Ex Parte Aoki et al

Board of Patent Appeals and Interferences

Sep 30, 2010

10443593 (B.P.A.I. Sep. 30, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
10/443,593 05/21/2003 Kei Roger Aoki 16952CON1CIP1 (BOT) 6992
7590 09/30/2010
STEPHEN DONOVAN
ALLERGAN, INC.
2525 Dupont Drive, T2-7H
Irvine, CA 92612
EXAMINER
GUPTA, ANISH
ART UNIT PAPER NUMBER
1654
MAIL DATE DELIVERY MODE
09/30/2010 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte KEI ROGER AOKI, MICHAEL W. GRAYSTON,
STEVEN R. CARLSON, and JUDITH M. LEON
__________

Appeal 2009-0111001
Application 10/443,593
Technology Center 1600
__________

Before CAROL A. SPIEGEL, TONI R. SCHEINER, and
FRANCISCO C. PRATS, Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL2

1 Heard June 23, 2010.
2 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.

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2
This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims 1, 4-7, 24, 25, 38-41, and 54, directed to a method for treating
strabismus by administering the neurotoxic component of a botulinum toxin.
The claims have been rejected as obvious. We have jurisdiction under 35
U.S.C. § 6(b).

STATEMENT OF THE CASE
Claim 1 is representative of the subject matter on appeal:
1. A method for treating strabismus, the method comprising the step of
administering to a patient a therapeutically effective amount of the
neurotoxic component of a botulinum toxin to thereby treat, strabismus
wherein the neurotoxic component administered to the patient has a
molecular weight of about 150 kilodaltons and comprises a short
polypeptide chain of about 50 kD which is responsible for the toxic
properties of the toxin by interfering with exocytosis of acetylcholine, and a
larger polypeptide of about 100 kD which is necessary to enable the
neurotoxic component to bind to a presynaptic membrane, the short
polypeptide chain and the long polypeptide chain being linked together by
means of a simple disulfide bridge.

The Examiner relies on the following evidence:

Aoki et al. US 6,113,915 Sep. 5, 2000

Chun K. Tse et al., Preparation and Characterisation of Homogeneous
Neurotoxin Type A from Clostridium botulinum, 122 EUR. J. BIOCHEM. 493-
500 (1982).

Robert J. Balkan & Taylor Poole, A Five-Year Analysis of Botulinum Toxin
Type A Injections: Some unusual Features, 23 ANN OPHTHALMOL 326-333
(1991).

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Edward J. Schantz & Eric A. Johnson, Properties and Use of Botulinum
Toxin and Other Microbial Neurotoxins in Medicine, 56 MICROBIOLOGICAL
REVIEWS 80-99 (1992).

A. Kohl et al., Comparison of the effect of botulinum toxin A (Botox ®) with
the highly-purified neurotoxin (NT 201) in the extensor digitorum brevis
muscle test, 15(Suppl 3) MOV DISORD 165 (2000).

Sueng Han Han et al., Effect of Botulinum Toxin A Chemodenervation in
Sensory Strabismus, 38 JOURNAL OF PEDIATRIC OPHTHALMOLOGY AND
STRABISMUS 68-71 (2001).

Appellants rely, in part, on the following evidence:

Elizabeth Moyer & Paulette E. Setler, Botulinum Toxin Type B:
Experimental and Clinical Experience, THERAPY WITH BOTULINUM TOXIN
71-85 (J. Jankovic et al., eds., 1994).

C. Lamanna et al., Cardiac Effects of Botulinal Toxin, 293 ARCH. INT.
PHARMACODYN. 69-83 (1988).

The claims stand rejected as follows:
Claims 1, 4-7, 24, 25, 38-41, and 54 under 35 U.S.C. § 103(a) as
unpatentable over Balkan or Han in view of Kohl, Tse, and Aoki ‘915.
We affirm.
ISSUES
Has the Examiner established a reasonable basis for refusing to grant
priority under 35 U.S.C. § 120 to parent application 08/173,996 on the
grounds that the claims are not adequately enabled?
Has the Examiner established that treating strabismus by
administering the neurotoxic component of a botulinum toxin, rather than a
complexed form of the botulinum toxin, would have been obvious over the
prior art?
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FINDINGS OF FACT
FF1 The present Specification, under the heading “Background of
the Invention,” teaches that:
Botulinum toxins, in particular Botulinum toxin type A, has
been used in the treatment of a number of neuromuscular
disorders and conditions involving muscular spasm; for
example, strabismus . . . The toxin binds rapidly and strongly to
presynaptic cholinergic nerve terminals and inhibits the
exocytosis of acetylcholine by decreasing the frequency of
acetylcholine release. This results in local paralysis and hence
relaxation of the muscle afflicted by spasm.

(Spec. 1: 30 to 2: 4.) Nearly identical language appears in column 1 of US
6,974,578 B1 - the immediate parent of the present application and a
continuation of abandoned parent application 08/173,996 (filed December
28, 1993).
FF2 The present Specification teaches that
The neurotoxic component of Botulinum toxin has a
molecular weight of about 150 kilodaltons and is thought to
comprise a short polypeptide chain of about 50 kD which is
considered to be responsible for the toxic properties of the
toxin, i.e., by interfering with the exocytosis of acetylcholine
. . . and a larger polypeptide chain of about 100 kD which is
believed to be necessary to enable the toxin to bind the
presynaptic membrane.

(Spec. 3: 10-19.) Nearly identical language appears in columns 1-2 of US
6,974,578 B1.
FF3 The neurotoxic component may exist in a dichain form, in
which “short” and “long” chains are linked together by a disulfide bridge, or
in the form of a single chain un-nicked protein (Spec. 3: 21-25). This
disclosure also appears in column 2 of US 6,794,578 B1.
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FF4 According to the present Specification, “[b]oth the single and
the dichain as well as the neurotoxic component are useful in the method of
the present invention” (Spec. 3: 28-30). Again, this language appears in
column 2 of US 6,794,578 B1.
FF5 The present Specification discloses that:
A patient with strabismus can be treated by injecting
between about 1 to about 5 units of the neurotoxic component
of a botulinum toxin type A free of the botulinum toxin
complex proteins (or between about 50 to about 250 units of the
neurotoxic component of botulinum toxin type B, free of the
botulinum toxin complex proteins) into extraocular muscles . . .
the amount injected varying based upon both the size of the
muscle to be injected and the extent of muscle paralysis desired
. . . .
(Spec. 20: 6-16; Example 13.) This Example does not appear in US
6,974,578 B1, the parent of the present application.
FF6 Schantz discusses the properties of botulinum toxins, including
the purified neurotoxic component. According to Schantz:
The nontoxic proteins bound to the neurotoxin apparently play
an important role in maintaining the toxic shape of the
neurotoxin. Careful handling of purified toxin is therefore
important for maintenance of stability. Botulinum toxin type A
is readily denatured by heat at temperatures above 40°C,
particularly at alkaline pH. Solutions of the toxin lose toxicity
when bubbles form at the air/liquid interface causing stretching
and pulling of the neurotoxin out of its toxic shape. This
denaturation also takes place in an atmosphere of nitrogen or
carbon dioxide. Dilution to extremely low concentrations
(nanograms per milliliter) also tends to decrease the stability of
the neurotoxin, but this can be prevented by diluting with a
buffered solution (at pH 6.8 or below) containing another
protein such as gelatin and certain albumins such as bovine or
human serum albumin. When the pH is raised above 7.3, the
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neurotoxin is liberated, which is very labile. Because of its
lability the neurotoxin is not practical for medical applications.
(Schantz 82, col. 2 (internal citations omitted).)
Most recent information concerning the structure and
pharmacology of botulinum toxin has been obtained with
purified neurotoxins, but it is unlikely that these will be used in
a clinical setting. The toxin complexes are much more stable
than neurotoxins and can be diluted and formulated with
retention of toxicity. Pure neurotoxins can be kept for several
weeks to months in solution in the cold but are inactivated on
dilution, formulation, and drying.
(Id. at 89, col. 2.)
FF7 Schantz teaches that purified botulinum neurotoxins “have high
specific toxicities” (Schantz 87, col. 2), and are capable of producing
paralysis in rats (id. at 89, col. 2).
FF8 Balkan discloses treating strabismus in humans with injections
of complexed botulinum toxin type A (Balkan, abstract).
FF9 Tse describes purification and characterization of the
neurotoxic component of type A botulinum toxin (Tse 494).
FF10 According to Tse, “[w]hen this neurotoxin . . . was injected into
rat hind-leg muscle, it produced local paralysis within 24 h” (Tse 498, col.
1). In addition, “[a]s clearly demonstrated with impure neurotoxin
complexes, pure neurotoxin specifically and characteristically inhibited
stimulated and spontaneous release of acetylcholine at the vertebrate
neuromuscular junction” (id. at 499, col. 2 (internal citations omitted)).
FF11 According to Moyer, “[r]elatively few studies have been
reported evaluating the in vivo muscle paralytic potency of BTX [botulinum
toxin] types other than type A. Usually, these studies have been performed
using rats, a species apparently particularly resistant to type B toxin” (Moyer
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76), unlike guinea pigs, which are equally susceptible to type A and type B
toxins. “In rats, no toxin studied [including type E and type F] has been
found to be as potent as type A” (id.).
FF12 Appellants note that Moyer concluded that “given the species-
specificity of the various toxin types, rodent studies must be considered
inconclusive with respect to predicting the relative clinical potency of the
various types of BTX” (Moyer 76; App. Br. 16).
FF13 Lamanna discloses “a purified sample of type A toxin free of
hemagglutinin . . . dissolved in a sterilized phosphate-0.2% gelatin buffer
(pH 6.2-6.7) for storage and i.v. injection” into mice, rats, and dogs
(Lammana 70). “[H]emagglutinin-free toxin had the same qualitative effects
on the heart” as hemagglutinin-containing (i.e., complexed) toxin, but was
more potent than the hemagglutinin-containing toxin on a weight to weight
basis (id. at 72).

LEGAL PRINCIPLES
[A] specification disclosure which contains a teaching of the
manner and process of making and using the invention in terms
which correspond in scope to those used in describing and
defining the subject matter sought to be patented must be taken
as in compliance with the enabling requirement of the first
paragraph of § 112 unless there is reason to doubt the objective
truth of the statements contained therein which must be relied
on for enabling support.
In re Marzocchi, 439 F.2d 220, 223 (CCPA 1971).
“Enablement does not require an inventor to meet lofty standards for
success in the commercial marketplace. Title 35 does not require that a
patent disclosure enable one of ordinary skill in the art to make and use a
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perfected, commercially viable embodiment absent a claim limitation to that
effect.” CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333, 1338 (Fed. Cir.
2003).
ANALYSIS
The Examiner rejected the claims as obvious over the combined
teachings of Balkan or Han in view of Kohl, Tse, and Aoki ‘915.
According to Appellants, the Han and Kohl references, published in
2001 and 2000 respectively, and the Aoki ‘915 patent, filed in 1999, “are not
prior art with regard to the pending claims” (App. Br. 15) because “the
claims are entitled to priority to the December 28, 1993 filing date” of their
parent application 08/173,996 (id.).
The Specification teaches that the neurotoxic component of botulinum
toxin recited in the appealed claims is useful in treating strabismus (FF4,
FF5). However, the Examiner concluded that the claims were not enabled
by parent application 08/173,996 - largely on the basis of Schantz’s
assessment that the neurotoxic component of botulinum toxin is not practical
for medical applications because of its lability (Ans. 5-7). As framed by the
Examiner, “[t]he question was not whether one could make or isolate the
purified toxin but whether one could use it in a clinical setting” (id. at 19-
20). According to the Examiner, “[t]he specification did not disclose
methods that one of ordinary skill in the art could utilize to render the pure
toxin clinically effective . . . [and] [w]ithout such guidance, one would be
burdened with undue experimentation to practice the claimed invention” (id.
at 7-8).
We disagree with the Examiner’s rationale for denying the present
claims priority to the parent application. Rather than establishing that the
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use of the claimed neurotoxic component of botulinum toxin would have
required undue experimentation, the evidence relied on by the Examiner
merely establishes that one of skill in the art would have expected the 150
kilodalton neurotoxic component of botulinum toxin to be less convenient to
administer to a patient in a clinical setting than the complexed form of the
toxin. Moreover, the Examiner has essentially dismissed evidence that the
purified neurotoxin, despite being more labile than the complexed toxin, had
been shown to exert effects comparable to the complexed toxin in animal
studies (FF7, FF10).
Accordingly, we agree with Appellants that the Han and Kohl
references, published in 2001 and 2000 respectively, and the Aoki ‘915
patent, filed in 1999, “are not prior art with regard to the pending claims”
(App. Br. 15).
Nevertheless, we conclude that the claimed invention is unpatentable
over Balkan and Tse, the remaining prior art references relied on by the
Examiner. The Examiner found that Balkan “teaches the administration of
botulinum toxin type A and type F for the treatment of strabismus” (Ans. 9),
and that Tse teaches that pure neurotoxin produces paralysis in rat muscles,
and inhibits release of acetylcholine at the vertebrate neuromuscular
junction, just like the corresponding complexed neurotoxin (id). We agree
with the Examiner’s conclusion that “it would have been obvious to one of
ordinary skill [in] the art to use pure neurotoxin for the treatment of
strabismus because [Tse teaches that] pure neurotoxin has similar activity in
the paralysis of muscles as complexed neurotoxin and has similar activity
against spontaneous release of actetylcholine” (id. at 10).
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Appellants contend that Balkan “relate[s] to the injection of
complexed botulinum toxin into a human muscle for treating strabismus”
(App. Br. 16), while Tse “relates to rat muscles” (id.). Appellants contend
that one of ordinary skill in the art wouldn’t combine Balkan and Tse
because Moyer provides evidence that the various toxin types are species-
specific; that rodent studies are inconclusive with respect to predicting the
relative clinical potency of the various types of botulinum toxin; and “the
effects of the neurotoxic component on mouse muscles cannot be applied to
human muscles” (id.). In addition, Appellants contend that “the teachings of
the Tse reference relate to improved vaccines and probes” (id. at 17).
Appellants contend that “[t]he use of a compound as a drug for treating
strabismus in humans is very different from the use of that compound as an
antigen or a probe, and the practice of the two methods may be entirely
incompatible” (id.).
Appellants’ arguments are not persuasive. Balkan teaches that
injections of complexed botulinum toxin type A can be used to treat
strabismus (FF8). Tse teaches that complexed toxin type A and the
neurotoxic component of type A recited in the appealed claims have
comparable activities in vivo, in that both “specifically and characteristically
inhibited stimulated and spontaneous release of acetylcholine at the
vertebrate neuromuscular junction” (Tse 499; FF10). The fact that Moyer
shows that different botulinum toxin types exhibit different species-
specificities (e.g., rats are resistant to type B, while guinea pigs are not
(FF11)) has no bearing on whether one would expect a given complexed
toxin and its corresponding purified neurotoxin to exhibit similar activities
in the same animal.
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Similarly, the fact that Tse suggests that “purified neurotoxin could
provide a superior and novel vaccine . . . to raise immunoglobulins for
therapeutic use and for development of immunoassays for the toxin in
clinical specimens and foodstuffs” and that it “could be an invaluable probe
for nerve membrane component(s)” (Tse 493, col. 2) has no bearing on
whether one would expect a given complexed toxin and its corresponding
purified neurotoxin to exhibit similar activities in vivo.
Finally, to the extent Appellants contend that Schantz (discussed
above in the context of enablement (App. Br. 12-14)) teaches away from the
claimed invention, we disagree. As discussed above, while we agree that
Schantz establishes that one of skill in the art would have expected the
neurotoxic component of botulinum toxin to be less convenient to administer
to a patient than the complexed form of the toxin, that is not the same as
teaching that it would be ineffective. In any case, as Appellants have
previously argued in the context of enablement (id. at 10), others of ordinary
skill in the art at the time of the invention (e.g., Lamanna) knew how to
prepare, store and administer the pure neurotoxic component of botulinum
toxin while maintaining its potency (FF13).
CONCLUSIONS OF LAW
The Examiner has not established a reasonable basis for refusing to
grant priority under 35 U.S.C. § 120 to parent application 08/173,996 on the
grounds that the claims are not adequately enabled. Accordingly, the Han,
Kohl, and Aoki ‘915 references do not qualify as prior art with respect to the
claims on appeal.
Nevertheless, the Examiner has established that treating strabismus by
administering the neurotoxic component of a botulinum toxin, rather than a
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complexed form of the botulinum toxin, would have been obvious over the
combined teachings of Balkan and Tse.
The rejection of claims 1, 4-7, 24, 25, 38-41, and 54 under 35 U.S.C.
§ 103(a) as unpatentable over Balkan and Tse is affirmed.

TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv)(2006).

AFFIRMED

dm

STEPHEN DONOVAN
ALLERGAN, INC.
2525 DUPONT DRIVE, T2-7H
IRVINE, CA 92612