Bass Biogen

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 IDEC International GmbH Patent Owner

____________

Case IPR Unassigned Patent 8,759,393

Title: UTILIZATION OF DIALKYLFUMARATES

____________

PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,759,393

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

i

TABLE OF CONTENTS

I. INTRODUCTION ............................................................................................. 1

II. MANDATORY NOTICES ............................................................................ 2

A. Real Party-In-Interest 37 C.F.R. 42.8(b)(1) ............................................... 2

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)) ............................... 4

III. FEES 37 C.F.R. 42.15(a) ............................................................................. 4

IV. REQUIREMENTS UNDER 37 C.F.R. 42.104 .......................................... 4

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

B. Identification of Challenge and Precise Relief Requested 37 C.F.R.

42.104(b) ................................................................................................................. 4

2. Specific Statutory Grounds for Challenge 42.104(b)(2) .................................. 5

V. UNPATENTABILITY OF THE 393 PATENT ......................................... 6

A. Brief History of dimethyl fumarate therapy .................................................. 6

B. Prosecution History of the 393 Patent ......................................................... 8

C. Person of Ordinary Skill in the Art ............................................................. 10

ii

D. Claim Construction ...................................................................................... 11

VI. DETAILED EXPLANATION OF THE CHALLENGES ........................ 22

A. Ground 1: Claims 1, 2, and 8 are anticipated by Nieboer ........................... 22

B. Ground 2: Claims 1-13 are obvious over Nieboer in view of Kolter .......... 26

VII. CONCLUSION .......................................................................................... 52

iii

TABLE OF AUTHORITIES Cases

In re Cuozzo Speed Technologies, LLC, 2014-1301 (Fed. Cir. 2015) ..................... 18

KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007) ........................... 31, 32

Titaniium Metals Corp. v. Banner, 778 F.2d 775 (Fed. Cir. 1985) ...... 38, 40, 48, 57

Verdegaal Bros. v. Union Oil Co. of California, 814 F.2d 628 (Fed. Cir. 1987) .... 21

Statutes

35 U.S.C. 102 ............................................................................................... 5, 6, 23

35 U.S.C. 103 ................................................................................................... 6, 26

Rules

37 C.F.R. 42.82, 3, 8

37 C.F.R. 42.15..4

37 C.F.R. 42.22..6

37 C.F.R. 42.100..11

37 C.F.R. 42.104....4, 5

iv

LIST OF EXHIBITS

Exhibit 1001 U.S. Patent No. 8,759,393, titled Utilization of

Dialkylfumarates to Joshi et al. (393 patent)

Exhibit 1002 C. Nieboer, et al., Systemic therapy with fumaric acid

derivatives: New possibilities in the treatment of psoriasis,

Journal of the American Academy of Dermatology, April 1989

Vol. 20, Number 4, pg. 601-608 (Nieboer)

Exhibit 1003 U.S. Patent No. 5,681,588, titled Delayed Release Microtablet

of -Phenylpropiophenone Derivatives to Kolter et al. (Kolter) Exhibit 1004 Declaration of Dr. James E. Polli

Exhibit 1005 Prosecution history of the 393 patent as contained in the Image

File Wrapper on PAIR

Exhibit 1006 Assignment record of the 393 patent as contained in USPTOs

Assignments on The Web at

http://assignment.uspto.gov/#/search?adv=patNum%3A875939

3&q=&sort=patAssignorEarliestExDate%20desc%2C%20id%2

0desc&synonyms=false

Exhibit 1007 Julian H. Fincher, Dictionary of Pharmacy, University of South

Carolina Press, 1986

v

Exhibit 1008 PubChem entry for Dimethyl Fumarate, U.S. National Library

of Medicine, National Center for Biotechnology Information,

the National Institute of Health at

https://pubchem.ncbi.nlm.nih.gov/compound/637568

Exhibit 1009 Dean E. Snyder, The Interpharm International Dictionary of

Biotechnology and Pharmaceutical Manufacturing, Interpharm

Press, Inc., 1992

Exhibit 1010 Friedrick Moll et al., Biodegradable Microtablets Made of Low

Molecular Weight Polyglycolic Acid, 1991

Exhibit 1011 Unassigned

Exhibit 1012 Curriculum Vitae of Dr. James E. Polli

Exhibit 1013 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 1014 Kokelj et al., Fumaric Acid and Its Derivatives in the Treatment

of Psoriasis Vulgaris: Our Experience in Forty-One Patients,

Acta Dermatovenerol Croat, 2009; 17(3):170-175

Exhibit 1015 FDA News Release, FDA approves new multiple sclerosis

treatment: Tecfidera, available at

vi

http://www.fda.gov/NewsEvents/Newsroom/PressAnnounceme

nts/ucm345528.htm

Exhibit 1016 Follonier et al., Various ways of modulating the release of

diltiazem hydrochloride from hot-melt extruded sustained

release pellets prepared using polymeric materials., Journal of

Controlled Release 36 (1995) 243-250

Exhibit 1017 Conine et al., Special Tablets, Pharmaceutical Dosage Forms,

Marcel Dekker, Inc., 1989, 329-366

1

I. INTRODUCTION The 393 patent, entitled Utilization of Dialkylfumarates and filed on

March 4, 2011 is a continuation of application no. 12/405,665 (now US 7,915,310)

filed on March 17, 2009, which is a continuation of application no. 11/765,578

(now US 7,619,001) filed on June 20, 2007, which is a continuation of application

no. 10/197,077 (now US 7,320,999) filed on July 17, 2002 which is a division of

application no. 09/831,620 (now US 6,509,376) filed on May 10, 2001 which is the

National Stage Entry of PCT/EP99/08215 filed on October 29, 1999 and published

in German on June 2, 2000, which claims priority to German application no.

19853487 filed on November 19, 1998. (Ex. 1005). The 393 patent was originally

assigned to Fumapharm AG. Fumapharm AG was acquired by Biogen IDEC

International AG in 2006 and the 393 patent was assigned to Biogen IDEC

International AG on May 15, 2007. (Ex. 1006). Biogen IDEC International AG

changed its name to Biogen IDEC International GMBH on May 15, 2007. (Ex.

1006).

In accordance with 35 U.S.C. 311-319 and 37 C.F.R. 42.1-.80 &

42.100-123, inter partes review is respectfully requested for claims 1-13 of U.S.

Patent No. 8,759,393 to Joshi et al., titled Utilization of Dialkylfumarates (393

patent) (Ex. 1001). This petition demonstrates that there is a reasonable likelihood

that the petitioner will prevail on at least one of the claims challenged in the

2

petition based on one or more prior art references. For the reasons provided herein,

claims 1-13 of the 393 patent should be canceled as unpatentable.

II. MANDATORY NOTICES

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

Pursuant to 37 C.F.R. 42.8(b)(1), Petitioner certifies that Coalition For

Affordable Drugs V LLC (CFAD), Hayman Credes Master Fund, L.P.

(Credes), Hayman Orange Fund SPC Portfolio A (HOF), Hayman Capital

Master Fund, L.P. (HCMF), Hayman Capital Management, L.P. (HCM),

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

(HI), nXn Partners, LLC (nXnP), IP Navigation Group, LLC (IPNav), J

Kyle Bass, and Erich Spangenberg are the real parties in interest (collectively,

RPI). The RPI hereby certify the following information: CFAD is a wholly

owned subsidiary of Credes. Credes is a limited partnership. HOF is a segregated

portfolio company. HCMF is a limited partnership. HCM is the general partner

and investment manager of Credes and HCMF. HCM is the investment manager of

HOF. HOM is the administrative general partner of Credes and HCMF. HI is the

general partner of HCM. J Kyle Bass is the sole member of HI and sole

shareholder of HOM. CFAD, Credes, HOF and HCMF act, directly or indirectly,

through HCM as the general partner and/or investment manager of Credes, HOF

and HCMF. nXnP is a paid consultant to HCM. Erich Spangenberg is 98.5%

3

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

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) To the best of Petitioners knowledge, there are no pending litigations or

other related matters related to the 393 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).

4

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) Petitioner authorizes the Director to charge the fee specified by 37 C.F.R.

42.15(a) and any additional fees associated with this Petition to Deposit Account

No. 50-2106.

IV. REQUIREMENTS UNDER 37 C.F.R. 42.104 A. Grounds for Standing 37 C.F.R. 42.104(a)

In accordance with 37 C.F.R. 42.104(a), Petitioner certifies that the

393 patent is available for inter partes review. Petitioner further certifies that

Petitioner is not barred or estopped from requesting an inter partes review

challenging the 393 patent on the grounds identified in this Petition.

B. Identification of Challenge and Precise Relief Requested 37 C.F.R.

42.104(b)

5

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

Petitioner relies on the following patents and printed publications to support

its grounds of challenge to claims 1-13 of the 393 patent in this Petition:

1. Nieboer, D. de Hoop, A.C. van Loenen, P.N.J. Langendijk, and E. van Dijk,

Systemic therapy with fumaric acid derivatives: New possibilities in the

treatment of psoriasis, Journal of the American Academy of Dermatology,

April 1989 (Nieboer). Ex. 1002. Nieboer is a printed publication at least under

35 U.S.C. 102(b) (pre-AIA) because it was published, catalogued, and

shelved at least as early as April 3, 1989, as can be seen on the University of

Wisconsin library intake stamp, more than one year prior to November 19,

1998, the earliest effective filing date for the claims of the 393 patent.

2. U.S. Patent No. 5,681,588, titled Delayed Release Microtablet of -Phenylpropiophenone Derivatives to Kolter et al. (Kolter). Ex. 1003. Kolter is

a patent at least under 35 U.S.C. 102(b) (pre-AIA) because it was published

more than one year prior to November 19, 1998, the earliest effective filing date

for the claims of the 393 patent.

2. Specific Statutory Grounds for Challenge 42.104(b)(2) Petitioner challenges claims 1-13 (the challenged claims) of the 393 patent

on the following grounds:

6

Ground 1: Claims 1, 2, and 8 are unpatentable under 35 U.S.C. 102(b) as

anticipated by Nieboer.

Ground 2: Claims 1-13 are unpatentable under 35 U.S.C. 103 as obvious

over Nieboer in view of Kolter.

None of these grounds is redundant. Challenged claims 1, 2, and 8 are

challenged in Ground 1 by a single reference and in Ground 2 by a combination of

references.

This Petition, supported by the Declaration of Dr. James Polli (Ex 1004)

filed with this Petition, demonstrates that there is a reasonable likelihood that

Petitioner will prevail with respect to at least one of the challenged claims and that

each of the challenged claims is unpatentable for the reasons cited in this Petition.

See 35 U.S.C. 314(a).

In accordance with 37 C.F.R. 42.22, Petitioner respectfully requests

cancellation of claims 1-13 of the 393 patent.

V. UNPATENTABILITY OF THE 393 PATENT A. Brief History of dimethyl fumarate therapy

Since at least 1969, fumaric acid was reported to have been a popular

treatment for psoriasis. Ex. 1002, Abstract. In 1966, Schweckendiek, a biochemist

who himself had psoriasis, introduced fumaric acid esters such as

monoethylfumaric ester (MEFAE) and dimethylfumaric ester (DMFAE) as a

7

treatment because fumaric acid was poorly absorbed by the gastrointestinal tract.

Ex. 1002, p601, 2:2-7. Fumaderm, a closely related product to the claimed

invention, comprises a combination of dimethyl fumarate1 with other fumaric acid

esters and was approved in Germany in 1994 for the treatment of psoriasis. See

Ex. 1014, Summary and p173, 2:12-16. However, several years prior to the

approval of Fumaderm, dimethyl fumarate monotherapies were being conducted.

Nieboer et al. found dimethyl fumarate given as enteric coated (EC) tablets given

orally were effective for treating psoriasis (Ex. 1013, Abstract and p34, 1:1-9,

narrative following Table I), concluding that [i]n summary one could state that the

treatment of psoriasis with FAC-EC (fumaric acid combination enteric coated)

does not result in a better therapeutic result compared to DMFAE-EC

(dimethylyfumaric acid ester enteric coated) monotherapy. Ex. 1013, p37, 1:1-3.

In March of 2013, the FDA approved the use of dimethyl fumarate monotherapy

for the treatment of multiple sclerosis in the United States. Ex. 1015, p1.

1 As Dr. Polli attests and as supported by Ex. 1008, dimethyl fumarate may be

referred to by any of several common, interchangeable names including dimethyl

fumaric acid; DMF; fumaric acid dimethyl ester; dimethylfumaric acid ester;

DMFAE; as well as the IUPAC designation of dimethyl (E)-but-2-enedioate. Ex.

1004, 20.

8

B. Prosecution History of the 393 Patent

The 393 patent was filed on March 4, 2011 and claims priority to German

application no. 19853487 filed on November 19, 1998. The prosecution history

shows that applicant used the terms tablets, micro-tablets, pellets, and

granulates without patentable distinction. Initially submitted claims 6 and 16

refer to the active ingredient being formulated in the form of tablets, micro-

tablets, pellets or granulates, optionally in capsules or sachets and tablets, micro-

tablets, pellets in capsules or sachets, respectively. Ex. 1005, p 585-86. On July

22, 2011, Applicant submitted a preliminary amendment cancelling all the claims

and submitting 13 new claims. Ex. 1005, pp542-43. The new claims recite only

the term micro-tablets.

On November 26, 2012, an Office Action was issued rejecting the newly

added claims on four separate grounds of nonstatutory obviousness-type double

patenting over certain claims of U.S. Patent No. 6,277,882 (microtablets

comprising one alkyl hydrogen fumarate and optionally in admixture with dialkyl

fumarate) to Joshi et al. and assigned to Fumapharm AG; U.S. Patent No.

6,335,676 [sic] (microtablets comprising one alkyl hydrogen fumarate and

9

optionally in admixture with dialkyl fumarate)2, U.S. Patent No. 6,509,376

(microtablets comprising one alkyl hydrogen fumarate and optionally in admixture

with dialkyl fumarate) to Joshi et al. and assigned to Fumapharm AG; and U.S.

Patent No. 7,915,310 (microtablets with dimethyl fumarate as the active ingredient

in dosage ranges from 10mg to 300mg) to Joshi et al. and assigned to Biogen Idec

International GmbH. Ex. 1005, p124-33.

In response to the Office Action of November 26, 2012, Applicant agreed to

submit terminal disclaimers over the 376 and the 310 patents and requested

reconsideration of the grounds for rejection over the 882 and 676 patents. Ex.

1005, p103-10. In the Office Action of April 26, 2013 the rejections over the 376

and the 310 patents were maintained by the USPTO while the rejections over the

882 and the 676 patents were withdrawn in view of the of Applicants previous

response. Ex. 1005, p94-100. On October 16, 2013 terminal disclaimers were

filed over the 376 and the 310 patents. Ex. 1005, p85-86. On February 14, 2014,

2 The patent number is in error because U.S. Patent No. 6,335,676 is entitled

Radio selective call receiver. The correct patent number should be U.S. Patent

No. 6,355,676 as evidenced in Footnote 1 of Applicants Remarks filed on

February 26, 2013 in response to the Office Action issued on November 26, 2012.

Ex. 1005, p106.

10

a notice of allowance was issued and the 393 patent was granted on June 24, 2014.

Ex. 1005, p15-17. The Examiner never entered a substantive rejection against any

of the pending claims nor was any prior art cited against the claims by the

Examiner during prosecution of the 393 patent in any Office Action. Ex. 1005.

The Examiner issued 393 patent claims 1-13 that only claim a

pharmaceutical preparation in the form of microtablets containing the active

pharmaceutical ingredient, dimethyl fumarate. Ex. 1001, 8:21-57. The 393 patent

claims do not claim a method of making the active pharmaceutical ingredient, but

instead only claim the pharmaceutical preparation. The 393 patent claims do not

claim a method of use of the active pharmaceutical. More importantly, the 393

patent claims do not claim to a method of making the preparation, generally, nor to

a method of making microtablets specifically.

C. Person of Ordinary Skill in the Art

The level of skill in the art at the time of the alleged invention may be

derived from a review of the relevant prior art. Petitioner submits an expert

declaration from Dr. Polli, Professor of Pharmaceutical Sciences and Ralph F.

Shangraw/Noxell Endowed Chair in Industrial Pharmacy and Pharmaceutics at the

University Of Maryland School Of Pharmacy. (Ex. 1004) Dr. Polli attests that a

person of ordinary skill in the art (POSITA) at the time of the alleged invention of

the 393 patent would have held a Ph.D. in industrial pharmacy, pharmaceutics or

11

pharmaceutical sciences or a related discipline, or a Pharm D degree; additionally

he or she would have had at least 3 years of experience with pharmaceutical

preparation and formulation of orally administered medicines. Ex. 1004, 11.

D. Claim Construction

The claims in an inter partes review should be accorded the broadest

reasonable construction, as commonly understood by those of ordinary skill in the

art in light of the specification of the patent in which it appears. See 37 C.F.R.

42.100(b). The Federal Circuit has recently affirmed the broadest reasonable

interpretation standard. See In re Cuozzo Speed Technologies, LLC 2014-1301, 16

(Fed. Cir. 2015) (stating We conclude that Congress implicitly adopted the

broadest reasonable interpretation standard in enacting the AIA.). Petitioner

contends that all of the terms in the challenged claims should be given their plain

and ordinary meaning.

Microtablets

The term microtablets or micro-tablets is used throughout the 393

patent, including in:

the abstract of the 393 patent, [t]he present invention relates to the use of

certain dialkyl fumarates for the preparation of pharmaceutical preparationsin

the micro-tablets;

12

certain dialkyl fumarates for preparing pharmaceutical preparationsin the

form of micro-tablets and micro-pellets containing these dialkyl fumarates. Ex.

1001, 3:1-6.

Preparations in the form of micro-tablets or pellets, optionally filled in

capsules or sachets are preferred Ex. 1001, 4:26-28;

According to a preferred embodiment, the size or the mean diameter,

respectively, of the pellets or micro-tablets is in the range from 300 to 2,000 m

Ex. 1001, 4:41-43;

In addition to the preparations for peroral administration in the form of

micro-pellets, micro-tablets, capsules Ex. 1001, 4:54-55;

This means that enteric-coated micro-tablets in the same dosage are

distributed already in the stomach and passed to the intestine in portions Ex. 1001,

5:41-42; and other locations in the 393 patent.

Dr. Polli explains that the claimed term, microtablets, is not defined in the

393 patent. Ex. 1004, 25. Moreover, a POSITA would have understood that the

term, microtablets, does not carry a special meaning in the pharmaceutical arts.

Id. Rather, the broadest reasonable interpretation of the term, microtablets, in

light of the 393 patent specification, is simply any oral solid pharmaceutical

preparation forms small enough to be filled into capsules. Id.

13

Dr. Polli attests that the 393 patent not only does not provide a definition

for the term microtablets, but in fact uses the terms granulates, pellets,

micro-pellets, tablets, and micro-tablets interchangeably and without any

distinction. Ex. 1004, 26. First, the 393 patent does not disclose that the

function of granulates, pellets, micro-pellets, tablets and micro-tablets

differs in any way. The 393 patent discloses that granulates, pellets, micro-

pellets, tablets and micro-tablets are suitable pharmaceutical preparations for

the invention citing Ex. 1001, 4:54-59. Id. The 393 patent states that the object of

the invention is to use certain dialkyl fumarates for preparing pharmaceutical

preparationsin the form of micro-tablets and micro-pellets containing these

dialkyl fumarates. citing Ex. 1001, 3:1-6. Id. The 393 patent also states:

Preferably, the active ingredients are used for preparing oral preparations in the

form of tablets, micro-tablets, pellets or granulates, optionally filled in capsules or

sachets. citing Ex. 1001, 4:25-26. Id. Also, the 393 patent states: In addition

to the preparations for peroral administration in the form of micro-pellets, micro-

tablets, capsules (such as soft and hard gelatin capsules), granulates and tablets

cited above, .Pharmaceutical preparations in the form of micro-tablets or micro-

pellets are preferred for the therapy of all autoimmune diseases mentioned above

citing Ex. 1001, 4:54-65. Id. In sum, Dr. Polli attests that the 393 patent discloses

that granulates, pellets, micro-pellets, tablets and micro-tablets do not

14

differ in function because they are all suitable pharmaceutical preparations for the

invention. Id.

Second, Dr. Polli attests that the 393 patent does not define that

granulates, pellets, micro-pellets, tablets and micro-tablets have any

difference in size. Ex. 1004, 27. The only mention of size in the description

section of the 393 patent is in column 4:41-44. Id. Dr. Polli points out that 393

patent states in column 4:41-44: According to a preferred embodiment, the size or

mean diameter, respectively, of the pellets or micro-tablets is in the range from 300

to 2,000 m . Id. This would have indicated to a POSITA that the pellets

and micro-tablets can have the same size, since they may take any size within the

range of 300 to 2,000m. Id. In Examples 1-4, the 393 patent does not disclose

that granulates, pellets, micro-pellets, tablets and micro-tablets have

any distinction in size. Id. Example 1 is titled, Preparation of Enteric-Coated

Micro-Tablets in Capsules, but refers to the preparation as containing

granulates, tablets and micro-tablets that are enteric coated that are filled

into capsules citing Ex. 1001, 6:3-47. Id. Example 1 of the 393 patent does not

disclose that that there is a difference in size between granulates, micro-tablets, or

tablets. Id. Example 2 is titled, Preparation of Enteric-Coated Micro-Tablets in

Capsules, but refers to the preparation as containing tablets or micro-tablets that

are enteric coated then filled into capsules citing Ex. 1001, 6:48-7:7. Id. Example

15

2 of the 393 patent discloses that the tablets and the enteric coated micro-tablets

that are filled into capsules are 2 mm in diameter, and thereby teaches that the size

of the tablets and micro-tablets are the same citing Ex. 1001, 6:64-7:7. Id.

Example 3 is titled, Preparation of Micro-Pellets in Capsules, but refers to the

preparation as being pellets or micro-pellets that are coated with Kollidon K-30 are

that filled into capsules citing Ex. 1001, 7:8-25. Id. Example 3 of the 393 patent

does not disclose that there is a difference in size between the pellets and micro-

pellets citing Ex. 1001, 6:64-7:7. Id. Example 4 describes granulates filled into

enteric coated capsules citing Ex. 1001, 7:26-53. Id. In Dr. Pollis opinion, a

POSITA would find that Examples 1-4 in the 393 patent show that granulates,

pellets, micro-pellets, tablets and micro-tablets do not differ in size. Id.

Third, Dr. Polli attests that the 393 patent specification uses the terms

granulates, pellets, micro-pellets, tablet and micro-tablet

interchangeably. Ex. 1004, 28. Dr. Polli points out that the 393 patent states:

The present invention relates to the use of dialkyl fumarates for preparing

pharmaceutical preparations for use in transplantation medicine or the therapy of

autoimmune diseases and pharmaceutical preparations in the form of micro-tablets

or micro-pellets containing dialkyl fumarates citing Ex. 1001, 1:15-19. Id. By

this statement, the 393 patent acknowledges that micro-tablets and micro-pellets

are interchangeable terms having the same meaning. Id. The 393 patent

16

Examples 1-4 use the terms granulates, pellets, micro-pellets, tablets and

micro-tablets interchangeably. Id. Example 1 uses the terms micro-tablet and

tablet interchangeably. Id. The title of Example 1 refers to Preparation of

Enteric-Coated Micro-Tablets in Capsules, while the protocol itself uses

granulates, tablets, and micro-tablets interchangeably citing Ex. 1001, 6:3-47. Id.

Example 2 uses the terms tablet and micro-tablet interchangeably. Id. The

title of Example 2 refers to Preparation of Enteric-Coated Micro-Tablets in

Capsules while the protocol itself describes making enteric coated tablets

citing Ex. 1001, 6:48-7:7. Id. Example 3 uses the terms pellets and micro-

pellets interchangeably. Id. The title of Example 3 refers to Preparation of

Micro-Pellets in Capsules..., while the protocol itself uses the word pellets four

times, ending with: After that, the pellets are filled into hard gelatine capsules

(126.5 mg pellets/capsule) citing Ex. 1001, 7:8-25. Id. Example 4 uses the term

granulates filled into a capsule. Id. Example 4 describes making a powder

mixture that is processed into a granulate in the customary manner and filled

into suitable capsules and may also be filled into suitable enteric-coated

capsules citing Ex. 1001, 7:26-53. Id. In Dr. Pollis opinion, a POSITA would

find that the 393 patents usage of the terms granulates, pellets, micro-

pellets, tablets and micro-tablets indicate that these are interchangeable terms

that mean the same thing. Id.

17

Fourth Dr. Polli attests that the 393 patent does not disclose that

granulates, pellets, micro-pellets and micro-tablets have any distinction as

to how they are made. Ex. 1004, 29. Moreover, Dr. Polli attests that the 393

patent does not teach that the micro-tablet has to be made in any particular way.

Id. The 393 patent discloses that the tablets or micro-pellet is made in classical

tableting processes citing Ex. 1001, 5:60-61. Id. Also, Dr. Polli points out that the

393 patents discloses [i]nstead of such classical tableting processes, other

methods for the preparation of tablets may be used, such as direct tableting and

processes for preparing solid dispersions in according with the melt method and

the spray drying method citing Ex. 1001, 5:61-65. Id. Dr. Polli attests that in

Examples 1 and 2, the 393 patent discloses that the tablets are made via

compression citing Ex. 1001, 6:25-64. Id. Dr. Polli attests that in Example 3, the

393 patent discloses that the Micro-Pellets are made via spraying onto

nonpareilles pellets citing Ex. 1001, 7:10-18. Id. Dr. Polli attests that in

Example 4, the 393 patent discloses that granulates are made via wet granulation

citing Ex. 1001, 7:42. Id. Dr. Polli attests that, moreover, a POSITA would have

known that classical tableting making processes for the 393 patent granulates,

pellets, micro-pellets and micro-tablets would not only include compression

and spraying but, also for example, hot-melt extrusion (see Ex 1016), and tablet

molding methods where a wet mortar mix is molded into tablets and then dried

18

(see Ex. 1017, p336-339). Id. In sum, the 393 patent claim term, micro-tablets

does not require a particular tablet making process. Id.

Dr. Polli attests that the 393 patents method of making microtablets is

consistent with prior art tablet making processes. Ex. 1004, 30. For example,

microtablets are well known to be made via wet granulation (such as in 393

patents Example 4) or dry granulation. Id. Spray drying (such as 393 patents

example 3) is a classic method to make microtablets. Id. Microtablets can be

made via compression (such as 393 patents Examples 1 and 2) or via a melt, as

performed by Moll. Ex. 1010, p940. Id. A POSITA would have known that

microtablets can also be manufactured via molding (i.e. to make molded tablets),

as described by Conine et al. (see Ex. 1017, p336-339) or can also be manufactured

via hot-melt extrusion, as performed by Follonier. Ex. 1016. Id.

Fifth, Dr. Polli attests that the 393 patent claims do not recite a distinction

between the terms, granulate, pellets, micro-pellets, tablets and micro-

tablets. Ex. 1004, 31. The 393 patent claims 1-13 only use the term

microtablets. Id.

Independent claims 1 and 8 do not limit the size of the claimed microtablets.

Claim 3, depending on claim 1, recites a mean diameter size in the range of 300

m to 2,000 m exclusive of any coating on the microtablets. Claim 4, ultimately

depending on claim 1, recites the mean diameter of the microtablets is about 2,000

19

m, exclusive of any coating on the microtablets. Claim 9, depending on

independent claim 8, recites microtablets having a core size of mean diameter

about 2,000 m, exclusive of any coating on the microtablets. Thus, based on the

doctrine of claim differentiation, the size of microtablets as recited in claims 1 and

8 is not limited. Because the size of microtablets as recited in claims 1 and 8 is

not limited, Dr. Polli attests that the claim term microtablets encompasses

granulates, pellets, micro-pellets, tablets and micro-tablets even if

arguably there could be a size difference. Id.

Claim 13 likewise recites a mean diameter of the microtablets is about

2,000 m, exclusive of any coating on the microtablets. In Dr. Pollis opinion the

term microtablets does not require any particular size, therefore microtablets in

claim 13 encompasses granulates, pellets, micro-pellets, tablets and

micro-tablets even if arguably there could be a size difference between these

forms. Ex. 1004, 31.1

Independent claims 1 and 8 do not limit the amount of the dimethyl fumarate

in the preparation. Claim 5, ultimately depending on claim 1, recites that the

preparation contains 10 mg to 300 mg of dimethyl fumarate. Claim 10, ultimately

depending on claim 8, recites that the preparation contains 10 mg to 300 mg of

dimethyl fumarate. The amount of dimethyl fumarate as recited in claim 1 and 8

therefore covers any amounts of dimethyl fumarate. Based upon claim

20

differentiation, the term microtablets as recited in claims 1 and 8 does not

require any specific amount of dimethyl fumarate. Dr. Polli attests that the term

microtablets encompasses granulates, pellets, micro-pellets, tablets and

micro-tablets even if arguably there could be a dosing difference between these

forms. Ex. 1004, 31.2.

Claim 13 likewise recites that the preparation contains 10 mg to 300 mg of

dimethyl fumarate. Because claim 13 limits the dosage amount with this additional

limitation, the term microtablets alone in claim 13 does not require any specific

amount of dimethyl fumarate. Dr. Polli attests that because the term

microtablets does not alone limit the claim to any specific amount of dimethyl

fumarate, microtablets encompasses granulates, pellets, micro-pellets,

tablets and micro-tablets even if arguably there could be a dosing difference

between these forms. Ex. 1004, 31.3.

In sum, the 393 patent claim term microtablets, under the broadest

reasonable interpretation in light of the 393 specification, is any oral

pharmaceutical preparation form small enough to be filled into capsules. Dr. Polli

attests that the 393 patent claim term microtablets, under the broadest

reasonable interpretation in light of the 393 specification, is any oral

pharmaceutical preparation form small enough to be filled into capsules. Ex. 1004,

32.

21

Carriers

The term carriers is used throughout the 393 patent, including in:

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. Ex. 1001, 4:32-35; and

13. A pharmaceutical preparation consisting essentially of an active

ingredient and one or more carriers and excipients, Ex. 1001, 8:50-51.

Dr. Polli explains in his declaration that the term carriers is not

specifically defined in the 393 patent. Ex. 1004, 33. However, a POSITA would

have looked at extrinsic evidence such as the Dictionary of Pharmacy for a

definition. Id. The term carriers is defined as [a] vehicle used to transport a

drug to its site of absorption or use. citing Ex. 1007, p4. Id.

Dr. Polli explains that examples of carriers as vehicles for the active

ingredient include capsules and enteric coatings. Ex. 1004, 34. The only mention

of the term carrier apart from Claim 13 appears as [t]he 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

citing Ex. 1001,4:32-35. Id.

In sum, the term carriers, under the broadest reasonable interpretation, are

vehicles used to transport a drug to its site of absorption or use. Ex. 1004, 35.

22

Excipients

The term excipients or excipient is used throughout the 393 patent,

including in:

Then an excipient mixture with the following composition is prepared: Ex.

1001, 6:14-15;

Then an excipient mixture composed as follows is prepared: Ex. 1001,

6:57-58; and

13. A pharmaceutical preparation consisting essentially of an active

ingredient and one or more carriers and excipients, Ex. 1001, 8:50-51.

Dr. Polli explains in his declaration that the term excipients is not

specifically defined in the 393 patent. Ex. 1004, 36. However, a POSITA would

have looked at extrinsic evidence such as the Dictionary of Pharmaceutical and

Pharmaceutical Manufacturing for a definition. The term excipients is defined as

nondrug component of a pharmaceutical formulation; excipients include diluents,

binders and adhesives, fillers, disintegrants, lubricants, glidants and flow

promoters, colors, flavors and sweeteners citing Ex 1009, p4.

In sum, the term excipients, under the broadest reasonable interpretation,

are any nondrug component of a pharmaceutical formulation. Ex. 1004, 37.

VI. DETAILED EXPLANATION OF THE CHALLENGES

A. Ground 1: Claims 1, 2, and 8 are anticipated by Nieboer

23

A patent claim is anticipated under 35 U.S.C. 102 if "each limitation of a

claim is found in a single reference, either expressly or inherently." Verdegaal

Bros. v. Union Oil Co. of California, 814 F.2d 628, 631 (Fed. Cir. 1987).

Nieboer teaches every element of claims 1, 2, and 8. Together these claims

generally recite four elements: 1) a pharmaceutical preparation comprising

dimethyl fumarate; 2) dimethyl fumarate as an active ingredient; 3) a

pharmaceutical preparation in the form of microtablets; and 4) enteric coated

microtablets. Each of those elements is plainly taught by Nieboer.

Claim 1: A pharmaceutical preparation, comprising dimethyl fumarate wherein the pharmaceutical preparation is in the form of microtablets.

The first element of claim 1 requires a pharmaceutical preparation

comprising dimethyl fumarate. Nieboer teaches a pharmaceutical preparation

comprising dimethyl fumarate. Nieboer discloses that [t]he medication consisted

of capsules filled with 60 mg enteric-coated granulate of DMFAE (dimethyl

fumaric acid ester) or with placebo granulate to a maximum dosage of up to four

capsules a day. Ex. 1002, p603, 2:35-38. Dr. Polli explains that DMFAE (or

dimethylfumaric acid ester) is simply another term for dimethyl fumarate. Ex.

1004, 20 and 38. See also Ex. 1008, p1.

The second element of claim 1 requires that the pharmaceutical preparation

is in the form of microtablets. As shown above in Section V. D., the broadest

24

reasonable interpretation of microtablets in light of the specification is any oral

pharmaceutical preparation form that can be filled into a capsule. Nieboers

teaching of granulates that can be filled into capsules reads on microtablets as

recited in claim 1 of the 393 patent. Nieboer teaches capsules filled with 60 mg

enteric-coated granulate of DMFAE. Ex. 1002, p604, 1:2-4, narrative following

Table I. The granulates of Nieboer are therefore within the scope of the 393

patent claim limitation microtablets. Ex. 1004, 39.

In sum, Nieboer teaches a pharmaceutical preparation comprising dimethyl

fumarate, wherein the pharmaceutical preparation is in the form of microtablets.

Thus, Nieboer anticipates claim 1 of the 393 patent. Ex. 1004, 40.

Claim 2: The pharmaceutical preparation of claim 1, wherein the microtablets are enteric coated

Claim 2 is dependent on claim 1 and therefore incorporates all its

limitations. Claim 2 further requires that the microtablets are enteric coated.

Nieboer further discloses that [t]he medication consisted of capsules filled with 60

mg enteric-coated granulate of DMFAE Ex. 1002, p603, 2:35-38, emphasis

added. In sum, Nieboer teaches the microtablets are enteric coated microtablets.

Thus, Nieboer anticipates claim 2 of the 393 patent. Ex. 1004, 41.

Claim 8: A pharmaceutical preparation, comprising an active ingredient, wherein the pharmaceutical preparation is in the form of microtablets and the active ingredient consists of dimethyl fumarate

25

The first element of independent claim 8 requires [a] pharmaceutical

preparation, comprising an active ingredient. Nieboer teaches a pharmaceutical

preparation comprising an active ingredient. Ex. 1004, 42. Nieboer discloses that

[t]he medication consisted of capsules filled with 60 mg enteric-coated granulate

of DMFAE. Ex. 1002, p603, 2:35-38. Dr. Pollis explains that Nieboer teaches

pharmaceutical preparations that contain an active ingredient. Id.


is in the form of microtablets. As argued above in Section VI.A., the granulates

of Nieboer meets the 393 patent claim limitation of microtablets. Ex. 1004,

43.

The third element of claim 8 requires that the active ingredient consists of

dimethyl fumarate. Nieboer discloses that [t]he medication consisted of capsules

filled with 60 mg enteric-coated granulate of DMFAE. Ex. 1002, p603, 2:35-

38. Dr. Polli explains that dimethylfumaric acid ester or DMFAE are simply other

terms for the active ingredient dimethyl fumarate. Ex. 1004, 44. See also Ex.

1008, p1.

In sum, Nieboer teaches a pharmaceutical preparation comprising an active

ingredient, wherein the preparation form is microtablets and the active ingredient

consists of dimethyl fumarate. Thus, Nieboer anticipates claim 8 of the 393

patent. Ex. 1004, 45.

26

B. Ground 2: Claims 1-13 are obvious over Nieboer in view of Kolter

A claim is unpatentable for obviousness when "the differences between the

subject matter sought to be patented and the prior art are such that the subject

matter as a whole would have been obvious at the time the invention was made to a

person having ordinary skill in the art to which said subject matter pertains." 35

U.S.C. 103.

The factual inquiries enunciated by the Supreme Court for an obviousness

analysis require: (1) the scope and content of the prior art; (2) the differences

between the claims and the prior art; (3) the level of ordinary skill in the pertinent

art; and (4) objective indicia of non-obviousness. KSR International Co. v. Teleflex

Inc., 550 U.S. 398, 406 (2007) (citing Graham v. John Deere Co. of Kan. City, 383

U.S. 1, 17-18 (1966). 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)).

27

As shown in Ground 1 above, Nieboer teaches the use of enteric-coated

granulates of dimethyl fumarate filled into capsules. Dr. Polli attests that Kolter

teaches microtablets produced by means of conventional pharmaceutical

equipment following well known and standard procedures such as granulation,

drying, mixing and tableting citing Ex 1003, 3:49-51. Ex. 1004, 46. Kolter also

teaches delayed-release microtablets that minimize gastrointestinal irritation. Id.

Kolter states that [t]he microtablets according to the invention furthermore have

the advantage that when introduced into gastric or intestinal fluid they show no

tendency to stick or adhere. This ensures that they pass as individual articles

through the gastrointestinal tract and, moreover, do not become attached to the

wall of the stomach or intestine and induce irritation. Ex. 1003, 3:25-30. Kolter

further discloses microtablets having a diameter of 1-3 mm and preferably 2mm.

Id. The microtablets of the examples always had a diameter and height each of 2

mm. Ex 1003, 4:65-66. See also A cylindrical delayed release microtabletthe

height and diameter are, independently of one another, 1-3mm. Ex 1003, 8:18-31.

Kolter states that the particle size of the active ingredient is, within the

conventional pharmaceutical range, of only minor or no importance in the

production of the microtablets according the invention. Ex 1003, 3:52-55.

Nieboer in view of Kolter teaches every element of claims 1-13. These

claims generally recite the following elements: 1) dimethyl fumarate as an

28

ingredient of a pharmaceutical preparation; 2) dimethyl fumarate as the active

ingredient of a pharmaceutical preparation; 3) microtablets; 4) enteric coated

microtablets; 5) microtablets with a mean diameter ranging from 300 m to 2,000

m (0.3 to 2 mm) exclusive of any coating; 6) microtablets with a mean diameter

of about 2,000m (2 mm) exclusive of any coating; 7) microtablets that contain

between 100 mg to 300 mg of dimethyl fumarate; 8) microtablets that contain

about 120 mg of dimethyl fumarate; 9) capsules containing microtablets; and 10)

carriers and excipients.

Claim 1: A pharmaceutical preparation, comprising dimethyl fumarate wherein the pharmaceutical preparation is in the form of microtablets.

The first element of claim 1 requires a pharmaceutical preparation

comprising dimethyl fumarate. Nieboer discloses that [t]he medication consisted

of capsules filled with 60 mg enteric-coated granulate of DMFAE. Ex. 1002,

p603, 2:35-38. Dr. Polli explains that dimethylfumaric acid ester or DMFAE are

simply other terms for dimethyl fumarate. Ex. 1004, 47. See also Ex. 1008, p1.


is in the form of microtablets. Nieboer discloses that [t]he medication consisted


p603, 2:35-38. Kolter teaches small microtablets with a mean diameter in the

range of 1-3 mm. Ex. 1003, 2:42-46. Kolter teaches that [t]he microtablets

29

according to the invention are produced in conventional pharmaceutical equipment

by the following steps: granulation, drying, mixing, tableting. Ex. 1004, 48.

Nieboer recognizes that the cause of gastrointestinal complaints in the study

was due to the rapid release of the active ingredient DMFAE. Dr. Polli attests that

Nieboer discloses that the gastrointestinal symptoms were caused because more

than 80% DMFAE of the enteric-coated granulated capsules were released within

30 minutes in acid medium which is a rapid release in the stomach citing Ex.

1002, p607, 1:17-28. Ex. 1004, 49.

Dr. Polli attests that Kolter solves this problem in two ways: 1) by

controlling the rate of release of the active ingredient and 2) by ensuring that the

dosage amount of active ingredient is distributed throughout the digestive tract in

order to alleviate unwanted gastrointestinal symptoms using microtablets. Ex.

1004, 50. Dr. Polli attests that Kolter controls the rate of release of the active

ingredient by adding a controlled amount of a wetting agent to the granules. Ex.

1004, 50.1. Dr. Polli explains that Kolter teaches that the rate of release increases

in parallel with the rise in the wetting agent concentration citing Ex. 1003, 4:26-37.

Id.

Dr. Polli attests that Kolter ensures that the dosage amount of active

ingredient is distributed throughout the digestive tract by making small size

microtablets. Ex. 1004, 50.2. Kolter discloses that prior art large diameter tablets

30

can result in release and absorption of their total content of active ingredient

concentrated at one site in the gastrointestinal tract citing Ex. 1003, 1:37-49. Id.

Kolter discloses that it is an object of Kolters invention to overcome the

disadvantages of the prior art by using small sized microtablets citing Ex. 1003,

1:37-49. Id. Kolter discloses [t]he microtablets of the examples always had a

diameter and height each of 2mm. Ex. 1003, 4:65-66. Dr. Polli attests that Kolter

discloses that the Kolter microtablets have the advantage that they show no

tendency to stick or adhere and this ensures that they pass as individual articles


wall of the stomach or intestine and induce irritation citing Ex. 1003, 3:25-30. Id.

Dr. Polli attests that a POSITA would have looked to the teachings of Kolter

to improve the Nieboer pharmaceutical preparation in order to solve the Nieboer

recognized problem of the rapid release of the active ingredient in the stomach

resulting in gastrointestinal complaints. Ex. 1004, 51. Dr. Polli attests that it

would have been obvious to a POSITA to use the teachings of Kolters

microtablets to modify the Nieboer pharmaceutical preparation in order to alleviate

unwanted gastrointestinal symptoms by controlling the rate of release of the active

ingredient and by ensuring that the dosage amount of active ingredient is

distributed throughout the digestive tract. Id. Dr. Polli explains that a POSITA

would have a reason to combine the teachings of Kolter with Nieboer to modify

31

the Nieboer pharmaceutical preparation in order to reduce the rate of release of the

active ingredient in the stomach and ensure distributive absorption throughout the

digestive tract of the dosage of the active ingredient in order to avoid unwanted

gastrointestinal distress caused by the pharmaceutical preparation as described by

Nieboer. Id.

In sum, claim 1 of the 393 patent would have been obvious in over Nieboer

in view of Kolter. Ex. 1004, 52.

Claim 2: The pharmaceutical preparation of claim 1, wherein the microtablets are enteric coated. Claim 2 is dependent on claim 1 and incorporates all its limitations. The

element of claim 2 requires that the microtablets are enteric coated.

Nieboer teaches enteric coating of the pharmaceutical preparation. Ex.

1002, p603, 2:35-38. See also Ex. 1002, p604, 1:2-4, narrative following Table I,

All patients were treated with capsules filled with 60 mg enteric-coated granulate

of DMFAE. Dr. Polli attests that Nieboer teaches enteric coating of the

pharmaceutical preparation. Ex. 1004, 54. As argued above, it would have been

obvious to a POSITA to use the teachings of Kolters small microtablets to modify

the Nieboer pharmaceutical preparation.

Kolter does not teach away from using the Nieboer enteric coating. Ex.

1004, 54.1. Kolter states that [a]s a rule, the microtablets can be packed into

gelatin capsules directly using conventional filling machines. Kolter teaches that

32

[i]t may occasionally be advantageous for the microtablets, before the packing

[using these filling machines], to be provided with a readily soluble film coating

which does not influence the release. Ex. 1003, 4:49-53. Dr. Polli attests that this

Kolter passage does not teach away from using enteric coatings on micro-tablets.

Ex. 1004, 54.1. Dr. Polli explains that this is because Kolter is solving a

packaging problem by adding a packaging coating and does not want the

packaging coating to affect the designed release rate of the micro-tablet. In Dr.

Pollis opinion, Kolter does not suggest that enteric coatings should not be used on

microtablets. Ex. 1004, 54.1

In sum, claim 2 of the 393 patent would have been obvious over Nieboer in

view of Kolter. Ex. 1004, 55.

Claim 3: The pharmaceutical preparation of claim 2, wherein the mean diameter of the microtablets ranges from 300m to 2,000m, exclusive of any coating on the microtablets. Claim 3 is dependent on claim 2 and incorporates all its limitations, i.e., an

enteric coating. Claim 3 requires the mean diameter of the microtablets ranges

from 300m to 2,000m, exclusive of any coating on the microtablets. Claim 3

only limits the size of the uncoated microtablet and does not limit the size of the

microtablet after it has been enteric coated.

Kolter teaches pharmaceutical preparation wherein the mean diameter of

the microtablets ranges from 300m to 2,000m, exclusive of any coating on the

33

microtablets. Ex. 1004, 58. First, Kolter teaches microtablets that are cylindrical

with a diameter and height which are preferably equal and, independently of

another, from 1 to 3, preferably 1.5 to 2.5mm, citing Ex. 1003, 2:42-46. Ex.

1004, 57.1. Second, Kolter teaches that the microtablets are made with a tableting

machine equipped with multiple microtablet punches resulting in a cylindrical

shape where the height and diameter can be varied independently of one another,

citing Ex. 1003, 4:18-22. Id.

Third, Kolter teaches that the microtablets dimensions are exclusive of any

coating on the microtablets. Ex. 1004, 57.2. Kolters examples 1-8 do not

include a coating on the microtablets citing Ex. 1003, 5:1-7:64. Id. Moreover

Kolter teaches that microtablets, as a rule, are packaged without a coating citing

Ex. 1003, 4:48-49. Id. Dr. Polli attests that Kolter teaches a range of sizes of the

microtablets where the mean diameter of the microtablets are within the ranges

from 300m to 2,000m, exclusive of any coating on the microtablets citing Ex.

1004, 57.2. Id. Dr. Polli attests that Kolter taught microtablets having a

cylindrical shape where the height and diameter each are approximately equal to

1.5mm, citing Ex. 1003, 2:42-46. Dr. Polli attests that the 1.5 mm diameter Kolter

microtablet exhibits one of the values in the claimed range of 0.3mm to 2mm

diameter, exclusive of any coating on the microtablets. Id.

34

[W]hen, as by a recitation of ranges or otherwise, a claim covers several

compositions, the claim is anticipated if one of them is in the prior art.

Titaniium Metals Corp. v. Banner, 778 F.2d 775, 782 (Fed. Cir. 1985) (citing In re

Petering, 301 F.2d 676, 682 (CCPA 1962).

In sum, the Kolter microtablet size meets a pharmaceutical preparation of

claim 3, wherein the mean diameter of the microtablets ranges from 300m to

2,000m, exclusive of any coating on the microtablets and therefore, claim 3 of

the 393 patent would have been obvious over Nieboer in view of Kolter. Ex.

1004, 58.

Claim 4: The pharmaceutical preparation of claim 3, wherein the mean diameter of the microtablets is about 2,000m, exclusive of any coating on the microtablets. Claim 4 is dependent on claim 3 and incorporates all its limitations. Claim 4

requires the mean diameter of the microtablets is about 2,000m, exclusive of any

coating on the microtablets. Claim 4 only limits the size of the uncoated

microtablet and does not limit the size of the microtablet after it has been enteric

coated.

Kolter teaches pharmaceutical preparation having a mean diameter of the

microtablets of about 2,000m, exclusive of any coating on the microtablets. Ex.

1004, 60. First, Kolter teaches examples of uncoated microtablets having a

diameter of 2mm, which equals 2,000m citing Ex. 1003, 4:65-66. Ex. 1004,

35

59.1. Second, Kolters examples 1-8 do not include a coating on the microtablets

citing Ex. 1003, 5:1-7:64. Id. Moreover Kolter teaches that microtablets, as a rule,

are packaged without a coating citing Ex. 1003, 4:48-49. Id. Dr. Polli attests that

Kolter teaches that the size of the microtablets in examples 1-8 have a diameter of

2,000m, exclusive of any coating. Id.

Kolter teaches that the microtablets of the examples 1-8 always had a

diameter and height each of 2 mm, citing Ex. 1003, 4:65-66. Ex. 1004, 59.2.

Dr. Polli attests that the mean value of the diameter of the Kolter microtablets

having a height and diameter of 2mm is one of the values in the claimed range of

about 2,000m, exclusive of any coating on the microtablets. Id. Dr. Polli attests

that Kolter microtablets having a diameter and a height each of 2,000m meets the

claim requirement of microtablets having a mean diameter of about 2,000m,

exclusive of any coating. Ex. 1004, 59.2.




Petering, 301 F.2d 676, 682 (CCPA 1962). Kolter teaches microtablets having a

mean diameter of 2mm which is one of the values in the claim range of about 2

mm diameter and thereby reads on the claimed range.

36


claim 3, wherein the mean diameter of the microtablets is about 2,000m,

exclusive of any coating on the microtablets. Ex. 1004, 60. Therefore, Dr. Polli

attests that claim 4 of the 393 patent would have been obvious over Nieboer in


Claim 5: The pharmaceutical preparation of claim 4, wherein the preparation contains 10 mg to 300 mg of dimethyl fumarate. Claim 5 is dependent on claim 4 and incorporates all its limitations. The

element of claim 5 requires that the preparation contains 10 mg to 300 mg of

dimethyl fumarate. Nieboer teaches that [a]ll patients were treated with capsules

filled with 60 mg enteric-coated granulate of DMFAE. Ex. 1002, p604, 1:2-4,

narrative following Table I. Dr. Polli explains that Nieboer teaches preparations

having dimethyl fumarate content within the range of 10 mg to 300 mg of dimethyl

fumarate. Ex. 1004, 63.



Claim 6: The pharmaceutical preparation of claim 5, wherein the preparation contains about 120 mg of dimethyl fumarate. Claim 6 is dependent on claim 5 and incorporates all its limitations. The

element of claim 6 requires that the preparation contains about 120 mg of

dimethyl fumarate. Claim 6 does not limit the preparation to a single capsule, but

37

instead the claim scope covers more than one capsule. Nieboer also teaches that

the [t]he medication consisted of capsules filled with 60 mg enteric-coated

granulate of DMFAE a maximum dosage of up to four capsules a day. Ex

1002, p603, 2:35-38. Further all patients were treated with capsules filled with 60

mg enteric-coated granulate of DMFAE. Dosages ranged from 60 to 240 mg a

day. Ex 1002, p604, 1:2-4. Because 120 mg dosage is within the Nieboer dosage

range, the dosage taught by Nieboer includes a pharmaceutical preparation of 120

mg of dimethyl fumarate as required by the claim. Ex. 1004, 65. Dr. Polli attests

that Nieboer teaches a preparation that contains about 120 mg of dimethyl

fumarate. Id.



Claim 7: The pharmaceutical preparation of claim 5, wherein the microtablets are contained in one or more capsules. Claim 7 is dependent on claim 5 and incorporates all its limitations. The

element of claim 7 requires that the microtablets are contained in one or more

capsules. Dr. Polli attests that Nieboer teaches that each capsule is filled with 60

mg enteric-coated granulate of dimethyl fumarate and that dosages of up to 240 mg

dimethyl fumarate were given to patients by increments of up to four capsules,

each capsule filled with 60 mg enteric-coated granulate of dimethyl fumarate,

citing Ex. 1002, p604, 1:2-4, narrative following Table I. Ex. 1004, 67. Kolter

38

also teaches that microtablets can be packed into gelatin capsules using

conventional filling machines. Ex. 1003, 4:49-50. Dr. Polli attests that both

Nieboer and Kolter teach the microtablets are contained in one or more capsules.

Id.



Claim 8: A pharmaceutical preparation, comprising an active ingredient, wherein the pharmaceutical preparation is in the form of microtablets and the active ingredient consists of dimethyl fumarate. The first element of independent claim 8 requires [a] pharmaceutical

preparation, comprising an active ingredient. Nieboer discloses that [t]he

medication consisted of capsules filled with 60 mg enteric-coated granulate of

DMFAE a maximum dosage of up to four capsules a day. Ex. 1002, p603, 2:35-

38. In Dr. Pollis opinion, Nieboers study concerns a systemic therapy involving

pharmaceutical preparations comprising an active ingredient wherein that active

ingredient consists of dimethyl fumarate. Ex. 1004, 69. Kolter teaches a

pharmaceutical preparation comprising an active ingredient. Ex. 1003, 2:11-16. Ex.

1004, 69


is in the form of microtablets. Nieboer discloses that [t]he medication consisted


39

p603, 2:35-38. Kolter teaches small microtablets in the range of 1-3 mm. Ex.

1003, 2:42-46. Kolter teaches that [t]he microtablets according to the invention

are produced in conventional pharmaceutical equipment by the following steps:

granulation, drying, mixing, tableting. Ex 1003, 3:49-51. Ex. 1004, 70.





30 minutes in acid medium which is a rapid release in the stomach citing Ex. 1002,

p607, 1:17-28. Ex. 1004, 71.







1004, 72.1. Dr. Polli explains that Kolter teaches that the rate of release increases


Id.

40



microtablets. Ex. 1004, 72.2. . Kolter discloses that prior art large diameter

tablets can result in release and absorption of their total content of active ingredient



disadvantages of the prior art by using the small sized microtablets citing Ex. 1003,










resulting in gastrointestinal complaints. Ex. 1004, 73 Dr. Polli attests that it




41



would have had a reason to combine the teachings of Kolter with Nieboer to

modify the Nieboer pharmaceutical preparation in order to reduce the rate of

release of the active ingredient in the stomach in order to avoid unwanted

gastrointestinal distress caused by the pharmaceutical preparation as described by

Nieboer. Id.

The third element of claim 8 requires active ingredient consists of dimethyl

fumarate. Nieboer discloses that [t]he medication consisted of capsules filled

with 60 mg enteric-coated granulate of DMFAE. Ex. 1002, p603, 2-35-38. Dr.

Polli explains that dimethylfumaric acid ester or DMFAE are simply other terms

for dimethyl fumarate. Ex. 1004, 74. See also Ex. 1008, p1.



Claim 9: The pharmaceutical preparation of claim 8, wherein the mean diameter of the microtablets is about 2,000 m, exclusive of any coating on the microtablets

Claim 9 is dependent on claim 8 and incorporates all its limitations. Claim 9

requires that the mean diameter of the microtablets is about 2,000m, exclusive of

any coating on the microtablets. Claim 9 only limits the size of the uncoated

42

microtablet and does not limit the size of the microtablet after it has been enteric

coated.

Kolter teaches pharmaceutical preparations having a mean diameter of the

microtablets that about 2,000m, exclusive of any coating on the microtablets. Ex.

1004, 77 First, Kolter teaches examples of uncoated microtablets having a

diameter of 2mm, which equals 2,000m citing Ex. 1003, 4:65-66. Id. Second,

Kolters examples 1-8 do not include a coating on the microtablets citing Ex. 1003,

5:1-7:64. Id. Moreover Kolter teaches that microtablets as a rule are packaged

without a coating citing Ex. 1003, 4:48-49. Id. Dr. Polli attests that Kolter teaches

that the microtablets in examples 1-8 have a diameter of 2,000m, exclusive of any

coating. Id.


diameter and height each of 2 mm, citing Ex. 1003, 4:65-66. Ex. 1004, 78. Dr.

Polli attests that the mean value of the diameter of the Kolter microtablets having a

height and diameter of 2mm is one of the values in the claimed range of about

2,000m, exclusive of any coating on the microtablets. Id. Dr. Polli attests that

the Kolter microtablets having a diameter and a height of 2,000m meet the claim

requirement of microtablets having a mean diameter of about 2,000m, exclusive

of any coating. Id.

43





mean diameter of 2mm which is one of the values in the claim range of about 2mm

diameter and thereby reads on the claimed range.



exclusive of any coating on the microtablets. Therefore, Dr. Polli attests that

claim 9 of the 393 patent would have been obvious over Nieboer in view of

Kolter. Ex. 1004, 78.1

Claim 10: The pharmaceutical preparation of claim 9, wherein the preparation contains 10 mg to 300mg of dimethyl fumarate. Claim 10 is dependent on claim 9 and incorporates all its limitations. The

element of claim 10 requires that the preparation contains 10 mg to 300 mg of

dimethyl fumarate. Nieboer teaches that [a]ll patients were treated with capsules

filled with 60 mg enteric-coated granulate of DMFAE. Ex 1002,p 604, 1:2-4,

narrative following Table I. Dr. Polli explains that Nieboer teaches preparations

having dimethyl fumarate content within the range of 10 mg to 300 mg of dimethyl

fumarate. Ex. 1004, 79.

44

In sum, claim 10 of the 393 patent would have been obvious over Nieboer


Claim 11: The pharmaceutical preparation of claim 10, wherein the preparation contains about 120 mg of dimethyl fumarate. Claim 11 is dependent on claim 10 and incorporates all its limitations. The

element of claim 11 requires that the preparation contains about 120 mg of

dimethyl fumarate. Nieboer also teaches that the [t]he medication consisted of

capsules filled with 60 mg enteric-coated granulate of DMFAE a maximum

dosage of up to four capsules a day. Ex 1002, p603, 2:35-38. Further all patients

were treated with capsules filled with 60 mg enteric-coated granulate of DMFAE.

Dosages ranged from 60 to 240 mg a day. Ex 1002, p604, 1:2-4. Because 120 mg

dosage is in the Nieboer dosage range, Nieboer teaches a dosage of 120 mg of

dimethyl fumarate. Ex. 1004, 81. Dr. Polli attests that Nieboer teaches a

preparation that contains about 120 mg of dimethyl fumarate as claimed. Id.



Claim 12: The pharmaceutical preparation of claim 10, wherein the microtablets are enteric coated and are contained in one or more capsules. Claim 12 is dependent on claim 10 and incorporates all its limitations. The

first element of claim 12 requires that the microtablets are enteric coated.

Nieboer teaches enteric coating of the pharmaceutical preparation. Ex. 1002, p603,

45

2:35-38. See also Ex. 1002, p604, 1:2-4, narrative following Table I. (All patients

were treated with capsules filled with 60 mg enteric-coated granulate of

DMFAE.) Dr. Polli attests that Nieboer teaches enteric coating of the

pharmaceutical preparation. Ex. 1004, 84.

Kolter does not teach away from using the Nieboer enteric coating. Ex.

1004, 84.1. Kolter states that [a]s a rule, the microtablets can be packed into

gelatin capsules directly using conventional filling machines. Ex. 1003, 4:48-49.

Kolter teaches it may occasionally be advantageous for the microtablets, before the

packing using these filling machines, to be provided with a readily soluble film

coating which does not influence the release. Ex. 1003, 4:49-53. Dr. Polli attests

that this Kolter passage does not teach away from using enteric coatings on micro-

tablets. Id. Dr. Polli explains that this is because Kolter is solving a packaging

problem by adding a packaging coating and does not want the packaging coating to

affect the designed release rate of the microtablet. In Dr. Pollis opinion, Kolter

does not suggest that enteric coatings should not be used on microtablets. Id.

The second element of claim 12 requires that the microtablets are contained

in one or more capsules. Dr. Polli attests that Nieboer teaches that each capsule is

filled with 60 mg enteric-coated granulate of dimethyl fumarate and that dosages

of up to 240 mg dimethyl fumarate were given to patients by increments of up to

four capsules, each capsule filled with 60 mg enteric-coated granulate of dimethyl

46

fumarate, citing Ex. 1002, p604, 1:2-4, narrative following Table I. Ex. 1004, 85.

Kolter also teaches that microtablets can be packed into gelatin capsules using

conventional filling machines. Ex. 1003, 4:49-50. Dr. Polli attests that both

Nieboer and Kolter teach the microtablets are contained in one or more capsules.

Id.



Claim 13: A pharmaceutical preparation consisting essentially of an active ingredient and one or more carriers and excipients wherein the active ingredient is dimethyl fumarate and the preparation contains 10 mg to 300 mg of dimethyl fumarate and wherein the pharmaceutical preparation is in the form of microtablets and the mean diameter of the microtablets is about 2,000 m, exclusive of any coating on the microtablets. The first element of independent claim 13 requires [a] pharmaceutical

preparation consisting essentially of an active ingredient. Nieboer discloses that

[t]he medication consisted of capsules filled with 60 mg enteric-coated granulate

of DMFAE a maximum dosage of up to four capsules a day. Ex. 1002, p603,

2:35-38. In Dr. Pollis opinion, Nieboers study concerns a systemic therapy

involving a pharmaceutical preparations consisting of an active ingredient wherein

that active ingredient is dimethyl fumarate. Ex. 1004, 87. Kolter teaches a

pharmaceutical preparation consisting essentially of an active ingredient. Ex. 1003,

2:11-16. Ex. 1004, 87

47

The second element of independent claim 13 requires one or more carriers

and excipients. Nieboer teaches using dimethyl fumarate as an active ingredient

of a pharmaceutical preparation in the form of enteric coated granulates that are

contained in one or more capsules. Ex 1002, p604, 1:2-4, narrative following Table

I. As attested by Dr. Polli, the term carriers, under the broadest reasonable

interpretation, are vehicles used to transport a drug to its site of absorption or use.

Ex. 1004, 88. Nieboer teaches carriers because the Nieboer pharmaceutical

preparation has both enteric coatings and capsules. Ex. 1004, 88. Dr. Polli

explains that examples of carriers as vehicles for the active ingredient include

capsules and enteric coatings. Ex. 1004, 88. As attested by Dr. Polli, the term

excipients, under the broadest reasonable interpretation, means any nondrug

component of a pharmaceutical formulation. Ex. 1004, 88.1. Dr. Polli further

explains that excipients include wetting agents. Ex. 1004, 88.1. Kolter teaches the

use of wetting agent such as polyethylene glycol. Ex. 1003, 4:33-34. Therefore,

the combination of Nieboer and Kolter teach one or more carriers and excipients.

as recited in claim 13. Ex. 1004, 88.1.

The third element of independent claim 13 requires the active ingredient is

dimethyl fumarate. Dr. Polli attests that Nieboer teaches the active ingredient is

dimethyl fumarate. Ex. 1004, 89. Nieboer discloses that [t]he medication

consisted of capsules filled with 60 mg enteric-coated granulate of DMFAE Ex.

48

1002, p603, 2-35-38. Dr. Polli explains that DMFAE or dimethylfumaric acid

ester are simply other terms for dimethyl fumarate. Ex. 1004, 89. See also Ex.

1008, p1.

The fourth element of claim 13 requires that and the preparation contains

10mg to 300mg of dimethyl fumarate. Nieboer teaches that [a]ll patients were

treated with capsules filled with 60 mg enteric-coated granulate of DMFAE. Ex.

1002, p604, 1:2-4, narrative following Table I. Because 60 mg is within 10 to 300

mg, in my opinion, Nieboer teaches preparations having dimethyl fumarate content

within the range of 10 mg to 300 mg of dimethyl fumarate. Ex. 1004, 89.1.

The fifth element of independent claim 13 requires that the preparation is in

the form of microtablets. Nieboer discloses that [t]he medication consisted of

capsules filled with 60 mg enteric-coated granulate of DMFAE. Ex. 1002,

p603, 2:35-38. Kolter teaches that [t]he microtablets according to the invention

are produced in conventional pharmaceutical equipment by the following steps:

granulation, drying, mixing, tabletting. Ex 1003, 3:49-51. Ex. 1004, 90.





49

30 minutes in acid medium which is a rapid release in the stomach. citing Ex.

1002, Ex. 1002, p607, 1:17-28. Ex 1004, 91.







1004, 92.1.Dr. Polli explains that Kolter teaches that the rate of release increases


Ex. 1004, 92.1.



microtablets. Ex. 1004, 92.2. Kolter discloses that prior art large diameter tablets

can result in release and absorption of their total content of active ingredient



disadvantages of the prior art by using the small sized microtablets citing Ex. 1003,



50








resulting in gastrointestinal complaints. Ex. 1004, 93. Dr. Polli attests that it






would have a reason to combine the teachings of Kolter with Nieboer to modify

the Nieboer pharmaceutical preparation in order to reduce the rate of release of the

active ingredient in the stomach in order to avoid unwanted gastrointestinal distress

caused by the pharmaceutical preparation as described by Nieboer. Id.

The sixth element of independent claim 13 requires that the mean diameter

of the microtablets is about 2,000 m, exclusive of any coating on the

microtablets. The fifth element of claim 13 only limits the size of the uncoated

51

microtablets and does not limit the size of the microtablets after they have been

enteric coated.

Kolter teaches pharmaceutical preparation having a mean diameter of the

microtablets of about 2,000m, exclusive of any coating on the microtablets. Ex.

1004, 94.1. First, Kolter teaches examples of uncoated microtablets having a

diameter of 2mm, which equals 2,000m citing Ex. 1003, 4:65-66. Id. Second,

Kolters examples 1-8 do not include a coating on the microtablets citing Ex. 1003,

5:1-7:64. Id. Moreover Kolter teaches that microtablets, as a rule, are packaged

without a coating citing Ex. 1003, 4:48-49. Id. Dr. Polli attests that Kolter teaches

that the size of the microtablets in examples 1-8 have a diameter of 2,000m,

exclusive of any coating. Id.


diameter and height each of 2 mm, citing Ex. 1003, 4:65-66. Ex. 1004, 94.2.

Dr. Polli attests that the mean value of the diameter of the Kolter microtablets

having a height and diameter of 2mm is one of the values in the claimed range of

about 2,000m, exclusive of any coating on the microtablets. Id. Dr. Polli attests

that Kolter microtablets having a diameter and a height of 2,000m meet the claim

requirement of microtablets having a mean diameter of about 2,000m, exclusive

of any coating. Id.

52





mean diameter of 2mm which is one of the values in the claim range of about 2mm

diameter and thereby reads on the claimed range.

In sum, the Kolter microtablet size meets the pharmaceutical preparation of


exclusive of any coating on the microtablets. Ex. 1004, 95.

Therefore, claim 13 of the 393 patent would have been obvious over

Nieboer in view of Kolter. Ex. 1004, 96.

VII. CONCLUSION

For the foregoing reasons, the petitioner respectfully requests that trial be instituted

and that claims 1-13 of the 393 patent be canceled.

/RobertHahl#33,893/ Robert W. Hahl, Reg. No. 33,893 Lead Counsel for the Petitioner Tel: 1-703-415-0012 Ext. 103 Email: [email protected] Backup Counsel for Petitioner Robert Mihail, Reg. No. 66,021 Tel: 1-703-415-0012 Ext. 107 Email: [email protected] Fax for lead and backup counsel for the Petitioner: 1-703-415-0013 Postal address for lead and backup counsel:

53

Neifeld IP Law, PC, 4813-B Eisenhower Avenue, Alexandria, VA 22304

54

42.6(e) CERTIFICATE OF SERVICE

I certify that this document was served or simultaneously is being served on each opposing party with the filing of this document. I certify that the following exhibits being filed along with this document, if any, have been or simultaneously are being served on each opposing party:

Exhibit Number

Description

1001 U.S. Patent No. 8,759,393, titled Utilization of Dialkylfumarates to Joshi et al. (393 patent)

1002 C. Nieboer, et al., Systemic therapy with fumaric acid derivatives: New possibilities in the treatment of psoriasis, Journal of the

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