Ex Parte Wilson

Board of Patent Appeals and Interferences

Apr 23, 2012

11568752 (B.P.A.I. Apr. 23, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte NESTOR ANTONIO LAGOS WILSON
__________

Appeal 2011-010797
Application 11/568,752
Technology Center 1600
__________

Before TONI R. SCHEINER, DONALD E. ADAMS, and
STEPHEN WALSH, Administrative Patent Judges.

WALSH, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) from the rejection of
claims directed to a method of treating a patient with a tricyclic 3,4-
propinoperhydropurine. The Patent Examiner rejected the claims for
obviousness. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
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STATEMENT OF THE CASE
“This invention relates to methods of treating muscle disorders and to
pharmaceutical compositions containing heterocyclic guanidine-type
compounds which can be used in the methods.” (Spec. 1, ll. 4-6.) The
Specification explains that “[p]aralytic shellfish poisoning (PSP) results
from a mixture of phycotoxins that bind reversibly to a receptor site on the
voltage-gated sodium channel found in excitable cells.” (Id. at ll. 9-18.)
The Specification further explains that (i) “gonyautoxins (GTXs) are the
most abundant PSP toxins found in shellfish extract accounting for over 80%
of the total toxin content” (id. at ll. 21-22); (ii) “gonyautoxins of the present
invention provide a local anesthetic for use in mammals either by injecting a
liquid preparation or as a topical anesthetic applied to the skin of mammal”
(id. at 29-31); and (iii) “gonyautoxins of the present invention also provide
surprising beneficial results in the treatment of a variety of ailments, which
may be caused or aggravated by muscle disorders, muscle spasms or muscle
action” (id. at 2, ll. 1-3).
Claims 18-34 are on appeal. Claim 18 is representative and reads as
follows (indents added):
18. A method of treating a patient afflicted with at least one ailment
selected from the group consisting of: carpal-tunnel syndrome, fibromyalgia,
join flare, joint pain, arthritis, sciatica, tendonitis, neck pain, back pain,
hemifacial spasm, hypetfunctional larynx, juvenile cerebral palsy, spasticity,
tension headaches, migraine headaches, writer's cramp, tremors, tics,
disorders of the upper and lower esophageal sphincter, gastroparesis,
hypertrophic pyloric stenosis, hemorrhoids, proctalgia fugax, irritable bowel
syndrome, vasospastic disorders, disorders involving uterine, or bladder
spasm, sphincter of Oddi dysfunction, and short-segment Hirschprung's, and
bruxism,
comprising the step of administering to a patient in need of such
treatment an effective amount of a composition comprising at least one
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tricyclic 3,4-propinoperhydropurine represented by formula I set forth
below:

Formula I

wherein Rl and R5 are independently selected from the group
consisting of -H and -OH; R2 and R3 are independently selected from the
group consisting of -H and -OSO3; and R4 is selected from the group
consisting of -H, -OH, -COONH2, -COONHSO-3 and -COOCH3, with the
proviso that either one of R2 and R3 must be -OSO-3, or R4 must be
-COONHSO-3, and a pharmacologically acceptable carrier.

The Examiner rejected claims 18-34 under 35 U.S.C. § 103(a) as
unpatentable over Gassner1 and Patockaa.2

OBVIOUSNESS
The Issue
In the Final Rejection, the Examiner found that Gassner taught it was
known to treat blepharaspasm, hemifacial spasms, and spasticity by
administering a toxin such as saxitoxin or tetrodotoxin, thus blocking nerve
and muscle cell sodium channels including instructions for mode of

1 Holger G. Gassner et al., US 6,447,787 B1, issued Sept. 10, 2002.
2 Jiri Patockaa et al., Brief Review Of Natural Nonprotein Neurotoxins, THE
ASA NEWSLETTER (2002), downloaded from
www.asanltr.com/newsletter/02-2/articles/Neurotoxins.htm, accessed Feb.
28, 2010.
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administration and doses to administer. (Final Rej. 3.) Although Gassner
did not teach administering a gonyautoxin, the Examiner found that
Patockaa disclosed that saxitoxins are potent neurotoxins that specifically
and selectively bind the sodium channel in neural cells, blocking neural
transmission, that saxitoxins are cholinergic agonists similar to botulinum
toxin, that there were a number of known saxitoxins, and that single
sulphated saxitoxins were known as gonyautoxins. (Id. at 3-4, citing
Patockaa’s “Saxitoxin” section and structural identification of GTX-I, GTX-
II, GTX-III, and GTX-IV in Figure 4.) The Examiner concluded that it
would have been obvious to substitute a gonyautoxin for the saxitoxin used
in Gassner’s method “because they share the common sodium channel
blocking activity with the compounds of the primary reference, and thus
would be reasonably predicted to provide corresponding therapeutic effects.”
(Id. at 4.) The Examiner further concluded “it would have been obvious to
one of ordinary skill in the art to optimize the dosage of the toxin to provide
the desired muscular tension.” (Id., citing In re Aller, 220 F.2d 454 (CCPA
1955).
In the Appeal Brief, Appellant contended that Gassner taught using
botulinum toxin A, not saxitoxin or tetrodotoxin, to treat blepharospasm,
hemifacial spasms, or spasticity. (App. Br. 6.) According to Appellant,
Gassner taught using saxitoxin or tetrodotoxin only in a method of treating
wounds. (Id.) As Patockaa did not teach any therapeutic uses for
gonyautoxins, Appellant argued the rejection should be reversed. (Id. at 7.)
Appellant pointed out the difference between saxitoxin (the name of a
particular compound) and saxitoxins (the name of a group of compounds).
Appellant noted that Patockaa disclosed that saxitoxin acts as botulinum
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toxin acts, but Patockaa did not say that all saxitoxins act in the same way.
According to Appellant, “[t]his is critical since the actual statement in
Patockaa refers to the specific chemical compound ‘saxitoxin’ and does not
apply to the general class of compounds including gonyautoxins which
Patockaa loosely refers to as ‘saxitoxins.’” (Id. at 7.) Appellant argued that
“[n]one of the cited references teaches or suggests that gonyautoxins are
cholinergic nerve agonists and thus the Examiner's conclusion that
gonyautoxins would be expected to function using the same mechanism as
Botulinum toxin is not supported by the evidence of record.” (Id. at 8.)
The Examiner’s Answer3 maintained the rejection, but revised the
explanation to state that (1) the “rejection relies directly upon Gassner's
teaching that administration of a chemodenervating agent can treat
blepharospasms, hemifacial spasms and spasticity” (Ans. 16-17);
(2) “Gassner teaches that saxitoxin and tetrodotoxin are suitable substitute
chemodenervating agents for botulinum toxin A. . . . Based on the common
mechanism of action, it would have been obvious to substitute a known
saxitoxin, such as a gonyautoxin for a known chemodenervating agent of
Gassner, such as saxitoxin” (id. at 17); and (3) it is “routine practice in the
pharmaceutical art to determine toxicity levels and appropriate dosages for
treatment” as evidenced by Patockaa at 3 and Gassner at column 4 (id. at
18).

3 Several versions of the Examiner’s Answer were mailed, apparently to
resolve formatting problems with line spacing, font uniformity and the fact
that the first versions mailed were incomplete in missing the final pages
including a signature page. Appellant cites to the first incomplete Answer
mailed on Feb. 16, 2011, (see Reply Br. 1), and we will generally do the
same, citing the last Answer mailed April 8, 2011, only where necessary.
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Addressing the revised rejection, Appellant again argues that the
distinction between singular “saxitoxin” and plural “saxitoxins” is critical
because Patockaa’s statement referred to one saxitoxin compound, not the
generic group of saxitoxins. (Reply Br. 2.) “Thus, Patockaa does not teach
that the claimed gonyautoxins are cholinergic agonists that inhibit the
release of acetylcholine or that gonyautoxins act in a similar manner to
botulinum toxin as the Examiner suggests.” (Id.) Appellant contends that
“[a] further problem with the Examiner's position is that it does not consider
that even among the various toxins there is a large variation in activities,
toxicities and other properties.” (Id. at 3.) Appellant contends that the
Examiner erred in finding that Patockaa taught that saxitoxins are tricyclic
compounds structurally related to tetrodotoxin because “[w]hat Patockaa
actually teaches is that the molecular skeletons of saxitoxins are structurally
related to tetrodotoxin.” (Id. at 4.) According to Appellant, the distinction is
important because “the skilled person would know that it is not the
molecular skeleton that determines the therapeutic activity of these
molecules, but rather, it is the various chemical substituents which are added
to the molecular skeleton are the important components of these molecules
for determining their activity.” (Id.) Appellant also contends that the
Examiner erred in characterizing Gassner as teaching that saxitoxin is a
suitable chemodenervating agent other than botulinum toxin, and Gassner
was addressing wound healing, not treatment of spasticity. (Id. at 5.)
The main issue on appeal is whether a person of ordinary skill in the
art would have found the evidence sufficient to support concluding that it
would have been obvious to substitute a gonyautoxin for botulinum toxin in
treating blepharaspasm, hemifacial spasms, or spasticity.
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Findings of Fact
1. Gassner’s patent is entitled “Methods for Enhancing Wound Healing.”
(Gassner, Title.)
2. The Examiner found: “Gassner teaches that:
“[n]onlimiting examples of chemodenervating agents include
botulinum toxin, saxitoxin, tetanus toxin, and tetrodotoxin ...
Botulinum toxin A has been used in the treatment of a wide variety of
disorders associated with muscle contraction. It has been
demonstrated to be effective in treating focal distonias such as
blepharospasm, nondystoninic disorders such as hemifacial spasms, ...
spa[s]ticity disorders ... and localized muscle spasm” (Gassner at col
3, lines 43-57).

“Other chemodenervating agents such as saxitoxin, tetanus toxin, and
tetrodotoxin are also suitable. The paralysis induced by saxitoxin,
however, does not last as long as that induced by botulinum toxin.
Consequently, repeated injections of saxitoxin may be needed.
Tetrodotoxin blocks the sodium channel of excitable membranes of
nerve and muscle tissue”. (Gassner at col 4, lines 21- 44).

Gassner teaches that administration may occur via
subcutaneous injection, intramuscular injection, perimuscular
injection, or percuteanous instillation (e.g. skin patch) (col. 4, lines
45-54). Gassner also teaches that tetrodotoxin blocks the sodium
channel of excitable membranes of nerve and muscle tissues (col. 4,
lines 21-44) and that a common dosage is 20 units of toxin and 1 %
lidocaine solution (col. 8, lines 1-21).

Gassner does not teach the use of gonyautoxins.

(Ans. 5-6.)
3. The Examiner found:
[Patockaa] teaches that Saxitoxins (STX) are tricyclic compounds
which are structurally related to tetrodotoxin [sic.] (Patocka at p.3,
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§ Saxitoxins, 2nd ¶). STX are potent neurotoxins that specifically and
selectively bind to the sodium channel in neural cells, blocking neural
transmissions (Id. at 2nd and 3rd ¶’s). There are a number of STX
variants generally divided into groups based on their structure or
organism of origin (Saxitoxins, 2nd ¶). “The single sulphated STXs
compounds are known as gonyautoxins (GTX).” (Id.) [Sic.] Patockaa
then teaches that

“STX was the first known and has been the most widely studied toxic
component of paralytic shellfish pois[o]ning. This toxin blocks
neuronal transmission by binding to the voltage-gated Na+ channels
in nerve cells, thus casuing [sic-causing] their neurotoxic effects.”
(Patockaa at p.3, § Saxitoxins, 2nd ¶.
“Saxitoxin acts in a similar manner to Botulinum toxin because it is a
cholinergic agonist that inhibits the release of acetylcholine at
synapses in the peripheral nervous system.” (Patockaa at p.3,
§ Saxitoxins, 3rd ¶).

Patockaa does not teach a method of treating neuromuscular disorders.

(Id. at 6-7.)

Analysis
Claim 18
First, we recognize Appellant’s point that Gassner’s invention
concerned wound healing, not a method for treating muscle spasms. In the
course of describing its invention, however, Gassner mentioned that
botulinum toxin was known for being effective for treating muscle spasms,
including several specific disorders that Appellant’s claim 18 lists. Gassner
then listed other toxins that have the same effects as botulinum toxin when
used for wound healing, including saxitoxin. Because Gassner discussed the
common mechanisms by which botulinum toxin and other toxins are
effective, we find the evidence sufficient to establish the prima facie
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obviousness of using saxitoxin to treat muscle spasm as botulinum toxin had
been used.
Patockaa disclosed that the compound saxitoxin, and saxitoxins
generically (aka paralytic shellfish poisons (PSPs)), had structural
similarities and differences as shown in Figure 4. We agree with the
Examiner that Patockaa disclosed convincing evidence that the gonyautoxins
and saxitoxin would have been reasonably expected to have similar
effectiveness. We find Appellant’s distinction between saxitoxin the
compound and the group of saxitoxins Patockaa described unpersuasive
because it discounts the fact that Patockaa indicated that all the saxitoxins,
including the gonyautoxins, had the same physiological effect – they were
known to be paralytic shellfish poisons. Similarly, Appellant’s argument
about the similarity of the saxitoxin and tetrodotoxin “molecular skeleton” is
unpersuasive, because Patockaa disclosed that, notwithstanding the small
variation in substituents attached to the saxitoxin and gonyautoxin molecular
skeletons, the saxitoxins were all PSPs.
In sum, we find the rejection established the prima facie obvious of
claim 18, and agree with the Examiner’s Response to Argument. (See Ans.
mailed Feb. 16, 2011 at 15-20; or Ans. mailed April 8, 2011 at 14-17 (same.)
Claim 19 has not been argued separately and therefore falls with claim
18. 37 C.F.R. § 41.37(c)(1)(vii).

Claims 20 and 27
Claim 20 limits the compound to be used in the method of claim 18 to
one selected from GTX-l, GTX-2, GTX-3, GTX-4 and GTX-5. Appellant
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contends “[t]he cited prior art provides no reason for the skilled person to
select one of Gonyautoxins 1-5 from among the various gonyautoxins that
are known.” (App. Br. 15.) The Examiner responds that Patockaa
specifically described GTX-1, -2, -3, and -4. (Ans. 20.) As Patockaa
described four of the listed gonyautoxins, we agree with the Examiner that
selecting one or more of the four for use in the method of claim 18 would
have been prima facie obvious.
Claim 27, which depends from claim 20, has not been argued
separately and therefore falls with claim 20. 37 C.F.R. § 41.37(c)(1)(vii).

Claim 21
Claim 21 further limits the method of claim 20 to using a composition
comprising GTX-2 and GTX-3. Appellant contends “[t]he cited prior art
provides no reason for the skilled person to select a mixtures [sic] of
gonyautoxins 2 and 3 from among the various gonyautoxins that are
known.” (App. Br. 15.) The Examiner responds that based on “the
knowledge that different saxitoxins can treat these conditions, the skilled
artisan would have found it obvious to combine different saxitoxins in order
to treat such conditions. See MPEP 2143(A).” (Ans. 20.) We agree with
the Examiner. “It is prima facie obvious to combine two compositions each
of which is taught by the prior art to be useful for the same purpose, in order
to form a third composition which is to be used for the very same purpose.”
In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980).

Claims 22-26
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Claims 22-26 each further limit the method of claim 20 by reciting
“wherein the effective amount of said composition contains [a range] units
of activity.” Appellant contends that “the cited prior art provides no reason
for the skilled person to select the particular amounts of gonyautoxins
claimed in claim [22, 23, 24, 25, 26].” (App. Br. 15-16.) The Examiner
responds by pointing to Gassner’s disclosure of doses of botulinum toxin,
and argues “[t]he amount of toxin administered could be optimized in order
to achieve the desired treatment.” (Ans. 20.) We recognize that Gassner’s
dosing was intended for wound healing. However, Gassner also taught that
it was known to use botulinum toxin for treating spasticity and other muscle
spasms. “[W]here the general conditions of a claim are disclosed in the
prior art, it is not inventive to discover optimum or workable ranges by
routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955).
Accordingly, we agree with the Examiner.

Claims 28 and 29
Claim 28 further limits the method of claim 20 by reciting “wherein
said composition further comprises a local anesthetic,” and claim 29
provides a list of anesthetics to be selected, including lidocaine. Appellant
contends “neither of the cited prior art references specifically teaches the use
of a combination of one or more gonyautoxins with a local anesthetic. Thus,
the cited prior art provides no reason for the skilled person to select this
particular combination.” (App. Br. 16-17.) The Examiner responds: “The
obviousness rejection herein is based on the substitution of gonyautoxins for
botulinum toxin A. Gassner teaches that botulinum toxin A is administered
with lidocaine, a local anesthetic. Thus, upon the substitution of gonyautoxin
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for botulinum toxin A, gonyautoxin would be administered with lidocaine.”
(Ans. mailed April 8, 2011, at 18-19.) The rejection pointed to Gassner’s
use of lidocaine. Appellant replies that Gassner only taught the combination
of botulium toxin with lidocaine for wound treatment. (Reply Br. 9.) We
find that the evidence supports finding that using lidocaine with
administered toxin was suggested, whether the toxin is administered to treat
wound healing or muscle spasm.

Claim 30
Claim 30 further limits the method of claim 18 by reciting “wherein
the composition is applied topically.” Appellant contends
neither of the cited prior art references specifically teaches the topical
application of gonyautoxins. Further, the only teaching in relation to
treatment of disorders such as blepharospasm, hemifacial spasms and
spasticity using Botulinum toxin A is by injection. See col. 3, lines
47-50 of Gassner. Thus, the cited prior art provides no reason for the
skilled person to topically apply compositions containing
gonyautoxins as claimed in claim 30.

(App. Br. 17.) The Examiner responds that “[o]ne of ordinary skill in the art
would understand that toxins can be administered to spastic muscles in a
variety of ways, including topically. This is particularly true given that
botulinum toxin was well known in the art at the time of the invention to be
administered topically.” (Ans. mailed April 8, 2011, at 18-19.) Appellant
replies “there is no evidence in this record supporting this conclusion,” and
Gassner indicated that muscle spasm treatment was by injection. (Reply Br.
9-10.)
The rejection directed attention to Gassner, col. 4, ll. 21-53, which
recites, in pertinent part: “[l]ocal administration of the chemodenervating
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agents typically occurs by subcutaneous (SQ), intramuscular (IM),
perimuscular injection, or percutaneous instillation (e.g., air gun or skin
patch).” Contrary to Appellant’s position, there is explicit evidence that a
toxin, such as botulinum toxin or saxitoxin, may be administered topically.

Claim 31
Claim 31 further limits the method of claim 20 by reciting “wherein
the topical composition comprises from 0.0001 % to 0.01 % by weight of
one or more compounds of the formula I, based on the total weight of the
composition.” Appellant contends “the cited prior art provides no reason for
the skilled person to select the particular amounts of gonyautoxins claimed
in claim 31.” (App. Br. 17.) The Examiner responds that the amount “could
be routinely optimized to obtain the desired potency of the composition.”
(Ans. mailed April 8, 2011, at 19.) We agree. See Aller, 220 F.2d at 456.

Claim 32
Claim 32 further limits the method of claim 19 by reciting “wherein
the composition is injected at multiple injection points.” Appellant contends
“the cited prior art provides no reason for the skilled person to inject
compositions containing gonyautoxins at multiple injection points as
claimed in claim 32.” (App. Br. 17.) The Examiner responds: “Gassner
teaches administration of toxins by injection. The skilled artisan would have
found it obvious to inject the toxins at different points in order to effectively
treat broad areas of blepharospasm, hemifacial spasms and spasticity.”
(Ans. mailed April 8, 2011, at 19.)

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Claim 34
Claim 34 further limits the method of claim 18 by reciting “wherein
the composition is applied transdermally.” Appellant contends “the cited
prior art provides no reason for the skilled person to administer compositions
containing gonyautoxins transdermally as claimed in claim 34.” (App. Br.
18.) The Examiner responds by referring to claim 30’s method of topical
administration, which “would effectively meet the broadest reasonable
interpretation of transdermal administration.” (Ans. mailed April 8, 2011, at
19-20.) We conclude that the rejection of claim 34 should be affirmed for
the same reason as the rejection of claim 30.

SUMMARY
We affirm the rejection of claims 18-34 under 35 U.S.C. § 103(a) as
unpatentable over Gassner and Patockaa.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED

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