumarate and one or more pharmaceutically acceptable excipients.


further requires, the pharmaceutical composition consists essentially of dimethyl

fumarate and one or more pharmaceutically acceptable excipients. Kappos 2005

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


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


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


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


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


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







Ex. 1004, p6:39-41. The ICH Guideline E4 instructed a POSITA to perform dosing




34





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








35






p1:7-10. In sum, a POSITA would have been motivated to conduct routine

experiments at a range of doses, including 480 mg/day, by orally administering

that dose and a 600 mg/day dosage strength to subjects in need of treatment for

MS. Ex. 1005, 62, 63. Therefore claim 11 of the 514 patent is obvious over

Kappos 2005 or ClinicalTrials NCT00168701 or admitted prior art, in view of ICH

Guideline E4.

Claim 12: The method of claim 11, wherein about 480 mg of dimethyl fumarate per day is administered to the subject.


further requires, wherein about 480 mg of dimethyl fumarate per day is

administered to the subject. As shown with regard to claim 11, it would have been

obvious to conduct routine experiments to determine the dose-response of DMF,

and thereby reveal that 480 mg per day is a therapeutically effective amount. Ex.

1005, 64. In sum, claim 12 of the 514 patent would have been obvious over

Kappos 2005 or ClinicalTrials NCT00168701 or admitted prior art, in view of ICH

Guideline E4.

36

Claim 13: The method of claim 12, wherein the dimethyl fumarate is administered in separate administrations of 2 equal doses.


further requires, wherein the dimethyl fumarate is administered in separate

administrations of 2 equal doses. As shown with regard to claim 4, it would have

been obvious to administer 480 mg/day DMF in separate administrations of 2

equal doses. Ex. 1005, 66. Thus, claim 13 is obvious over Kappos 2005 or


Claim 14: The method of claim 12, wherein the dimethyl fumarate is administered in separate administrations of 3 equal doses.


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


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






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







Ex. 1004, p6:39-41 The ICH Guideline E4 instructed a POSITA to perform dosing








Kappos 2005 teaches BG00012, which is a composition containing DMF as

the sole active agent (patients randomized to receive BG00012 120 mg PO once

40


times daily (720 mg/day)). Ex. 1003, pII/148, P574, 2:1-3. Dr. Linberg attests, a

POSITA would have designed additional dose-ranging studies using doses between

240 mg and 600 mg in multiples of 120 mg or 240 mg, as disclosed by Kappos

2005. Dr. Linberg explains that a POSITA would have had reason to modify the













p1:7-10. Ex. 1005, 74.

The third element of claim 15 requires, (b) one or more pharmaceutically

acceptable excipients. DMF is poorly tolerated by patients (Ex. 1019, p35, 2:6-

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


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


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)).


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


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.


further requires, wherein the expression level of NQOl in the subject is elevated

after administering to the subject about 480 mg per day of dimethyl fumarate,

monomethyl fumarate, or a combination thereof. The motivation to administer

480 mg/day is shown above with respect to claim 11 and the increase of expression

levels of NQO1 are shown as inherent for the same reasons as set forth above in

claim 17. An elevated expression of NQO1 is an inherent property of

administering 480 mg/day of DMF to the subject and the expression level of

NQO1 is necessarily elevated as a result of administering 480 mg/day DMF to the

subject. Ex. 1005, 87, 88.

In sum, it would have been obvious for a POSITA to combine the teachings

of Kappos2005 or ClinicalTrials NCT00168701 or admitted prior art in the 514




elevated after administering to the subject said pharmaceutical composition Ex.

1005, 89. Therefore, claim 18 is obvious over Kappos 2005 or ClinicalTrials


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.


further requires, wherein the expression level of NQO1 in the subject is elevated

after administering to the subject the therapeutically effective amount of dimethyl

fumarate. Dr. Linberg attests that an elevated expression of NQO1 is an

inherent property of administering 480 mg/day of DMF to the subject and that

the expression level of NQO1 is necessarily elevated as a result of administering

480 mg/day DMF to the subject for the same reasons as set forth above in claim

17. In sum, it would have been obvious for a POSITA to combine the teachings of

Kappos2005 or ClinicalTrials NCT00168701 or admitted prior art in the 514




elevated after administering to the subject said pharmaceutical composition Ex.

1005, 90, 91. Therefore, claim 19 is obvious over Kappos 2005 or ClinicalTrials


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.






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



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.

Kyle Bass, Biogen IPR Petition, Patent '514

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