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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: jmahoney@mayerbrown.com 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:jkim@mayerbrown.com Counsel for Petitioner
TABLE OF CONTENTS
i 716021485
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
ii 716021485
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
iii 716021485
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
iv 716021485
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
1 716021485
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
2 716021485
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
3 716021485
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
4 716021485
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:
5 716021485
Lead Counsel Back-up Counsel
Joseph A. Mahoney (Reg. No. 38,956) jmahoney@mayerbrown.com 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) jkim@mayerbrown.com 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:
6 716021485
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).
7 716021485
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
8 716021485
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
9 716021485
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
10 716021485
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
11 716021485
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
12 716021485
“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.
13 716021485
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
14 716021485
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
15 716021485
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.
16 716021485
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
Claim Smelt (Ex. 1003)
(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.
“Aqueous suspensions were prepared containing: soya concentrate 9.1%; glucose 0.54%; locust bean gum 0.36%; and water 90%.” Ex. 1003 at 76.
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
Claim Smelt (Ex. 1003)
“Six strains of Cl. Botulinum, four type A and two proteolytic type B, were used.” Id. at 76.
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.
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.
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;
“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.
“Six strains of Cl. Botulinum, four type A and two proteolytic type B, were used.” Id. at 76.
(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
Claim Smelt (Ex. 1003)
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)
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;
Smelt
“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.
(b) 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).” 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
“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 each of a pair of mice.” Ex. 1009 at 527.
33 716021485
Claim Smelt and Schantz (Exs. 1003 and 1004)
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.
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
“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.
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.
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.
“Six strains of Cl. Botulinum, four type A and two proteolytic type B, were used.” Id. at 76.
Schantz
“The type A toxin Hall strain was chosen for production of toxin.” Ex. 1004 at 82.
34 716021485
Claim Smelt and Schantz (Exs. 1003 and 1004)
4. The method of claim 1, wherein the botulinum toxin is botulinum toxin types A.
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.
“Six strains of Cl. Botulinum, four type A and two proteolytic type B, were used.” Id. at 76.
5. The method of claim 1, wherein the botulinum toxin is further purified.
10. The method of claim 7, wherein the botulinum toxin is further purified.
Smelt
“The presence of botulinum 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 each of a pair of mice.” Ex. 1009 at 527.
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.
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;
Smelt
“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.
35 716021485
Claim Smelt and Schantz (Exs. 1003 and 1004)
“Six strains of Cl. Botulinum, four type A and two proteolytic type B, were used.” Id. at 76.
(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.
(c) 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)” 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 each of a pair of mice.” Ex. 1009 at 527.
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.
wherein the fermentation medium comprises a protein product obtained from yeast or from a vegetable and wherein the
Smelt
“Aqueous suspensions were prepared containing: soya concentrate 9.1%; glucose 0.54%; locust bean gum 0.36%; and water 90%.” Ex. 1003 at 76.
36 716021485
Claim Smelt and Schantz (Exs. 1003 and 1004)
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
Claim Smelt and Schantz (Exs. 1003 and 1004)
(iii) recovering a biologically active botulinum toxin from the fermentation medium;
Smelt
“The presence of botulinum 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 each of a pair of mice.” Ex. 1009 at 527.
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
“Aqueous suspensions were prepared containing: soya concentrate 9.1%; glucose 0.54%; locust bean gum 0.36%; and water 90%.” Ex. 1003 at 76.
38 716021485
Claim Smelt and Schantz (Exs. 1003 and 1004)
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
“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.
“Six strains of Cl. Botulinum, four type A and two proteolytic type B, were used.” Id. 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 type A bacterium in the
Smelt
“When spores of Cl. botulinum were inoculated into pasteurized soya suspensions they initiated growth
39 716021485
Claim Smelt and Schantz (Exs. 1003 and 1004)
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.
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.
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
Claim Smelt and Schantz (Exs. 1003 and 1004)
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
“Aqueous suspensions were prepared containing: soya concentrate 9.1%; glucose 0.54%; locust bean gum 0.36%; and water 90%.” Ex. 1003 at 76.
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)
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;
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).
(b) 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 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
Claim Whitmer, Demain and Schantz (Exs. 1005, 1006 and 1004)
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.
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.
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.
“[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
Claim Whitmer, Demain and Schantz (Exs. 1005, 1006 and 1004)
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
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.
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.
“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.
Schantz
“The type A toxin Hall strain was chosen for production of toxin.” Ex. 1004 at 82
50 716021485
Claim Whitmer, Demain and Schantz (Exs. 1005, 1006 and 1004)
4. The method of claim 1, wherein the botulinum toxin is botulinum toxin types A.
9. The method of claim 7, wherein the botulinum toxin is botulinum toxin type A.
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.
“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.
Schantz
“The type A toxin Hall strain was chosen for production of toxin.” Ex. 1004 at 82
5. The method of claim 1, wherein the botulinum toxin is further purified.
10. The method of claim 7, wherein the botulinum toxin is further purified.
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.
“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
Claim Whitmer, Demain and Schantz (Exs. 1005, 1006 and 1004)
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
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;
Whitmer
“The compositions of the chemically defined minimal media are listed in Table 4.” Ex. 1004 at 757.
“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. 1004 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.” Ex. 1004 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)
(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
Claim Whitmer, Demain and Schantz (Exs. 1005, 1006 and 1004)
and; 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 type A from the fermentation medium
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.
“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, col. 13, lns. 7-11.
wherein the fermentation medium
Demain
53 716021485
Claim Whitmer, Demain and Schantz (Exs. 1005, 1006 and 1004)
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
“The compositions of the chemically defined minimal media are listed in Table 4.” Ex. 1005 at 757.
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
Claim Whitmer, Demain and Schantz (Exs. 1005, 1006 and 1004)
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.
(iii) recovering a biologically active botulinum toxin from the fermentation medium;
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.
“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 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
Claim Whitmer, Demain and Schantz (Exs. 1005, 1006 and 1004)
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
“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.
“[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 compositions of the chemically defined minimal media are listed in Table 4.” Ex. 1005 at 757.
“The C. botulinum (types A to G, 34 strains) and C.
56 716021485
Claim Whitmer, Demain and Schantz (Exs. 1005, 1006 and 1004)
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
“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.” Id. at 7 (emphasis added)
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 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
Claim Whitmer, Demain and Schantz (Exs. 1005, 1006 and 1004)
botulinum toxin type A, and;
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.
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
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.
“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.
“Table 7. Toxin titers of representative C. botulinum and C. sporogenes strains cultured in MI and MII minimal medium.” Id. at 758.
58 716021485
Claim Whitmer, Demain and Schantz (Exs. 1005, 1006 and 1004)
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, col. 13, lns. 7-11.
(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 human serum albumin was adopted for medical use” Ex. 1004 at 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
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
Claim Whitmer, Demain and Schantz (Exs. 1005, 1006 and 1004)
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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