UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE …716021485 71 South Wacker Drive Chicago, IL 60606 Telephone: (312) 701-8979 Facsimile: (312) 706-8530 Email: [email protected]

UNITED STATES PATENT AND TRADEMARK OFFICE __________

BEFORE THE PATENT TRIAL AND APPEAL BOARD

__________

GALDERMA SA; GALDERMA LABORATORIES, INC.; GALDERMA LABORATORIES LP; GALDERMA RESEARCH & DEVELOPMENT SNC;

AND NESTLÉ SKIN HEALTH, INC., Petitioner,

v.

ALLERGAN, INC.,

Patent Owner __________

Case 2015-01119

U.S. Patent No. 7,148,041 __________

PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 7,148,041

UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. § 42.100 ET SEQ.

Mail Stop PATENT BOARD Patent Trial and Appeal Board United States Patent and Trademark Office P.O. Box 1450 Alexandria, VA 22313-1450 Dated: April 29, 2015 Filed by:

Joseph A. Mahoney (Lead Counsel)

Registration No. 38,956 MAYER BROWN LLP

716021485

71 South Wacker Drive Chicago, IL 60606 Telephone: (312) 701-8979 Facsimile: (312) 706-8530 Email: [email protected] Jonathan H. Kim (Back-Up Counsel) Registration No. 65,439 MAYER BROWN LLP 71 South Wacker Drive Chicago, IL 60606 Telephone: (312) 701-8592 Facsimile: (312) 706-8378 Email:[email protected] Counsel for Petitioner

TABLE OF CONTENTS

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

II. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(a)(1) ......................... 4

A. Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1) ........................... 4

B. Related Matters Under 37 C.F.R. § 42.8(b)(2) .................................... 4

C. Lead and Back-up Counsel Under 37 C.F.R. § 42.8(b)(3) .................. 4

D. Service Information Under 37 C.F.R. § 42.8(b)(4) .............................. 5

III. REQUIREMENTS FOR INTER PARTES REVIEW UNDER 37 C.F.R. § 42.104 ............................................................................................... 5

A. Grounds for Standing (37 C.F.R. § 42.104(a)) ................................... 5

B. Identification of Challenge § 42.104(b) ............................................... 5

IV. U.S. PATENT NO. 7,148,041 ........................................................................ 7

A. Brief Description of the Challenged Patent ......................................... 7

B. Prosecution History .............................................................................. 8

C. Related European Patent EP1664292 ................................................... 9

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

E. Claim Construction ............................................................................ 10

1. “fermentation medium” ........................................................... 11

2. “free of an animal product” ...................................................... 11

3. “recovering a biologically active botulinum toxin” ................. 12

4. “culturing” ................................................................................ 13

5. “botulinum toxin is further purified” ....................................... 13

6. “suitable excipient” .................................................................. 14

V. RELEVANT PRIOR ART ........................................................................... 14

A. Technology Background .................................................................... 14

B. Prior Art References Underlying the Grounds for Rejection ............. 16

1. Smelt and Whitmer Disclose Animal Product-Free Media for Growth of C. botulinum and Toxin Production ................. 16

2. Schantz Discloses the Preparation and Therapeutic Applications of C. botulinum and C. Tetani Toxin ................. 18

TABLE OF CONTENTS

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3. Demain Discloses Animal Product-Free Media for Growth of C. Tetani and Production of Tetanus Toxin ........... 19

VI. STATEMENT OF PRECISE RELIEF REQUESTED AND THE REASONS THEREFOR (37 C.F.R. § 42.22(a)) ......................................... 21

A. Explanation of Ground 1 for Unpatentability – Claims 1 and 3-6 are Anticipated by Smelt ................................................................. 21

B. Explanation of Ground 2 for Unpatentability – Claims 1-11 are Obvious Over Smelt in View of Schantz ........................................... 25

1. Independent Claims 1, 6, 7 and 11 are Obvious Over Smelt in View of Schantz ........................................................ 25

2. Dependent Claims 2-5 and 8-10 Are Obvious Over Smelt in View of Schantz ................................................................... 30

3. Summary of the Obviousness Rejection under Ground 2 ....... 32

C. Explanation of Ground 3 for Unpatentability – Claims 1-11 are Obvious Over Whitmer in View of Demain and Schantz .................. 40

1. Independent Claims 1, 6, 7 and 11 are Obvious Over Whitmer in View of Demains and Schantz ............................. 40

2. Dependent Claims Are Obvious Over Whitmer in View of Demain and Schantz ............................................................ 45

3. Summary of the Obviousness Rejection under Ground 3 ....... 47

VII. CONCLUSION ............................................................................................. 59

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TABLE OF AUTHORITIES

Page(s)

Cases

Allergan, Inc. v. Apotex, 754 F.3d 952 (Fed. Cir. 2014) ............................................................................ 26

Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286 (Fed. Cir. 2006) .......................................................................... 27

In re Cuozzo Speed Techs., LLC, Case No. 2014-1301, --- F.3d ---, 2015 WL 448667 (Fed. Cir. Feb 4, 2015) ............................................................................................................... 10

Dystar Textilfarben GMBH & Co., v. C.H. Patrick, 464 F.3d 1356 (Fed. Cir. 2006) .......................................................................... 27

King Pharmaceuticals, Inc. v. EON Labs, Inc., 616 F.3d 1267 (Fed. Cir. 2010) .......................................................................... 21

KSR Int'l Co. v. Teleflex, Inc., 550 U.S. 398, 127 S.Ct. 1727 (2007) .................................................................. 26

Sciele Pharma Inc. v. Lupin Ltd., 684 F.3d 1253 (Fed. Cir. 2012) .......................................................................... 26

Statutes

35 U.S.C. 103(a) ........................................................................................................ 8

35 U.S.C. § 102 .......................................................................................................... 6

35 U.S.C. § 102(b) ..................................................................................................... 6

35 U.S.C. §103 ........................................................................................................... 6

35 U.S.C. § 103(a) ................................................................................................... 26

35 U.S.C. § 312 .......................................................................................................... 1

35 U.S.C. § 314(a) ..................................................................................................... 1

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Other Authorities

37 C.F.R. § 42.8(a)(1) ................................................................................................ 4

37 C.F.R. § 42.8(b)(1) ................................................................................................ 4

37 C.F.R. § 42.8(b)(2) ................................................................................................ 4

37 C.F.R. § 42.8(b)(3) ................................................................................................ 4

37 C.F.R. § 42.8(b)(4) ................................................................................................ 5

37 C.F.R. § 42.10(a) ................................................................................................... 4

37 C.F.R. § 42.104 ..................................................................................................... 5

37 C.F.R. § 42.104(a) ................................................................................................. 5

37 C.F.R. § 42.108 ..................................................................................................... 1

37 C.F.R. § 42.204(b) ................................................................................................ 6

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I. INTRODUCTION

Galderma S.A., Galderma Laboratories, Inc., Galderma Laboratories LP,

Galderma Research & Development SNC (collectively, “Galderma”), and Nestlé

Skin Health, Inc. (Nestlé) (collectively with Galderma, “Petitioner”) request inter

partes review under 35 U.S.C. § 312 and 37 C.F.R. § 42.108 of Claims 1-11 of

U.S. Patent No. 7,148,041 (“the ’041 patent”). The ’041 patent issued on

December 12, 2006 to sole inventor and prosecuting attorney Stephen Donovan

and was assigned to Allergan, Inc. A petition for inter partes review must

demonstrate “a reasonable likelihood that the petitioner would prevail with respect

to at least one of the claims challenged in the petition.” 35 U.S.C. § 314(a). This

petition meets this threshold for the reasons outlined below.

Petitioner has identified at least four prior art references that anticipate

and/or render obvious all of the claims of the ’041 patent—Smelt et al., “Growth

and toxin formation by Clostridium botulinum at low pH values,” J. OF APPLIED

BACTERIOLOGY" 52: 75-82 (1982) (Ex. 1003); Schantz et al., “Properties and Use

of Botulinum Toxin and Other Microbial Neurotoxin in Medicine,”

MICROBIOLOGICAL REVIEWS 56:80-99 (1992) (Ex. 1004); Whitmer & Johnson,

“Development of Improved Defined Media for Clostridium botulinum Serotypes A,

B, and E,” APPL. ENVIRON. MICROBIOL. 54(3):753-759 (1988) (Ex. 1005); and

Demain et al., Int. Publ. No. WO 01/05997 entitled “Method for Production of

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Tetanus Toxin Using Media Substantially Free of Animal Products” (2001) (Ex.

1006).

The claims of the ’041 patent broadly recite a method of obtaining

biologically active botulinum toxin comprising the steps of (a) providing a

fermentation medium which is free of an animal product wherein the

fermentation medium comprises a protein product obtained from yeast or from a

vegetable selected from the group consisting of soy, malt and corn; (b) culturing

Clostridium botulinum in the fermentation medium; and (c) recovering the

botulinum toxin from the fermentation medium. However, this method has been

known in the prior art for decades.

First, Smelt (Ex. 1003) clearly anticipates claims 1 and 3-6 by describing the

production of botulinum toxin types A and B in aqueous suspensions of soy protein

(i.e., free of an animal product).

Second, Smelt combined with Schantz renders obvious claims 1-11. Based

on the teachings of Schantz of the desirability for a botulinum toxin to be free of an

animal product for pharmaceutical use, the person of ordinary skill in the art

(“POSA”) would have been motivated to employ the animal-free soy fermentation

medium of Smelt to achieve such toxin. Schantz in fact counsels the POSA to

culture without “animal meat products,” and to avoid proteins (e.g., prions) and

viral contamination of the toxin obtained. Ex. 1004 at 81-82. And, based on such

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teachings—and the decades-old general state of the art of culturing, recovering and

pharmaceutical formulations—the POSA would have had a high likelihood of

success of achieving the method as claimed.

Third, Whitmer combined with Demain and Schantz renders obvious claims

1-11. Whitmer discloses animal product-free media for culturing and recovering

C. botulinum types A, B, E, and F toxins. Specifically, Whitmer employed

chemically defined minimal media, free of animal proteins, for culturing and

recovering such toxins. Demain teaches that soy protein is a substitute for animal

protein in the fermentation medium for the production of Clostridium tetani toxin.

Based on the teachings of Schantz that C. botulinum and C. tetani have similar

morphology and culturing methods, a POSA would been motivated to include soy

protein to the chemically defined (animal-product free) medium of Whitmer, and

have a high likelihood of success in the culturing and recovering of C. botulinum

toxin.

Not only are these facts establishing invalidity made plain in the prior art

references themselves, but they are also supported by the expert opinions provided

in the Declaration of Eric A. Johnson Sc.D. (Ex. 1002). Dr. Johnson is a Professor

of Bacteriology at the University of Wisconsin-Madison and a leading expert of

Clostridium bacteria and specifically C. botulinum. As reflected in his declaration

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and curriculum vitae (Ex. 1019), he has deep experience of more than 30 years

handling, culturing, isolating and characterizing Clostridium botulinum toxin.

II. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(a)(1)

As set forth below and pursuant to 37 C.F.R. § 42.8(a)(1), the following

mandatory notices are provided as part of this Petition:

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

Galderma S.A., Galderma Laboratories, Inc., Galderma Laboratories LP,

Galderma Research & Development SNC, and Nestlé Skin Health, Inc. are the real

party-in-interest for Petitioner. While it is petitioner’s position that Nestlé need not

be identified as a real party-in-interest, it has done so solely out of an abundance of

caution.

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

None.

C. Lead and Back-up Counsel Under 37 C.F.R. § 42.8(b)(3)

Pursuant to 37 C.F.R. § 42.8(b)(3) and 42.10(a), Galderma provides the

following designation of counsel:

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Lead Counsel Back-up Counsel

Joseph A. Mahoney (Reg. No. 38,956) [email protected] Postal and Hand Delivery Address Mayer Brown LLP 71 South Wacker Drive Chicago, IL 60606 Telephone: (312) 701-8979 Facsimile: (312) 706-8530

Jonathan H Kim (Reg. No. 65,439) [email protected] Postal and Hand Delivery Address Mayer Brown LLP 71 South Wacker Drive Chicago, IL 60606 Telephone: (312) 701-8592 Facsimile: (312) 706-8378

D. Service Information Under 37 C.F.R. § 42.8(b)(4)

Please address all correspondence to the lead counsel at the address shown

above. Petitioner also consents to electronic service by email to the email

addresses listed above.

III. REQUIREMENTS FOR INTER PARTES REVIEW UNDER 37 C.F.R. § 42.104

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

Petitioner certifies that the ’041 patent is available for inter partes review

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

challenging the patent claims on the grounds identified in this petition.

B. Identification of Challenge § 42.104(b)

Petitioner respectfully requests that the Board cancel claims 1-11 of U.S.

Patent No. 7,148,041 (Ex. 1001) based on the following grounds of

unpatentability:

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Ground 1: Claims 1 and 3-6 are unpatentable under 35 U.S.C. § 102 as

anticipated by Smelt (Ex. 1003). Smelt qualifies as prior art under 35 U.S.C. §

102(b).

Ground 2: Claims 1-11 are unpatentable under 35 U.S.C. §103 as obvious

over Smelt in view of Schantz (Ex. 1004). Schantz qualifies as prior art under 35

U.S.C. § 102(b).

Ground 3: Claims 1-11 are unpatentable under 35 U.S.C. §103 as obvious

over Whitmer (Ex. 1005) in view of Demain (Ex. 1006) and Schantz. Whitmer,

Demain, and Schantz qualify as prior art under 35 U.S.C. § 102(b).

Pursuant to 37 C.F.R. § 42.204(b), a detailed explanation of the precise relief

requested for each challenged claim including where each element is found in the

prior art patents or publications, the relevance of the prior art reference, and the

exhibit numbers of the supporting evidence is provided in Sections V and VI

below, including detailed claim charts. The proposed construction of the

challenged claims is found in Section IV.E. Additional explanation and support

for each ground of rejection is set forth in the Declaration of Professor Eric A.

Johnson, Sc.D., (Ex. 1002).

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IV. U.S. PATENT NO. 7,148,041

A. Brief Description of the Challenged Patent

The ’041 patent, entitled “Animal Product Free Media and Processes for

Obtaining a Botulinum Toxin,” was filed as U.S. Patent Application Serial No.

10/672,876 (“the ‘876 application”) on September 25, 2003. The ‘876 application

does not claim priority to any earlier application.

The ’041 patent discloses that vegetable-based products, such as soy or

Lupinus campertris seed, can replace animal-based products in the media used for

growth and fermentation of C. botulinum. Ex. 1001 at 11:33-35; see also, 11:55-

60. For example, the ’041 patent discloses a medium comprising hydrolyzed soy,

glucose, NaCl, Na2HPO4, MgSO47H2O, KH2PO4, L-cysteine, L-tyrosine, and

powered iron. Id. at 14:40-44. Patentability before the Examiner was based on the

premise that it was “surprising” that animal-based products or by-products are not

required in media for growth of C. bolulinum. Ex. 1001 at 11:19-35.

The ’041 patent specification contains no actual data. Rather, it provides

prophetic examples of (1) the preparation of an animal product-free seed and

fermentation media; (2) the growth of C. botulinum in the animal product-free

fermentation media; and (3) the determination of botulinum toxin production. Ex.

1001 at 15:40-64:64. However, there was nothing “surprising” to employ known

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methods of the prior art to yield predictable results—in fact, results established by

the prior art with actual data.

B. Prosecution History

During prosecution of the ’876 application, the Examiner rejected the claims

as, inter alia, obvious. See, e.g., Ex. 1013, Office Actions dated February 17, 2006

and July 19, 2006. Specifically, the Examiner rejected the claims as obvious over

Lewis (Ex. 1010) asserting that:

Lewis et al., disclose a culture media containing basal

medium having Difco yeast extract 0.5%, glucose

(cerelose) 0.6%, thioglycolic acid 0.05%, and tap water,

adjusted to pH 7.5, and supplements including 0.1% of

Pepticase (a tryptic digest of casein) and 2.5% of Gluten

(granular product from corn) are used to produce

botulinum toxin A having toxicity 10,000 MLD.

Ex. 1013 (emphasis added). Applicant acknowledged that “the media of Lewis can

contain less than 1% animal product” (see id., Response to Office Action dated

August 4, 2006), and responded to the rejection by amending the claims from

“providing a fermentation medium of which not more than about 1 weight percent

comprises an animal product” to “providing a fermentation medium which is free

of an animal derived product.” Id.(emphasis added). Based on such amendment,

the Examiner issued a Notice of Allowance on October 16, 2006. The Examiner

explained that “[t]he previous rejection of claims 1, 5, 13-15, 17-19 and 21 under

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35 U.S.C. 103(a) as being unpatentable over Lewis et al. . . . is withdrawn in view

of applicants’ amendment to the claim, and applicants’ response at page 4 of the

amendment filed August 4, 2006.” See Ex. 1013, Notice of Allowance, at 2.

C. Related European Patent EP1664292

European Patent No. EP1664292, entitled “Animal Product Free Media and

Processes for Obtaining a Botulinum Toxin,” was filed on August 25, 2004 and

claims priority to the ’041 patent. EP1664292 issued on May 26, 2010, but was

later revoked by the Opposition Division of the European Patent Office on

September 5, 2012. See Ex. 1020, EP1664292, Decision Revoking the European

Patent, dated September 5, 2012. The claims of EP1664292 were found obvious

over the prior art. Importantly, the revoked claims of EP1664292 are similar,

almost verbatim to the ’041 patent. A comparison of representative claim 1 of the

’041 patent and claim 1 of EP1664292 is provided below:

The ’041 Patent EP1664292

1. A method for obtaining a

biologically active botulinum toxin,

comprising the steps of:

(a) providing a fermentation medium

which is free of an animal product;

(b) culturing a Clostridium botulinum

bacterium in the fermentation medium

under conditions which permit

1. A method for obtaining a

biologically active botulinum toxin,

comprising the steps of:

(a) providing a fermentation medium

that is free of an animal derived product,

the fermentation medium comprising

hydrolyzed soy;

(b) culturing a Clostridium botulinum

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The ’041 Patent EP1664292

production of a botulinum toxin, and;

(c) recovering a biologically active

botulinum toxin from the fermentation

medium,

wherein the fermentation medium

comprises a protein product obtained

from yeast or from a vegetable, and

wherein the vegetable is selected from

the group consisting of soy, malt and

corn.

bacterium in the fermentation medium

under conditions which permit

production of a botulinum toxin, and;

(c) recovering a biologically active

botulinum toxin from the fermentation

medium.

D. Person of Ordinary Skill in the Art

A POSA at the time of the effective filing date of the claims of the ’041

patent would have had an advanced degree in biotechnology, food science,

fermentation science, physiology or a related field. A POSA may also have a

bachelor’s degree in one of these fields with an additional three to five years of

laboratory experience in biotechnology or food science. The research experience

may overlap with the period of education. Ex. 1002 at ¶ 38.

E. Claim Construction

The Board is charged with applying the broadest reasonable interpretation

consistent with the specification, and claim language should be read in light of the

specification as it would be understood by one of ordinary skill in the art. In re

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Cuozzo Speed Techs., LLC, Case No. 2014-1301, --- F.3d ---, 2015 WL 448667, at

*5-7 (Fed. Cir. Feb 4, 2015) (affirming the PTAB’s application of the broadest

reasonable interpretation standard in an inter partes review).

1. “fermentation medium”

The fermentation medium as described in the '041 patent is consistent with

any understanding of this term and how a POSA would interpret it. Specifically,

and in the context of the claims, it means the medium used to culture C. botulinum.

However, it is distinct from the seed medium containing C. botulinum. Ex. 1002 at

¶¶ 41-44. Seed media are used for inoculation of the C. botulinum strain into

fermentation media used for the production of botulinum neurotoxin. Id.

2. “free of an animal product”

The proper construction for “free of an animal product” is the complete

absence of animal products. Ex. 1002 at ¶ 45. This construction is consistent with

the specification and the prosecution history of the ’041 patent. The specification

differentiates “animal product free” and “substantially animal product free” as “the

absence or substantial absence of blood derived, blood pooled and other animal

derived products or compounds.” Ex. 1001 at 8:41-45. Further, the specification

distinguishes “substantially free” as “entirely free,” which is defined as “that

within the detection range of the instrument or process being used, the substance

cannot be detected or its presence cannot be confirmed (id. at 9:16-19) and

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“essentially free,” which is defined as “only trace amounts of the substance can be

detected.” (id. at 9:20-21). Thus, “free” is the absence of the animal product as

compared to “entirely free” and “essentially free,” which allows the presence of

animal product to the limit of detection or trace amounts. Ex. 1002 at ¶ 46.

Further, the prosecution history also supports petitioner’s construction. As

discussed in Section IV.B, supra, during prosecution of the ’876 application,

applicant amended the claims from “a fermentation medium of which not more

than about 1 weight percent comprises an animal product” to “a fermentation

medium which is free of an animal product” in order to overcome an obviousness

rejection over Lewis (Ex. 1010). Lewis discloses a culture media containing, inter

alia, 0.1% of Pepticase (a tryptic digest of casein). Thus, “free of an animal

product” must be construed as the complete absence of animal product. Ex. 1002

at ¶ 47.

3. “recovering a biologically active botulinum toxin”

The phrase “recovering a biologically active botulinum toxin” should be

construed to mean any form of recovery of the biologically active botulinum toxin,

including but not limited to, centrifugation, filtration, precipitation, and any other

processes well known in the art. Ex. 1002 at ¶ 49. The term “recovering” can

range from a simple process of centrifugation and/or filtration to more intensive

purification processes, such as precipitation and/or crystallization of the toxin. Id.

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4. “culturing”

The proper construction of “culturing” is the fermentation of C. botulinum

for the production of botulinum toxin. Ex. 1002 at ¶ 48. Although the conditions

or parameters of fermentation permitting production of the toxin are not recited in

the claims, culturing was well-known in the art before the effective filing date of

the ’041 patent. Id.

5. “botulinum toxin is further purified”

The proper construction of “botulinum toxin is further purified” is a

botulinum toxin isolated from other proteins. Ex. 1002 at ¶ 50. The ’041 patent

defines “purified botulinum toxin” as “a botulinum toxin that is isolated, or

substantially isolated, from other proteins, including proteins that form a

botulinum toxin complex.” Ex. 1001 at 9: 3-6 (emphasis added). The specification

further provides percent purity ranges of purified botulinum toxin (id. at 9:6-8).

However, the claims do not recite any limitation on the purity. Thus, so long as the

botulinum toxin is isolated from any other protein(s), it is “further purified.” Ex.

1002 at ¶ 50.

The ’041 patent does not describe any purification methods but simply states

that botulinum toxin is purified “using methods of protein purification well known

to those of ordinary skill in the art.” Id. at 13:7-9. Consequently, neither the

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recovery nor purification steps as claimed confer anything new to the art. Ex.

1002 at ¶ 50.

6. “suitable excipient”

The proper construction of “suitable excipient” is any ingredient,

component, or substance, other than botulinum toxin, that is suitable for

administration (i.e., by intramuscular or subcutaneous injection or by insertion of a

depot or implant) in a “human or animal for therapeutic, diagnostic, research or

cosmetic purpose.” Ex. 1002 at ¶ 52.; Ex. 1001 at 1:15-17. The ’041 patent

defines “pharmaceutical composition” as “a formulation in which an active

ingredient can be a bolulinum toxin. The word ‘formulation’ means that there is at

least one additional ingredient in the pharmaceutical composition besides a

neurotoxin active ingredient.” Ex. 1001 at 9:48-52. Similarly, “[t]he

pharmaceutical composition can also include one or more excipients, buffers,

carriers, stabilizers, preservatives and/or bulking agents.” Id. at 1:17-20.

Accordingly, “suitable excipient” is broadly any ingredient, component, or

substance, other than botulinum toxin, that is suitable for administration in human

or animal. Ex. 1002 at ¶ 52.

V. RELEVANT PRIOR ART

A. Technology Background

Well before the priority date of the ’041 patent, botulinum type A toxin

(BOTOX®) was commercially available. Ex. 1001 at 2:15-18. For example, the

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use of botulinum type A toxin in the treatment of periorbital wrinkles was

described by Keen et al. (Ex. 1011). Bushara describes the use of botulinum type

A toxin in the treatment of sweating (Ex. 1012). Furthermore, botulinum type A

toxin by Allergan, Inc. was approved as an orphan drug by the Food and Drug

Administration (FDA) in 1989 for the treatment of strabismus, blepharospasm, and

hemifacial spasm. Botulinum toxin type B received FDA approval for treatment of

cervical dystonia in December 2000. Such prior art commercial forms of

botulinum toxin (e.g., BOTOX® and others) were in the form of pharmaceutical

compositions containing carriers and excipients. Ex. 1002 at ¶ 96.

In addition, the safety concerns regarding the potential transfer of viruses

and other pathogens from using animal-derived products that drove the

pharmaceutical industry away from such animal products were also well known

before the priority date of the ’041 patent. Id. at ¶ 15. Such market-based need—

one essential to patient safety—is discussed in a number of prior art references. Id.

Moreover, this need was tacitly acknowledged by patent owner in the

“Background” section of the ’041 patent as an impetus to use the animal product-

free media of the prior art. Ex. 1001 at 1:20-52. However, contrary to the claims

of the ’041 patent, this problem had long before been solved by the prior art.

Indeed, since the 1920s, it was known that C. botulinum could grow in vegetables.

Ex. 1002 at ¶ 17.

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B. Prior Art References Underlying the Grounds for Rejection

1. Smelt and Whitmer Disclose Animal Product-Free Media for Growth of C. botulinum and Toxin Production

Smelt reports on the growth and toxin formation by C. botulinum at low pH

values. Ex. 1002 at ¶¶ 20 & 53. More specifically, spores of C. botulinum were

found to initiate growth and to produce botulinum toxin types A and B in animal

product-free aqueous suspensions of soya protein (a/k/a soy protein) at pH values

as low as 4.2. Id. The aqueous suspensions contain: “soy concentrate1 9.1%;

glucose 0.54%; locust bean gum 0.36%; and water 90%.” Ex. 1003 at 76. Smelt

found that as little as 5% soy concentrate supported growth and toxin production

by C. botulinum. Id., at 78. While Smelt was concerned with the influence of pH

and the type of acid on the development of C. botulinum, it nonetheless discloses

the growth and toxigenesis of C. botulinum in a soy media free of animal

products.2 Id., at 78-79; Ex. 1002 at ¶ 63.

1 The soy concentrate contains protein 60%; insoluble carbohydrates 29%; sucrose

4%; stachyose 1.5%; raffinose 0.5%; and ash 5%. Ex. 1003 at 76.

2 Starin, W.A., “Relationship of Incubation Temperature to Viability, Rate of

Growth and Toxin Production of Cl. Botulinum In Different Vegetables,” JOURNAL

OF INFECTIOUS DISEASES 38:106-114 (1926) (Ex. 1014) teaches essentially the

same things as Smelt except with corn.

17 716021485

Whitmer reports the minimal nutritional growth and toxigenesis

requirements for C. botulinum strains Okra B and Iwanai E, as well as other stains

of C. botulinum group I and II. Ex. 1005; Ex. 1002 at ¶ 26. Whitmer found that

Okra B and Iwanai E adapted readily to a chemically defined minimal essential

medium containing an amino acid mixture and glucose as its principal organic

constituent, vitamins and salts. Ex. 1005 at ¶ 755. The composition of the

minimal media is listed in Table 4. From Table 4, Whitmer further defined the

essential amino acids and vitamins need to support growth and toxigenesis of Okra

B and Iwanai E. Ex. 1005. In summary, Okra B required ten amino acids and five

vitamins;3 Iwanai E required seven amino acids and five vitamins.4 Ex. 1005 at

755-756 and Tables 2 and 3. Moreover, several carbon and energy sources, such

as fructose, glucose, maltose, sorbitol, sucrose and starch, were shown to support

growth and toxin formation in the minimal media. Id., at 757. In addition to Okra

B and Iwanai E, several strains of C. botulinum group I and II, including types A,

3 Okra B required the amino acids arginine, isoleucine, leucine, methionine,

phenylalanine, tryptophan, tyrosine, valine, histidine and glycine; and the vitamins

pyridoxamine, thiamine, biotin, p-aminobenzoic acid and nicotinic acid.

4 Iwanai E required the amino acids isoleucine, leucine, tryptophan, tyrosine,

valine, histidine and serine; and the vitamins choline, nicotinamide, biotin,

thiamine and folic acid.

18 716021485

B, E and F were found to grow and produce toxin in the chemically defined

minimal media free of any animal products. Id., at 757 and Table 7. Ex. 1002 at ¶

26. In fact, none of the ingredients used in Whitmer contained animal products.

Id.

2. Schantz Discloses the Preparation and Therapeutic Applications of C. botulinum and C. Tetani Toxin

Schantz provides a review of the preparation and therapeutic use of

botulinum toxin, tetanus toxin, and other microbial neurotoxins. In particular,

Schantz described the production of botulinum toxin from cultured C. botulinum

and its clinical applications. Botulinum toxin is the first microbial protein to be

used for treatment of human disease. Ex. 1002 at ¶ 21; Ex. 1004 at 81. For human

use, the botulinum toxin must meet approval by the FDA:

The production by culturing and the purification had to

be carried out so that the toxin was not exposed to any

substance that might contaminate the final product in

trace amounts and cause undue reactions in the patient.

These restrictions required culturing in simplified

medium without the use of animal meat products and

purification by procedures not involving synthetic

solvents or resins.”

Ex. 1004 at 81 (emphasis added).

Schantz discloses the fermentation of C. botulinum and production of toxin

in a nutritive medium. Growth is usually complete in 24 to 36 hours, at which time

19 716021485

cells undergo lysis with complete cell lysis and clearing of the culture taking 2 to 3

days. The toxin is purified from the culture by the simplest of procedures. Id. at

82. Schantz describes the purification of botulinum type A. Id.

Schantz discloses that C. tetani and C. botulinum are anaerobic spore-

forming rods that have similar morphology and cultured by similar fermentation

methods. Ex. 1004 at 89-90. Further, tetanus toxin and botulinum toxin have a

similar primary structure. Id. at 91; Ex. 1002 at ¶ 23. Both tetanus and botulinum

toxins are produced in the cell as protoxins and released by autolytic growth and

proteolytic cleavage to the active toxin. Id. at 90. Since at least 1993, a protein-

free medium has been used for tetanus toxin production. Id.

3. Demain Discloses Animal Product-Free Media for Growth of C. Tetani and Production of Tetanus Toxin

Demain (Ex. 1006) is a patent application directed to a method of producing

C. tetani toxin using media free of animal products. Ex. 1002 at ¶ 28. C. tetani is

in the same family as C. botulinum. Id. Demain makes clear the motivation for an

animal product-free medium for clostridia toxins – “some Toxoid preparations

could contain carry-over amounts of undesirable contaminants, such as the protein

agent (prion) that cause Bovine Spongiform Encephalopathy (BSE), or antigenic

peptides that stimulate undesired immune reactions (e.g., anaphylactic reactions) in

immunized subjects.” Ex. 1006 at 2. For this reason, there was an industry need

20 716021485

for an animal-product free medium for culturing, not only C. tetani, but other

bacteria, such as C. botulinum. Ex. 1002 at ¶ 28.

Demain found that animal-based products typically employed in the seed

and fermentation media for growth and toxigenesis by C. tetani are not required,

but instead, vegetable-based products can replace these animal-based products.

Ex. 1006 at 6. More specifically, Demain discloses soy-based fermentation media

for growth and toxin production of C. tetani. For example, hydrolyzed soy can

replace animal product, such as such as beef heart infusion (BHI) and NZ-

Case/NZ-CaseTT (digested casein), as a source of amino acids. Accordingly, a

“soy-based fermentation media can comprise a soy-based product, a source of

carbon such as glucose, salts such as NaCl and KCl, phosphate-containing

ingredients such as Na2HPO4, KH2PO4, divalent cations such as iron and

magnesium, iron powder, and amino acids such as L-cysteine and L-tyrosine.” Id.,

at 7.

Demain further discloses a method for growing C. tetani in animal product-

free medium. Id., at 8. Growth is monitored by optical density (O.D.), and

fermentation is stopped after cell lysis has proceeded for at least 48 hours as

determined by O.D. Id., at 12. The tetanus toxin “may be isolated and purified

using methods of protein purification well known to those of ordinary skill in the

protein purification art.” Id., at 9.

21 716021485

VI. STATEMENT OF PRECISE RELIEF REQUESTED AND THE REASONS THEREFOR (37 C.F.R. § 42.22(a))

A. Explanation of Ground 1 for Unpatentability – Claims 1 and 3-6 are Anticipated by Smelt

Smelt anticipates claims 1 and 3-6 of the ’041 patent because it discloses

each limitation either expressly or inherently. Ex. 1002 at ¶ 53. See, e.g., King

Pharmaceuticals, Inc. v. EON Labs, Inc., 616 F.3d 1267, 1374 (Fed. Cir. 2010).

Smelt discloses methods for growing C. botulinum in aqueous suspensions (i.e.,

media) of soya (“soy”) protein that is free of animal products, and obtaining

botulinum toxin. The aqueous suspensions contains: “soya concentrate 9.1%;

glucose 0.54%; locust bean gum 0.36%; and water 90%.” Ex. 1003 at 76.

Further, Smelt experimented with various levels of soy concentrate to determine

the optimal growth and toxin production. When mixed cultures of C. botulinum

type A and B were cultured in pasteurized or sterilized soy suspensions, they were

found to produce botulinum toxin. Id., at 78 and Table 1. The Cl. botulinum

strains used to produce spores were, according to Smelt, “obtained in cooked meat

medium.” However, that medium is not the “fermentation medium” as claimed.

Ex. 1002 at ¶ 60. Nor would such spores of Smelt transfer any animal products

into a medium or the claimed fermentation medium. Id. Thus, the fermentation

medium of Smelt was completely free of animal products. Id.

22 716021485

The botulinum toxin was recovered using the methods of Smelt and Haas

(Ex. 1008) or Baird-Parker (Ex. 1009). Specifically, Baird-Parker discloses that

“cultures [of C. botulinum] are centrifuged and the supernatants sterilized by

passing then through a membrane filter; 0.25 ml of the sterile filtrates are injected

intraperitoneally (IP) into each of a pair of mice.” Ex. 1009 at 527. The recovered

toxin was toxic to mice even after dilution by 100-fold. Ex. 1003 at 79.

Accordingly, Smelt discloses all the requirements of independent claims 1 and 6.

Ex. 1002 at ¶¶ 67 and 76.

Furthermore, Smelt teaches culturing C. botulinum type A and B in an

animal product-free media to produce botulinum toxin. The botulinum toxin is

recovered from the fermentation medium by centrifugation and purified by

membrane filtration. Ex. 1002 at ¶ 73; Ex. 1009 at 527. Thus, Smelt discloses all

the limitations of claims 3-5. Id.

In sum, Smelt anticipates independent claims 1 and 6 and dependent claims

3-5 as illustrated in the chart below:

Claim Smelt (Ex. 1003)

1. A method for obtaining a biologically active botulinum toxin, comprising the steps of: (a) providing a fermentation medium which is free of an animal product;

“Aqueous suspensions were prepared containing: soya concentrate 9.1%; glucose 0.54%; locust bean gum 0.36%; and water 90%.” Ex. 1003 at 76.

“The soya protein concentrate was obtained as a powder [] and contained protein 60%; insoluble carbohydrates 29%; sucrose 4%; stachyose 1.5%; raffinose 0.5%; and ash 5%.” Id. at 76.

23 716021485


(b) culturing a Clostridium botulinum bacterium in the fermentation medium under conditions which permit production of a botulinum toxin, and;

“When spores of Cl. botulinum were inoculated into pasteurized soya suspensions they initiated growth and formed toxin over the pH range of 4.2-4.4 (Table 1).” Id. at 77-78.

“When the soya suspensions were sterilized and inoculated with Cl. botulinum and the two bacilli, growth of Cl. botulinum and toxin production were associated with growth of the bacilli (Fig. 2).” Id. at 78-79.

(c) recovering a biologically active botulinum toxin from the fermentation medium,

“The presence of botulinum toxin was detected in mice . . . by the method of Baird-Parker (1969)” Id. at 77.

Baird-Parker (1969) discloses that “cultures are centrifuged and the supernatants sterilized by passing them through a membrane filter; 0.25 ml of the sterile filtrates are injected intraperitoneally (IP) into each of a pair of mice.” Ex. 1009 at 527.

wherein the fermentation medium comprises a protein product obtained from yeast or from a vegetable, and wherein the vegetable is selected from the group consisting of soy, malt and corn.


3. The method of claim 1, wherein the botlinum toxin is selected from the group consisting of botulinum toxins types A, B, C, D, E, F and G.

“Most of the experiments were done with mixed cultures of Cl. Botulinum types A and B in the presence of two strains of Bacillus subtilis.” Id. at Abstract.

“Six strains of Cl. Botulinum, four type A and two proteolytic type B, were used.” Id. at 76.

4. The method of claim 1, wherein the botulinum toxin is botulinum toxin types A.

“Most of the experiments were done with mixed cultures of Cl. Botulinum types A and B in the presence of two strains of Bacilus subtilis.” Id. at Abstract.

24 716021485



5. The method of claim 1, wherein the botulinum toxin is further purified.

“The presence of botulinum was detected in mice . . . by the method of Baird-Parker (1969)” Ex. 1003 at 77.


6. A method for obtaining a biologically active botulinum toxin type A, the method comprising the steps of: (a) providing a fermentation medium which is free of an animal product;




(b) culturing a Clostridium botulinum type A bacterium in the fermentation medium under conditions which permit production of a botulinum toxin type A, and;

“When spores of Cl. botulinum were inoculated into pasteurized soya suspensions they initiated growth and formed toxin over the pH range of 4.2-4.4 (Table 1).” Id. at 77-78.

“When the soya suspensions were sterilized and inoculated with Cl. botulinum and the two bacilli, growth of Cl. botulinum and toxin production were associated with growth of the bacilli (Fig. 2).” Id. at 78-79.

(c) recovering a biologically active botulinum toxin type A from the fermentation medium

“The presence of botulinum toxin was detected in mice . . . by the method of Baird-Parker (1969)” Ex. 1003 at 77.

Baird-Parker (1969) discloses that “cultures are centrifuged and the supernatants sterilized by passing them through a membrane filter; 0.25 ml of the sterile filtrates are injected intraperitoneally (IP) into

25 716021485


each of a pair of mice.” Ex. 1009 at 527.

wherein the fermentation medium comprises a protein product obtained from yeast or from a vegetable and wherein the vegetable is selected from the group consisting of soy, malt and corn.

“Aqueous suspensions were prepared containing: soya concentrate 9.1%; glucose 0.54%; locust bean gum 0.36%; and water 90%.” Id. at 76.

See Ex. 1002 at ¶¶ 53-76.

B. Explanation of Ground 2 for Unpatentability – Claims 1-11 are Obvious Over Smelt in View of Schantz

1. Independent Claims 1, 6, 7 and 11 are Obvious Over Smelt in View of Schantz

Claims 1, 6, 7 and 11 are invalid as obvious over Smelt in view of Schantz.

Ex. 1002 at ¶ 77. Claim 1 describes a method for obtaining a biologically active

botulinum toxin by culturing Cl. botulinum in a fermentation medium containing

yeast, soy, malt, or corn, but free of any animal product, and recovering the

biologically active botulinum toxin. Ex. 1001 at 19:8-20. Claim 6 is limited to C.

botulinum type A bacterium. Id. at 19:31-43. Claims 7 and 11 describe methods

for making a substantially animal product-free pharmaceutical composition of

botulinum toxin and, specifically, botulinum toxin type A, respectively. Id. at

19:44-20:17; 20:25-45. These methods would have been obvious to a POSA in

light of: (1) the disclosure by Smelt (Ex. 1003) of an aqueous soy suspension (i.e,

26 716021485

fermentation medium) free of animal products for the growth of C. botulinum and

the production of botulinum toxin coupled with (2) Schantz (Ex. 1004), which

teaches the preparation and therapeutic applications of botulinum toxin.

A patent is invalid as obvious “if the difference 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 of

ordinary skill in the art to which the subject matter pertains.” Allergan, Inc. v.

Apotex, 754 F.3d 952, 961 (Fed. Cir. 2014) citing 35 U.S.C. § 103(a). This

analysis “entails an expansive and flexible approach.” Sciele Pharma Inc. v. Lupin

Ltd., 684 F.3d 1253, 1259 (Fed. Cir. 2012) quoting KSR Int'l Co. v. Teleflex, Inc.,

550 U.S. 398, 415, 127 S.Ct. 1727 (2007) (internal quotes omitted). Encompassed

within this flexible approach is an understanding that motivation may be found

implicitly in the prior art or the common knowledge and common sense of those of

ordinary skill in the art. Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286, 1291

(Fed. Cir. 2006); Dystar Textilfarben GMBH & Co., v. C.H. Patrick, 464 F.3d

1356, 1367 (Fed. Cir. 2006).

A POSA would have been motivated to combine Smelt with Schantz with a

reasonable expectation of success in achieving the claims of the ’041 patent.

Schantz discloses the preparation of botulinum toxin type A, and its clinical uses.

27 716021485

Ex. 1002 at ¶ 21. In so doing, Schantz points out the need for an animal product-

free medium in preparing botulinum toxin for human treatment —

“The production by culturing and the purification had to

be carried out so that the toxin was not exposed to any

substance that might contaminate the final product in

trace amounts and cause undue reactions in the patient.

These restrictions required culturing in simplified

medium without the use of animal meat products and

purification by procedures not involving synthetic

solvents or resins.”

Ex. 1004 at 81; Ex. 1002 at ¶ 78. (emphasis added). Indeed, it was known that

animal products posed a potential risk of contamination by biological molecules,

such as protein agents (e.g., prions), antigenic proteins, and viruses, which can

pose a health risk to patients. Ex. 1006, at 6. Further, animal-based media was

cost-prohibitive causing a need for a less expensive, more readily available source

of media suitable for culturing clostridia. Ex. 1007 at 59; Ex. 1010 at 213.

As discussed above, Smelt discloses an aqueous soya suspension (i.e.,

medium) free of animal products for culturing C. botulinum type A and B and

obtaining botulinum toxin. Based on Schantz, a POSA would have been motivated

to employ a medium free of animal products, such as Smelt, to culture C.

botulinum for toxin production to avoid potential carry-over contamination. As

suggested by Smelt, a POSA would have replaced the animal product with soy in

28 716021485

the medium. Further, Schantz discloses a process for purifying botulinum type A

toxin, i.e., the botulinum toxin is precipitated from the medium and

crystallized/recrystallized to obtain purified botulinum toxin. Ex. 1004 at 82-83.

For therapeutic applications, Schantz teaches that “[c]rystalline botulinum

toxin type A was the first microbial protein of this complexity to be considered an

injectable substance by the FDA.” Id., at 83. The botulinum type A toxin can be

used to treated a “wide variety of disorders characterized by involuntary

movements of muscle groups (Table 2), particularly those involved in focal or

segmental dystonias.” Id., at 83-84 and Table 2. Schantz teaches that formulating

botulinum type A toxin as a pharmaceutical composition “for dispensing as a drug

and compatible for injection into muscle required (i) dilution in a suitable medium

for stability of toxicity, (ii) filtration for sterility, and (iii) drying. Diluting a

solution of botulinum toxin type A from a concentration of 1 or 2 mg/ml to

nanogram concentrations causes detoxification unless another protein is added for

protection . . . human serum albumin was adopted for medical use.” Id., at 83.

Based on these teachings, the motivation to combine Smelt and Schantz is

undeniable. First, the prior art specifically teaches the desire for and use of animal

product-free media for the culture of C. botulinum and production of toxin. See,

e.g., Ex. 1003 and 1004; see also Ex. 1006 and 1014. Each reference expresses a

need for an animal product-free medium due to the potential health risks posed by

29 716021485

contamination from animal products of protein agents, antigenic peptides, and

viruses. Ex. 1002 at ¶ 82.

Second, the prior art provides an alternative (and desirable) source of media

free of animal products. Id. at ¶ 83. For example, Smelt discloses an aqueous soy

media free of animal product that supports culturing of C. botulinum and recovery

of the botulinum toxin. Id. Likewise, Starin discloses vegetable medium,

including corn, string beans, peas and spinach, suitable for the growth of C.

botulinum and the production of botulinum toxin. Id.

Third, the patent owner simply combined known elements from Smelt (i.e.,

aqueous soy medium) and Schantz (i.e., well-known fermentation and isolation

processes and a pharmaceutical composition for botulinum toxin) to obtain a

method that yields predictable results – biologically active botulinum toxin and

pharmaceutical compositions thereof. Id. at ¶ 84.

Fourth, the patent owner simply identified a finite number of solutions, such

as soy and corn media, that the prior art disclosed and demonstrated would support

the growth of C. botulinum and the production of toxin. The ’041 patent did not

contribute any knowledge to the art. This is evident as the ’041 patent

specification contains no actual data, but only prophetic examples based upon

results established by the actual data in the prior art. Id. at ¶ 88.

30 716021485

Fifth, although the ’041 patent purports that it was “surprising . . .that

animal-based product are not required in media for growth of Clostridium

botulinum,” (Ex. 1001 at 11:31-33) there is, in fact, no evidence in the prior art that

such result was unexpected. On the contrary, the prior art teaches that vegetable-

based media, such as soy and corn, are suitable for growth and toxin production by

C. botulinum. Ex. 1002 at ¶ 86. As discussed above, the claims of the ’041 patent

simply combine well-known elements in Smelt and Schantz to describe a method

that yields predictable results. Thus, there is no evidence of objective indicia of

nonobviousness sufficient to find the claims nonobvious over the teachings of

Smelt and Schantz. Id.

2. Dependent Claims 2-5 and 8-10 Are Obvious Over Smelt in View of Schantz

The additional limitation of the dependent claims do not deter the conclusion

that Smelt and Schantz render the dependent claims of the ’041 patent obvious. Id.

at ¶ 87. Claim 2 requires that the culturing is performed until at least 48 hours

after an initial drop in cell density due to cell lysis. Ex. 1001 at 19:21-23. Schantz

discloses a process for producing botulinum toxin. Briefly, C. botulinum is

inoculated in medium and “growth is usually complete in 24 to 36 h, at which time

cells undergo lysis. Complete lysis and clearing of the culture take 2 to 3 days.”

Ex. 1004 at 82. Accordingly, once cell lysis begins (i.e., drop in cell density),

culturing continues for at least 48 hours to complete lysis and clear the culture.

31 716021485

This is because “[t]he toxin is liberated during the lysis and is activated by

proteases present in the culture broth that convert a poorly active protoxin to highly

potent toxin.” Ex. 1004 at 82; see also Ex. 1006 at 12 (for production of C. tetani

toxin, a similar microbial neurotoxin, “[f]ermentation preferably is stopped after

cell lysis has proceeded for at least 48 hours as determined by growth measurement

(optical density). As cells lyse, the O.D. of the medium will decrease”). As the

prior art teaches all of the limitations, claim 2 is obvious in view of the discussion

above. Ex. 1002 at ¶ 87.

Claims 3, 4, 8 and 9 describe the types of botulinum toxin — type A, B, C,

D, E, F and G and, more specifically, type A. Smelt discloses mixed cultures of C.

botulinum type A and B in soy suspensions for production of botulinum toxin types

A and B. Likewise, Schantz teaches the preparation of botulinum type A toxin.

Accordingly, claims 3, 4, 8 and 9 are obvious in view of the discussion above. Ex.

1002 at ¶ 88.

Claim 5 and 10 require that the botulinum toxin is further purified. Schantz

teaches that botulinum toxin is purified “by the simplest procedures and avoided

exposure to substances such as added enzymes or columns of synthetic resins, used

in some methods, that could contaminate the preparation and be carried into the

final injected preparations.” Ex. 1004 at 82. Schantz describes the purification

process in which the botulinum toxin is precipitated from the medium and

32 716021485

crystallized/recrystallized to obtain the purified botulinum toxin. Id., at 82-83. As

the prior art teaches all of the limitations, claims 5 and 10 are obvious in view of

the discussion above. Ex. 1002 at ¶ 89.

3. Summary of the Obviousness Rejection under Ground 2

Claim Smelt and Schantz (Exs. 1003 and 1004)


Smelt




Smelt

When spores of Cl. botulinum were inoculated into pasteurized soya suspensions they initiated growth and formed toxin over the pH range of 4.2-4.4 (Table 1).” Id. at 77-78.

“When the soya suspensions were sterilized and inoculated with Cl. botulinum and the two bacilli, growth of Cl. botulinum ad toxin production were associated with growth of the bacilli (Fig. 2).” Id. at 78-79.

(c) recovering a biologically active botulinum toxin from the fermentation medium,

Smelt



33 716021485


Schantz

“The purification of botulinum toxin type A in our laboratory for human use was designed to be carried out by the simplest procedures and avoided exposure to substances such as added enzymes or columns of synthetic resins, used in some methods, that could contaminate the preparation and be carried into the final injected preparations. It is briefly described as follows.” Ex. 1004 at 82.


Smelt

“Aqueous suspensions were prepared containing: soy concentrate 9.1%; glucose 0.54%; locust bean gum 0.36%; and water 90%.” Ex. 1003 at 76.

2. The method of claim 1, wherein in the step of culturing, the culturing is performed until at least 48 hours after initial drop in cell density due to cell lysis.

Schantz

“Following inoculation, growth is usually complete in 24 to 36 h, at which time cells undergo lysis. Complete lysis and clearing of the culture takes 2 to 3 days.” Ex. 1004 at 82.


8. The method of claim 7, wherein the botulinum toxin is selected from the group consisting of botulinum toxins types A, B, C, D, E, F and G.

Smelt

“Most of the experiments were done with mixed cultures of Cl. Botulinum types A and B in the presence of two strains of Bacilus subtilis.” Ex. 1003 at Abstract.


Schantz

“The type A toxin Hall strain was chosen for production of toxin.” Ex. 1004 at 82.

34 716021485



9. The method of claim 7, wherein the botulinum toxin is botulinum toxin type A.

Smelt

“Most of the experiments were done with mixed cultures of Cl. Botulinum types A and B in the presence of two strains of Bacilus subtilis.” Ex. 1003 at Abstract.




Smelt



Schantz



Smelt



35 716021485



(b) culturing a Clostridium botulinum type A bacterium in the fermentation medium under conditions which permit production of a botulinum toxin type A, and;

Smelt

“When spores of Cl. botulinum were inoculated into pasteurized soya suspensions they initiated growth and formed toxin over the pH range of 4.2-4.4 (Table 1).” Ex. 1003 at 77-78.

“When the soya suspensions were sterilized and inoculated with Cl. botulinum adm the two bacilli, growth of Cl. botulinum and toxin production were associated with growth of the bacilli (Fig. 2).” Id. at 78-79.


Smelt



Schantz


wherein the fermentation medium comprises a protein product obtained from yeast or from a vegetable and wherein the

Smelt


36 716021485


vegetable is selected from the group consisting of soy, malt and corn. 7. A method for making a substantially animal product free pharmaceutical composition in which the active ingredient is a botulinum toxin, the method comprising the steps of: (a) obtaining a biologically active botulinum toxin by: (i) providing a fermentation medium which is free of an animal product;

Smelt

“Aqueous suspensions were prepared containing: soya concentrate 9.1%; glucose 0.54%; locust bean gum 0.36%; and water 90%.” Id. at 76.

“The soya protein concentrate was obtained as a powder [] and contained protein 60%; insoluble carbohydrates 29%; sucrose 4%; stachyose 1.5%; raffinose 0.5%; and ash 5%.” Ex. 1003 at 76.

Schantz

“Crystalline botulinum toxin type A was the first microbial protein of this complexity to be considered an injectable substance by the FDA.” Ex. 1004 at 83.

“Preparation of the toxin for dispensing as a drug and compatible for injection into muscle required (i) dilution in a suitable medium for stability of toxicity, (ii) filtration for sterility, and (iii) drying. Diluting a solution of botulinum toxin type A from a concentration of 1 or 2 mg/ml to nanogram concentrations causes detoxification unless another protein is added for protection. . . . human serum albumin was adopted for medical use.” Id. at 83.

(ii) culturing a Clostridium botulinum bacterium in the fermentation medium under conditions which permit production of a botulinum toxin, and;

Smelt

When spores of Cl. botulinum were inoculated into pasteurized soya suspensions they initiated growth and formed toxin over the pH range of 4.2-4.4 (Table 1).” Ex. 1003 at 77-78.

“When the soya suspensions were sterilized and inoculated with Cl. botulinum and the two bacilli, growth of Cl. botulinum ad toxin production were associated with growth of the bacilli (Fig. 2).” Id. at 78-79.

37 716021485


(iii) recovering a biologically active botulinum toxin from the fermentation medium;

Smelt



Schantz

“The purification of botulinum toxin type A in our laboratory for human use was designed to be carried out by the simplest procedures and avoided exposure to substances such as added enzymes or columns of synthetic resins, used in some methods, that could contaminate the preparation and be carried into the final injected preparations. It is briefly described as follows.” Ex. 1004 at 82

(b) formulating the botulinum toxin with a suitable excipient,

Schantz

“Preparation of the toxin for dispensing as a drug and compatible for injection into muscle required (i) dilution in a suitable medium for stability of toxicity, (ii) filtration for sterility, and (iii) drying. Diluting a solution of botulinum toxin type A from a concentration of 1 or 2 mg/ml to nanogram concentrations causes detoxification unless another protein is added for protection. . . . human serum albumin was adopted for medical use.” Ex. 1004 at 83.

thereby making a substantially animal product free pharmaceutical composition in which the active ingredient is a

Smelt


38 716021485


botulinum toxin, wherein the fermentation medium comprises a protein product obtained from yeast or from a vegetable, and wherein the vegetable is selected from the group consisting of soy, malt and corn.

11. A method for making an animal product free pharmaceutical composition in which the active ingredient is a botulinum toxin type A, the method comprising the steps of: (a) obtaining a biologically active botulinum toxin type A by: (i) providing a fermentation medium which is free of an animal product;

Smelt




Schantz

“Crystalline botulinum toxin type A was the first microbial protein of this complexity to be considered an injectable substance by the FDA.” Ex. 1004 at 83.

“Preparation of the toxin for dispensing as a drug and compatible for injection into muscle required (i) dilution in a suitable medium for stability of toxicity, (ii) filtration for sterility, and (iii) drying. Diluting a solution of botulinum toxin type A from a concentration of 1 or 2 mg/ml to nanogram concentrations causes detoxification unless another protein is added for protection. . . . human serum albumin was adopted for medical use.” Id. at 83.

(ii) culturing a Clostridium botulinum type A bacterium in the

Smelt

“When spores of Cl. botulinum were inoculated into pasteurized soya suspensions they initiated growth

39 716021485


fermentation medium under conditions which permit production of a botulinum toxin type A, and;

and formed toxin over the pH range of 4.2-4.4 (Table 1).” Ex. 1003 at 77-78.

“When the soya suspensions were sterilized and inoculated with Cl. botulinum adm the two bacilli, growth of Cl. botulinum and toxin production were associated with growth of the bacilli (Fig. 2).” Id. at 78

(iii) recovering a biologically active botulinum toxin type A from the fermentation medium;

Smelt

“The presence of botulinum toxin was detected in mice . . . by the method of Baird-Parker (1969).” Id. at 77.


Schantz

“The purification of botulinum toxin type A in our laboratory for human use was designed to be carried out by the simplest procedures and avoided exposure to substances such as added enzymes or columns of synthetic resins, used in some methods, that could contaminate the preparation and be carried into the final injected preparations. It is briefly described as follows.” Ex. 1004 at 82

(b) formulating the botulinum toxin type A with a suitable excipient,

Schantz

“Preparation of the toxin for dispensing as a drug and compatible for injection into muscle required (i) dilution in a suitable medium for stability of toxicity, (ii) filtration for sterility, and (iii) drying. Diluting a solution of botulinum toxin type A from a concentration of 1 or 2 mg/ml to nanogram concentrations causes detoxification unless another protein is added for protection. . . . human serum albumin was adopted for medical use.” Ex. 1004 at

40 716021485


83.

thereby making an animal product free pharmaceutical composition in which the active ingredient is a botulinum toxin type A, wherein the fermentation medium comprises a protein product obtained from yeast or from a vegetable, and wherein the vegetable is selected from the group consisting of soy, malt and corn.

Smelt


See Ex. 1002 at ¶¶77-89 and Table in X.C.

C. Explanation of Ground 3 for Unpatentability – Claims 1-11 are Obvious Over Whitmer in View of Demain and Schantz

1. Independent Claims 1, 6, 7 and 11 are Obvious Over Whitmer in View of Demains and Schantz

Claims 1, 6, 7 and 11 are invalid as obvious over Whitmer (Ex. 1005) in

view of Demain (Ex. 1006) and Schantz (Ex. 1006). Ex. 1002 at ¶ 90. Claims 1,

6, 7 and 11 describes a method for obtaining a biologically active botulinum toxin,

in particular, botulinum type A, and a pharmaceutical composition thereof, by

culturing C. botulinum in a fermentation medium containing yeast, soy, malt, or

corn, but free of an animal product, and recovering the biologically active

botulinum toxin.

41 716021485

Whitmer (Ex. 1005) discloses the minimal media requirements for

nutritional growth and toxigenesis for different strains of C. botulinum type A, B,

E and F. Ex. 1005 at 757 and Table 6. According to Whitmer, the “minimal media

containing the minimum number of nutrients for growth were prepared by using

inorganic salts (see Materials and Methods), amino acids, vitamins, and glucose at

appropriate concentrations (Table 4).” Id., at 756. Table 4 is discussed above in

Section V.B.1, supra. This minimal media is free of any animal product. Ex. 1002

at ¶ 91.

C. botulinum strains cultured on minimal media produced toxin albeit at titer

levels approximately 5 to 50 times less than those usually obtained in complex

toxin production media (i.e., animal-based). Ex. 1005 at 757 and Table 7.

However, this latter fact is irrelevant as no limitation is claimed. Ex. 1002 at ¶ 92.

Whitmer teaches that the minimal media, free of any animal product, can be used

to culture C. botulinum and obtain botulinum toxin. Ex. 1002 at ¶ 92. Whitmer

does not disclose whether the minimal media contain a yeast or vegetable protein

source. However, Demain teaches that soy protein (e.g., hydrolyzed soy) is a

substitute for animal protein in media. Ex. 1006.

Demain (Ex. 1006) discloses an animal protein-free culture medium for the

production by C. tetani toxin. Demain clearly expresses that “all media and

cultures used for the growth of C. tetani for the production of Tetanus Toxin are

42 716021485

substantially or completely free of animal-derived products.” Ex. 1006 at 7

(emphasis added). Demain found “that animal-based products are not required as

ingredients in media for the growth of C. tetani, and particularly that vegetable-

based products can replace the animal-based products typically employed in such

media for the growth of C. tetani.” Id., at 6. Specifically, Demain teaches that

soy, and in particular hydrolyzed soy, can replace all animal based products, such

as BHI and NZ-Case/NZ-CaseTT, in media. Id.

Similar to the reasons stated above, a POSA would have been motivated to

combine Whitmer with Demain with a reasonable expectation of success in

achieving the claims of the ’041 patent. Both Whitmer and Demain are directed to

methods of culturing Clostridia (i.e., C. botulinum and C. tetani, respectively) in

an animal product-free media for production of a neurotoxin. Whitmer does not

disclose whether the amino acids are from yeast or vegetable sources. However,

Demain teaches that soy (and hydrolyzed soy) can be used as an animal-substitute

protein source. Demain teaches “that toxin production in C. tetani grown in . . .

medium containg Hy-Soy as a replacement for BHI and NZ-CaseTT reached (or

exceeded) levels attained in media containing BHI and NZ-CaseTT.” Ex. 1002 at

¶93. Therefore, a POSA would have been motivated to supplement soy (or

hydrolyzed soy) into the minimal media of Whitmer (free of animal products) to

attain optimal growth and toxin production. Ex. 1002 at ¶ 94.

43 716021485

Although Demain is related to C. tetani and not C. botulinum, Schantz

teaches that C. tetani and C. botulinum are very similar in: (a) morphology

(“[t]etanus toxin, like botulinum toxin, is produced by an anaerobic sporefoming

rod that has a similar morphology to C. botulinum.” Ex. 1004 at 89) and (b)

culturing methods (“[t]etanus toxin is produced in deep culture by methods similar

to those described for botulinum toxin.” id., at 90.). Moreover, both tetanus and

botulinum toxins have similar primary structures. Ex. 1004 at 91. It follows that a

POSA would not have considered the differences between C. tetani and C.

botulinum an obstacle at all. Ex. 1002 at ¶ 95. Rather, due to their similarity in

morphology and culturing methods, as well as their similarity in toxin primary

structures, a POSA would have been motivated to apply the teachings of Demain—

i.e., use of soy as an animal-substitute in medium—to the minimal media of

Whitmer to culture C. botulinum, and have a reasonable expectation of success in

the production of botulinum toxin. Id.

A POSA would also have been motivated to formulate a pharmaceutical

composition comprising the botulinum toxin produced from the culture of C.

botulinum in the animal product-free medium. Id. at ¶ 96. The prior art is replete

with methods of preparing pharmaceutical compositions and is standard practice in

the industry. Id. Schantz teaches that formulating botulinum type A toxin as a

pharmaceutical composition “for dispensing as a drug and compatible for injection

44 716021485

into muscle required (i) dilution in a suitable medium for stability of toxicity, (ii)

filtration for sterility, and (iii) drying. Diluting a solution of botulinum toxin type

A from a concentration of 1 or 2 mg/ml to nanogram concentrations causes

detoxification unless another protein is added for protection. . . . human human

serum albumin was adopted for medical use” Ex. 1004 at 83. Indeed, botulinum

type A toxin had already been formulation as a pharmaceutical composition

approved by the FDA for injection, i.e., BOTOX®.

Based on the foregoing, a POSA would have been motivated to combine the

teachings of Whitmer, Demain, and Schantz to culture C. botulinum in Whitmer’s

minimal media containing hydrolyzed soy and free of animal product, and would

have had a reasonable expectation of obtaining a biologically active botulinum

toxin and making a pharmaceutical composition thereof.

As discussed in Section VI.B.1, supra, the prior art specifically teaches the

desire for and use of animal product-free media for the culture of C. botulinum and

production of toxin due to the potential health risk posed by contamination from

animal products. See, e.g., Exs. 1004, 1005 and 1006. Further, the prior art

provides an alternative source of media, which is free of animal products. For

example, Whitmer (Ex. 1005) teaches a chemically defined media and Demain

(Ex. 1006) teaches that hydrolyzed soy is a substitute for animal products in media.

Patent owner simply combined known elements from a finite number of prior art

45 716021485

solutions. Indeed, patent owner combined Whitmer (i.e., chemically defined

minimal media) with Demain (i.e., substituted hydrolyzed soy for animal product)

and Schantz (i.e., well-known fermentation and isolation processes and

pharmaceutical composition for botulinum toxin) to yield predictable results–

biologically active botulinum toxin and pharmaceutical compositions thereof. In

short, there is no evidence in the prior art that claims of the ’041 patent were

unexpected. In fact, the prior art teaches that vegetable based media, such as soy

and corn, are suitable for growth and toxin production by C. botulinum. Ex. 1002

at ¶ 98; Exs. 1006 and 1014. Thus, there is no evidence of objective indicia of

nonobviousness sufficient to negate obviousness.

2. Dependent Claims Are Obvious Over Whitmer in View of Demain and Schantz

Dependent claims 2-5 and 8-10 are similarly obvious over Whitmer in view

of Demain and Schantz. Ex. 1002 at ¶ 99. Demain discloses that “[f]ermentation

preferably is stopped after cell lysis has proceeded for at least 48 hours as

determined by growth measurements (optical density). As cells lyse, the O.D. of

the medium will decrease.” Ex. 1006 at 12. Likewise, Schantz teaches that C.

botulinum “growth is usually complete in 24 to 36 h, at which time cells undergo

lysis. Complete lysis and clearing of the culture takes 2 to 3 days.” Ex. 1004 at

82. Thus, Demain and Schantz teach that culturing is performed until at least 48

46 716021485

hours after initial drop in cell density due to cell lysis, and renders claim 2 obvious.

Ex. 1002 at ¶ 99.

Whitmer “tested the abilities of several group I and II C. botulinum strains to

grow in the minimal media (Table 6). Numerous proteolytic group I strains of

serotypes A, B, and F grew well in MI, and the five type E strains also grew well in

MII.” Ex. 1005 at 757. Likewise, Schantz uses the type A toxin Hall strain for

production of toxin. Thus, claims 3, 4, 8 and 9 are obvious. Ex. 1002 at ¶ 100.

Claims 5 and 10 are obvious in light of Demain, which teaches that “Tetanus

Toxin may be isolated and purified using methods of protein purification well

known to those of ordinary skill in the protein purification art” citing Coligan (Ex.

1021) and Ozutsumi (Ex. 1022). Ex. 1006 at 9. The ’041 patent admits the same

for C. botulinum: “A botulinum toxin can be isolated and purified using methods

of protein purification well known to those of ordinary skill in the protein

purification art” likewise citing Coligan (Ex. 1021) and Ozutsumi (Ex. 1022). Ex.

1001 at 13:7-11. In fact, the ’041 patent is almost word for word and cites the

same prior art references as Demain. Schantz also describes a process for the

purification of botulinum type A toxin. Ex. 1004 at 82.

47 716021485

3. Summary of the Obviousness Rejection under Ground 3

Claim Whitmer, Demain and Schantz (Exs. 1005, 1006 and 1004)


Whitmer

“The compositions of the chemically defined minimal media are listed in Table 4.” Ex. 1005 at 757.

Demain

“The present invention encompasses the finding that animal-based products are not required as ingredients in media for the growth of C. tetani, and particularly that vegetable-based products can replace the animal-based products typically employed in such media for the growth of C. tetani.” Ex. 1006 at 6.

“Most preferably, all media and cultures used for the growth of C. tetani for the production of Tetanus Toxin are substantially or completely free of animal-derived products.” Ex. 1006 at 7 (emphasis added).


Whitmer

“The objective of the present study was to define and compare the minimal organic nutrient requirements for growth and toxigenesis by C. botulinum Okra B and Iwanai E and to develop defined minimal media that support good growth of C. botulinum groups I and II.” Ex. 1005 at 758.

“We tested the abilities of several group I and II C. botulinum strains to grow in the minimal media (Table 6). Numerous proteolytic group I strains of serotypes A, B, and F grew well in MI, and the five type E strains also grew well in MII.” Ex. 1005 at 757.

“The formation of neurotoxin was determined for group I and II strains after growth for 5 days in the respective minimal media (Table 7).” Ex. 1005 at 757.

(c) recovering a biologically active botulinum toxin from

Whitmer

Toxin formation is tested “injecting culture fluid intraperitoneally into mice and noting the time to death.”

48 716021485


the fermentation medium,

Ex. 1005 at 754 and Table 7, footnote a.

“The titers ranged from 6 x 102 to 8 x 104 50% minimum lethal doses (mouse) per ml, depending on the strain tested.” Ex. 1005 at 757.

Demain

“Tetanus Toxin may be isolated and purified using methods of protein purification well known to those of ordinary skill in the protein purification art (Coligan et al. Current Protocols in Protein Science, Wiley & Sons; Ozutsumi et al. Appl. Environ. Microbiol. 49; 939-943:1985.” Ex. 1006 at 9.

’041 Patent

The ’041 patent admits: “A botulinum toxin can be isolated and purified using methods of protein purification well known to those of ordinary skill in the protein purification art (Coligan et al. Current Protocols in Protein Science, Wiley & Sons; Ozutsumi et al. Appl. Environ. Microbiol. 49; 939-943:1985).” Ex. 1001 at 11:7-11.


Whitmer


Demain


“[T]he data in Table 25 indicate that toxin production by C. tetani grown in seed medium and fermentation medium containing Hy-Soy as a replacement for BHI and NZCaseTT reached (or exceeded) levels attained in

49 716021485


media containing BHI and NZ-CaseTT.” Ex. 1006 at 16, see also 54 (In addition, the seed culture of Hy-Soy or [Hy-Soy + Hy-Yest] supported excellent cell growth and toxin production in different fermentation media including fermentation media free of BHI and NZ-CaseTT.

Schantz

“Tetanus toxin is produced in deep culture by methods similar to those described for botulinum toxin” Ex. 1004 at 90.

“Computer searches using the primary sequence of tetanus toxin have not revealed primary structural similarities with any proteins other than botulinum toxin” Ex. 1004 at 91.

2. The method of claim 1, wherein in the step of culturing, the culturing is performed until at least 48 hours after initial drop in cell density due to cell lysis.

Demain

“Growth is monitored by measuring the optical density (O.D.) of the medium. Fermentation preferably is stopped after cell lysis has proceeded for at least 48 hours as determined by growth measurement (optical density). As cells lyse, the O.D. of the medium will decrease.” Ex. 1006 at 12


8. The method of claim 7, wherein the botulinum toxin is selected from the group consisting of botulinum toxins types A, B, C, D, E, F and G.

Whitmer

“The C. botulinum (types A to G, 34 strains) and C. sporogenes (11 strains) strains used in this study are listed in Table 1.” Ex. 1005 at 754 and Table 1.


Schantz

“The type A toxin Hall strain was chosen for production of toxin.” Ex. 1004 at 82

50 716021485



9. The method of claim 7, wherein the botulinum toxin is botulinum toxin type A.

Whitmer



Schantz

“The type A toxin Hall strain was chosen for production of toxin.” Ex. 1004 at 82



Demain


“C. tetani and C. botulinum had primary structure similarity and are cultured by similar methods.” Ex. 1004 at 90-91.

Schantz

“Tetanus toxin is produced in deep culture by methods similar to those described for botulinum toxin” Ex. 1004 at 90. “Computer searches using the primary sequence of tetanus toxin have not revealed primary structural similarities with any proteins other than botulinum toxin” Ex. 1004 at 91.

“The purification of botulinum toxin type A in our laboratory for human use was designed to be carried out by the simplest procedures and avoided exposure to

51 716021485


substances such as added enzymes or columns of synthetic resins, used in some methods, that could contaminate the preparation and be carried into the final injected preparations. It is briefly described as follows.” Ex. 1004 at 82


Whitmer




Demain


“Most preferably, all media and cultures used for the growth of C. tetani for the production of Tetanus Toxin are substantially or completely free of animal-derived products.” Ex. 1006 at 7 (emphasis added)

(b) culturing a Clostridium botulinum type A bacterium in the fermentation medium under conditions which permit production of a botulinum toxin type A,

Whitmer

“The objective of the present study was to define and compare the minimal organic nutrient requirements for growth and toxigenesis by C. botulinum Okra B and Iwanai E and to develop defined minimal media that support good growth of C. botulinum groups I and II.”

52 716021485


and; Ex. 1005 at 758.




Whitmer

Toxin formation is tested “injecting culture fluid intraperitoneally into mice and noting the time to death.” Ex. 1005 at 754 and Table 7, footnote a.


Demain


’041 Patent

The ’041 patent admits: “A botulinum toxin can be isolated and purified using methods of protein purification well known to those of ordinary skill in the protein purification art (Coligan et al. Current Protocols in Protein Science, Wiley & Sons; Ozutsumi et al. Appl. Environ. Microbiol. 49; 939-943:1985.” Ex. 1001, col. 13, lns. 7-11.

wherein the fermentation medium

Demain

53 716021485


comprises a protein product obtained from yeast or from a vegetable and wherein the vegetable is selected from the group consisting of soy, malt and corn.

“The present invention encompasses the finding that animal-based products are not required as ingredients in media for the growth of C. tetani, and particularly that vegetable-based products can replace the animal-based products typically employed in such media for the growth of C. tetani.” Ex. 1006 at 6

7. A method for making a substantially animal product free pharmaceutical composition in which the active ingredient is a botulinum toxin, the method comprising the steps of: (a) obtaining a biologically active botulinum toxin by: (i) providing a fermentation medium which is free of an animal product;

Whitmer


Demain

“In another preferred embodiment of the present invention, the medium used for fermentation of C. tetani is free of animal by-products.” Ex. 1006 at 12.

Schantz

“Preparation of the toxin for dispensing as a drug and compatible for injection into muscle required (i) dilution in a suitable medium for stability of toxicity, (ii) filtration for sterility, and (iii) drying. Diluting a solution of botulinum toxin type A from a concentration of 1 or 2 mg/ml to nanogram concentrations causes detoxification unless another protein is added for protection. . . . human human serum albumin was adopted for medical use” Ex. 1004 at 83.

(ii) culturing a Clostridium botulinum bacterium in the fermentation medium under conditions which permit production of a botulinum toxin, and;

Whitmer

“The objective of the present study was to define and compare the minimal organic nutrient requirements for growth and toxigenesis by C. botulinum Okra B and Iwanai E and to develop defined minimal media that support good growth of C. botulinum groups I and II.” Ex. 1005 at 758.

“We tested the abilities of several group I and II C. botulinum strains to grow in the minimal media (Table

54 716021485


6). Numerous proteolytic group I strains of serotypes A, B, and F grew well in MI, and the five type E strains also grew well in MII.” Ex. 1005 at 757.


(iii) recovering a biologically active botulinum toxin from the fermentation medium;

Whitmer



Demain


’041 Patent

The ’041 patent admits: “A botulinum toxin can be isolated and purified using methods of protein purification well known to those of ordinary skill in the protein purification art (Coligan et al. Current Protocols in Protein Science, Wiley & Sons; Ozutsumi et al. Appl. Environ. Microbiol. 49; 939-943:1985.” Ex. 1001 at 13:7-11.

(b) formulating the botulinum toxin with a suitable excipient,

Schantz

“Preparation of the toxin for dispensing as a drug and compatible for injection into muscle required (i) dilution in a suitable medium for stability of toxicity, (ii) filtration for sterility, and (iii) drying. Diluting a

55 716021485


solution of botulinum toxin type A from a concentration of 1 or 2 mg/ml to nanogram concentrations causes detoxification unless another protein is added for protection. . . . human human serum albumin was adopted for medical use” Ex. 1004 at 83.

thereby making a substantially animal product free pharmaceutical composition in which the active ingredient is a botulinum toxin, wherein the fermentation medium comprises a protein product obtained from yeast or from a vegetable, and wherein the vegetable is selected from the group consisting of soy, malt and corn.

Demain


“[T]he data in Table 25 indicate that toxin production by C. tetani grown in seed medium and fermentation medium containing Hy-Soy as a replacement for BHI and NZCaseTT reached (or exceeded) levels attained in media containing BHI and NZ-CaseTT.” Ex. 1006 at 16, see also 54 (In addition, the seed culture of Hy-Soy or [Hy-Soy + Hy-Yest] supported excellent cell growth and toxin production in different fermentation media including fermentation media free of BHI and NZ-CaseTT.

Schantz

“Tetanus toxin is produced in deep culture by methods similar to those described for botulinum toxin” Ex. 1004 at 90.

“Computer searches using the primary sequence of tetanus toxin have not revealed primary structural similarities with any proteins other than botulinum toxin” Ex. 1004 at 91.

11. A method for making an animal product free pharmaceutical

Whitmer


“The C. botulinum (types A to G, 34 strains) and C.

56 716021485


composition in which the active ingredient is a botulinum toxin type A, the method comprising the steps of: (a) obtaining a biologically active botulinum toxin type A by: (i) providing a fermentation medium which is free of an animal product;

sporogenes (11 strains) strains used in this study are listed in Table 1.” Ex. 1005 at 754 and Table 1.

“We tested the abilities of several group I and II C. botulinum strains to grow in the minimal media (Table 6). Numerous proteolytic group I strains of serotypes A, B, and F grew well in MI, and the five type E strains also grew well in MII.” Id. at 757.

Demain


“Most preferably, all media and cultures used for the growth of C. tetani for the production of Tetanus Toxin are substantially or completely free of animal-derived products.” Id. at 7 (emphasis added)

Schantz


(ii) culturing a Clostridium botulinum type A bacterium in the fermentation medium under conditions which permit production of a

Whitmer

“The objective of the present study was to define and compare the minimal organic nutrient requirements for growth and toxigenesis by C. botulinum Okra B and Iwanai E and to develop defined minimal media that support good growth of C. botulinum groups I and II.”

57 716021485


botulinum toxin type A, and;

Ex. 1005 at 758.



Demain

“In another preferred embodiment of the present invention, the medium used for fermentation of C. tetani is free of animal by-products.” Ex. 1006 at 12.

“[T]he data in Table 25 indicate that toxin production by C. tetani grown in seed medium and fermentation medium containing Hy-Soy as a replacement for BHI and NZCaseTT reached (or exceeded) levels attained in media containing BHI and NZ-CaseTT.” Id. at 16, see also 54 (In addition, the seed culture of Hy-Soy or [Hy-Soy + Hy-Yest] supported excellent cell growth and toxin production in different fermentation media including fermentation media free of BHI and NZ-CaseTT.

(iii) recovering a biologically active botulinum toxin type A from the fermentation medium;

Whitmer



“Table 7. Toxin titers of representative C. botulinum and C. sporogenes strains cultured in MI and MII minimal medium.” Id. at 758.

58 716021485


Demain


’041 Patent

The ’041 patent admits: “A botulinum toxin can be isolated and purified using methods of protein purification well known to those of ordinary skill in the protein purification art (Coligan et al. Current Protocols in Protein Science, Wiley & Sons; Ozutsumi et al. Appl. Environ. Microbiol. 49; 939-943:1985.” Ex. 1001, col. 13, lns. 7-11.

(b) formulating the botulinum toxin type A with a suitable excipient,

Schantz


thereby making an animal product free pharmaceutical composition in which the active ingredient is a botulinum toxin type A, wherein the fermentation medium comprises a protein

Demain

“The present invention encompasses the finding that animal-based products are not required as ingredients in media for the growth of C. tetani, and particularly that vegetable-based products can replace the animal-based products typically employed in such media for the growth of C. tetani.” Ex. 1006 at 6

59 716021485


product obtained from yeast or from a vegetable, and wherein the vegetable is selected from the group consisting of soy, malt and corn.

See Ex. 1002 at ¶¶90-100 and Table in XI.C.

VII. CONCLUSION

Petitioner submits that this Petition and the accompanying exhibits

demonstrate a reasonable likelihood that claims 1-11 of the ’041 patent are

unpatentable as anticipated and/or obvious in view of the prior art. Petitioner

therefore requests that the Board grant inter partes review for each of those claims.

Please charge any fees or credit overpayment to Deposit Account 13-0019.

60 716021485

Dated: April 29, 2015 Respectfully submitted, By: /s/Joseph A. Mahoney

Joseph A. Mahoney, Reg. No. 38,956 Joseph A. Mahoney Jonathan H. Kim MAYER BROWN LLP 71 South Wacker Drive Chicago, IL 60606 Telephone: (312) 701-8979 Facsimile: (312) 706-8530 Counsel for Petitioner

716021485

CERTIFICATE OF SERVICE

I hereby certify that true and correct copies of the foregoing Petition for

Inter Partes Review of U.S. Pat. No. 7,148,041 and Exhibits 1001-1028 were

served on Patent Owner’s Chief Executive Officer and Stephen Donovan, via UPS

overnight delivery service to the correspondence address for Allergan, Inc., the

assignee of the ’041 patent, at the address listed below:

Allergan, Inc. Allergan, Inc. Attn: Chief Executive Officer Attn: Stephen Donovan 2525 Dupont Drive, T2-7H 2525 Dupont Drive, T2-TH Irvine CA 92612 Irvine, CA 92612

Dated: April 29, 2015 /s/Joseph A. Mahoney

Joseph A. Mahoney, Reg. No. 38,956 Counsel for Petitioner

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UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE …716021485 71 South Wacker Drive Chicago, IL 60606 Telephone: (312) 701-8979 Facsimile: (312) 706-8530 Email: [email protected]