Ex Parte BLUMENFELD et al

Patent Trial and Appeal Board

May 8, 2018

12578518 (P.T.A.B. May. 8, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/578,518 10/13/2009
51957 7590 05/10/2018
ALLERGAN, INC.
2525 DUPONT DRIVE, T2-7H
IRVINE, CA 92612-1599
FIRST NAMED INVENTOR
Andrew M. BLUMENFELD
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
18458 (BOT) 6495
EXAMINER
LYONS, MARY M
ART UNIT PAPER NUMBER
1645
NOTIFICATION DATE DELIVERY MODE
05/10/2018 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
patents_ip@allergan.com
pair_allergan@firsttofile.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ANDREW M. BLUMENFELD and RYAN A. IRVINE
Appeal2017-006686
Application 12/578,518
Technology Center 1600
Before FRANCISCO C. PRATS, TIMOTHY G. MAJORS, and
DAVID COTTA, Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
Appellants 1 submit this appeal under 35 U.S.C. § 134 involving
claims to methods of preventing muscle spasticity or of modulating
maladaptive neuronal plasticity in a patient. The Examiner rejected the
claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
1 Appellants identify the Real Party in Interest as Allergan, Inc. App. Br. 3.
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Application 12/578,518
STATEMENT OF THE CASE
Appellants' "invention relates to methods of treating or preventing
muscular disorders associated with upper motor neuron lesions." Spec. ,-r 2.
As background, the Specification discloses that "[ u ]pper motor neuron
lesions can lead to a multitude of symptoms, one of which includes muscle
spasticity ... [and] spastic muscles are treated using botulinum toxins once
spasticity has developed and is apparent." Id. ,-r 3. The Specification further
indicates that "[i]t is common for the spasticity in the affected muscles
resulting from an upper motor neuron lesion to involve central nervous
system changes that develop over time and commonly lead to maladaptive
neuronal plasticity, which is permanent." Id. ,-r 35. 2
The Specification describes "injection of a low dose of botulinum
toxin into the mid portion or belly of at least one muscle, specifically to the
IA afferents of the intrafusal fibers." Id. ,-r 37; id. ,-r 5 ("One unit of
BOTOX® ... contains about 50 picograms ... ofbotulinum toxin type A
complex."). According to the Specification:
By injecting botulinum toxin at a sufficiently low dose, into the
belly of a muscle for example, which does not result in paralysis,
atrophy, or even weakness of the muscle, the sensory component
of the central nervous system can be modulated and the patient
will not develop, or will develop to a lesser degree, spasticity in
the treated region and/or maladaptive neuronal plasticity.
2 The Specification explains that upper motor neuron lesions result from, for
example, stroke or a spinal cord injury. Spec. ,-r 43. The Specification
further explains that, "[i]n patients suffering from such traumatic events
[e.g., stroke], it is almost axiomatic that the patient will eventually suffer
from muscle spasticity and maladaptive neuronal plasticity." Id. ,-r 51.
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Id. iT 37.
Claims 1, 3, 4, 7, 8, 10, 12, 13, 16, 17, and 19-28 are on appeal.
Independent claims 1, 10, 19, and 20 are reproduced below:
1. A method of preventing spasticity in a patient in need
thereof, comprising the step of administering a therapeutically
effective amount of a botulinum toxin type A to at least a portion
of a 1 A sensory afferent on or within intrafusal fibers of at least
one muscle prior to development of spasticity in said at least one
muscle, wherein said therapeutically effective amount is
sufficiently low as to not induce muscle weakness of the at least
one muscle.
10. A method of modulating maladaptive neuronal plasticity in
a patient in need thereof, comprising the step of administering a
therapeutically effective amount of a botulinum toxin type A to
at least a portion of a 1 A sensory afferent on or within intrafusal
fiber of at least one muscle and wherein said administration
prevents or attenuates the development of said maladaptive
neuronal plasticity, and further wherein said therapeutically
effective amount is sufficiently low as to not induce muscle
weakness of the at least one muscle.
19. A method of preventing spasticity resulting from an upper
motor neuron lesion, comprising the step of administering to a
patient a therapeutically effective amount of botulinum toxin
type A to at least a portion of a 1 A sensory afferent on or within
intrafusal fibers of at least one muscle of an upper or lower limb
prior to development of spasticity, said therapeutically effective
amount is sufficiently low as to not induce muscle weakness of
the at least one muscle.
20. A method of modulating maladaptive neuronal plasticity
resulting from an occurrence of an upper motor neuron lesion
occurrence in a patient, comprising the step of administering to
the patient a therapeutically effective amount ofbotulinum toxin
type A to at least a portion of a IA sensory afferent on or within
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intrafusal fibers of at least one muscle of the upper or lower limb
prior to development of maladaptive neuronal plasticity, said
therapeutically effective amount is sufficiently low as to not
induce muscle weakness of the at least one muscle, and the
botulinum toxin is administered within 6 months of the
occurrence of upper motor neuron lesion.
App. Br. 16-18 (Claims App.).
The claims stand rejected as follows:
I. Claims 1, 3, 4, 7, 8, 19, 21, and 23-25 under 35 U.S.C. § 103(a)
as obvious over Grazko, 3 Brin, 4 and Cosgrove. 5
II. Claims 10, 12, 13, 16, 17, 20, 22, and 26-28 under 35 U.S.C.
§ 103(a) as obvious over Grazko and Brin.
DISCUSSION
Issue
We first address the rejection of claims 10, 12, 13, 16, 17, 20, 22, and
26-28 over Grazko and Brin (hereafter "Rejection I"), and then address the
rejection of claims 1, 3, 4, 7, 8, 19, 21, and 23-25 over Grazko, Brin, and
Cosgrove (hereafter "Rejection II"), which is the order in which the
rejections are addressed by Appellants and the Examiner. App. Br. 10, 13;
Ans. 2, 7; Final Act. (Apr. 29, 2016) 4, 12.
3 Marybeth A. Grazko, MD et al., Botulinum Toxin A for Spasticity, Muscle
Spasms, and Rigidity, 45 NEUROLOGY 712-17 (1995).
4 Mitchell F. Brin, MD et al., Botulinum Toxin Type A: Pharmacology,
Spasticity: Etiology, Evaluation, Management and the Role of Botulinum
Toxin, 110-24 (Mayer Nathaniel H, ed. 2002).
5 A. P. Cosgrove et al., Botulinum Toxin A Prevents the Development of
Contractures in the Hereditary Spastic Mode, 36:5 DEV MED CHILD NEUROL
379-85 (1994).
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As to Rejection I, Appellants assert that independent claims 10 and 20
are argued separately. App. Br. 10. As to Rejection II, Appellants assert
that independent claims 1 and 19 are argued separately. Id. at 13.
Appellants do not provide separate argument on the dependent claims. Id. at
10, 13. Accordingly, for purposes of this appeal, the patentability of the
dependent claims will rise or fall with the patentability of the respective
independent claims. 37 C.F.R. § 41.37(c)(l)(iv).
The issues on appeal are as follows:
1) Whether the preponderance of the evidence supports the
Examiner's conclusion that claims 10 and 20 would have been
obvious over Grazko and Brin; and
2) Whether the preponderance of the evidence supports the
Examiner's conclusion that claims 1 and 19 would have been
obvious over Grazko, Brin, and Cosgrove.
Findings of Fact (FF)
The Examiner's findings of fact and statement of the rejections are
provided in the Examiner's April 29, 2016 Final Rejection at pages 2-9
(Rejection I) and 12-15 (Rejection II). See also Final Act. 10-12, 16
(Response to Arguments). We adopt those findings, and provide the
following for emphasis and convenient reference.
FF 1. Grazko teaches the administration of botulinum toxin A to treat
spasticity and rigidity in patients diagnosed with, for example, stroke,
multiple sclerosis, and brain trauma. Grazko Abstract ("We studied the
effects of botulin um toxin A in 12 patients with spasticity ... [and] [ w] e
conclude that botulinum toxin A is effective against disabling effects of
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spasticity and rigidity."); id. at 714 (Table 1). Grazko defines spasticity "as
a motor disorder characterized by a velocity-dependent increase in tonic
stretch reflexes with exaggerated tendon jerks resulting from
hyperexcitability of the stretch reflex as one component of the upper motor
neuron syndrome." Id. at 712. Grazko teaches that "[p]athophysiologically,
spasticity is a disturbed processing of peripheral afferent messages at the
spinal cord level as well as release and imbalance of the supraspinal control
of reflex pathways." Id. at 713.
FF 2. Grazko teaches administering therapeutically effective amounts
(e.g., 2.5-5.0 units) ofbotulinum toxin A to the muscles. Id. at 713 ("The
amount of toxin used was determined primarily by muscle size, with a range
of 20 to 120 U used for large muscles and 2.5 to 40 U for small [muscles].");
see also id. at 714 (Table 1, describing, for example, administration of 5
units to the Flexor digitorum profundus (a muscle of the forearm) in a
patient diagnosed with stroke).
FF 3. The Examiner finds that a dose of 2.5 units ofBOTOX®, as
taught in Grazko, would be "sufficiently low as to not induce muscle
weakness" as recited in the claims "because the dose falls squarely within
the range taught by the instant specification." Final Act. 5; Spec. i-f 64 ("As
a general guide [to] the practitioner, typically, no less than about 1 units and
no more than about 500 units ofbotulinum toxin type A (such as BOTOX®)
is administered per injection site .... ").
FF 4. In describing the effects on spasticity, Grazko teaches "a
significant reduction in tone (two grades or more) after botulinum toxin
injections" was demonstrated, as well as "improvements of movement and
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posture" and that "[ n Jo significant muscle weakness was noted after
botulinum toxin injection." Grazko 713-714.
FF 5. Grazko teaches:
The degree of muscle weakness that occurs after administration
of botulinum toxin remains a concern in the treatment of
spasticity and rigidity. In hyperkinetic movement disorders, a
favorable response to botulinum toxin is often associated with
some degree of muscle weakness. Our experience indicates that
significant muscle weakness can be avoided by titration of the
dose against the muscle bulk. Assessment of mild weakness in
spastic and rigid patients is difficult and may be overshadowed
by decreased muscle tone and functional improvement.
Id. at 716.
FF 6. Brin teaches that "botulinum toxin type A (BTX-A) has been
used increasingly in the treatment of numerous other disorders characterized
by excessive or inappropriate muscle contraction," including "spasticity."
Brin 110. Brin teaches "[ c ]onditions characterized by excessive muscle
contraction for which botulinum toxin has been shown to have either proven
efficacy or promising experimental results" include, inter alia, "[ s ]pasticity:
stroke, cerebral palsy, head injury, ... [and] multiple sclerosis." Id. at 111.
FF 7. According to Brin, botulinum toxin type A "appears to have
afferent effects, possibly acting on the muscle spindle to modify the sensory
feedback loop to the central nervous system." Id. Abstract; see also id. at
112 ("BTX-A may also modify the sensory feedback loop to the central
nervous system."). Citing prior studies, Brin describes "the possibility that
toxin might have a direct effect on sensory afferents by blocking intrafusal
fibers, resulting in decreased activation of muscle spindles. This would
effectively change the sensory afferent system by reducing the Ia traffic."
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Id. at 112 (describing a study "establishing that local injections ofBTX-A
directly reduce afferent 1 a fiber traffic, and therefore exert a modulatory
effect on sensory feedback"). Brin describes a "model" in the scientific
literature and teaches that "this model of blocking Ia afferents supports the
proposed mechanism of afferent action with BTX-A in conditions associated
with excessive muscle contraction." Id. at 113.
FF 8. Brin teaches that antibody-mediated resistance to botulinum
toxin type A is a recognized side effect, which can render the patient
unresponsive to treatment. Id. Abstract, 118, 120. Brin teaches such
immunoresistance "may be minimized by using the lowest effective dose
with at least three months between injections." Id. Abstract; see also id.
118, 120 (suggesting "use [of] the smallest possible effective dose").
FF 9. Brin teaches that "[ e ]xcess weakness" is a "major adverse
effect[] of BTX therapy," which varies with, inter alia, dose and injection
site. Id. at 118.
Analysis
Rejection I - Claim 10
The Examiner finds that Grazko teaches or suggests the method of
claim 10, except for "the specific locations for the injections." Final Act. 6-
7. 6 Claim 10 recites that an effective amount of botulinum toxin type A is
6 Regarding the preamble language of claims 10 and 20, reciting
"modulating maladaptive neuronal plasticity," the Examiner finds that
spasticity leads to maladaptive neuronal plasticity and, thus, attenuating
spasticity (as in Grazko) "naturally and necessarily also modulates (e.g.
attenuates the development of maladaptive neuronal plasticity .... ").
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administered "to at least a portion of a IA sensory afferent on or within
intrafusal fibers of at least one muscle." App. Br. 17.
The Examiner turns to Brin as teaching or suggesting administering
botulinum toxin type A to the location recited in claim 10. Final Act. 7.
According to the Examiner, Brin teaches, among other things, "that local
injections of Botulinum toxin A (Btx-A) have a direct effect on sensory
afferents by blocking intrafusal fibers, resulting in decreased activation of
muscle spindles, and effectively changing the sensory afferent system by
reducing the la fiber traffic." Id.
Based on the combined teachings of the Grazko and Brin, the
Examiner concludes the subject matter of claim 10 would have been
obvious. Id. The Examiner reasons the skilled artisan would have been
motivated to modulate maladaptive neuronal plasticity (attenuating the
spasticity that precedes it), by
administering a therapeutically effective amount (e.g. as low as
2.5 units) of botulinum toxin type A to affected muscles, as
taught by Grazko et al., by selecting injection sites for targeting
administration of the toxin to a portion of the 1 a sensory
afferents, including injections on or within the intrafusal fibers
found in the mid-portion of the affected muscle.
Id. According to the Examiner, this administration would be expected to
"block the 1 a afferents in conditions of excessive muscle contraction (e.g.
spasticity), as taught by Brin ... [and to] optimize[] the therapeutic benefit
of the botulinum toxin A by reducing la fiber traffic (i.e. stops la afferents
from firing), as taught by Brin." Id. at 8. The Examiner further reasons that,
by optimizing the injection sites to the la afferents, "a lower effective dose"
could be used, which lower dosing would have also been beneficial to
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"minimize antibody-mediated resistance to botulinum toxins as taught by
Brin." Id. at 8-9.
We agree with and adopt the Examiner's findings, reasoning, and
conclusion that claim 10 would have been obvious over Grazko and Brin.
Final Act. 2-12. In short, Grazko and Brin teach that administration of
botulinum toxin type A attenuates spasticity that may result from, for
example, stroke. FF 1, 6. Grazko teaches administration of amounts of
botulinum toxin type A that overlap with suitable amounts described in
Appellants' Specification, and that significant muscle weakness can be
avoided by titration of the dose. FF 2-5. Brin suggests blocking la
afferents/traffic in the intrafusal fibers (in the muscle mid portion) with
botulinum toxin type A to modulate sensory feedback and muscle activity,
thus suggesting administration at that site. FF 7. Brin further teaches the
lowest effective doses should be administered to minimize resistance to the
toxin. FF8. We are persuaded on this record that the skilled person would
have, with a reasonable expectation of success, administered low doses (e.g.,
2.5 units) to the la sensory afferents of a muscle and titrated and optimized
the doses accordingly to attenuate spasticity while avoiding toxin resistance
and muscle weakness, which, on balance, the art indicates is an undesired
side effect ofbotulinum toxin type A administration. FF 4--5, 8-9.
Appellants argue that Grazko and Brin teach away from the claimed
subject matter and, specifically, administration of a "therapeutically
effective amount [that] is sufficiently low as to not induce muscle
weakness." App. Br. 11-12. According to Appellants, "Grazko makes clear
that the dose administered should induce some degree of muscle weakness"
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because Grazko discloses that "[i]n hyperkinetic movement disorders, a
favorable response to botulinum toxin is often associated with some degree
of muscle weakness." Id. at 11. And, Appellants contend, Brin identifies
"excess weakness" and "weakness ... in muscles distal to the site of
injection" as side effects, but not muscle weakness, per se. Id. at 12 (quoting
Brin, 118-119) (emphasis added by Appellants).
Appellants' argument is unpersuasive. Unlike Appellants, we do not
read the prior art as suggesting that muscle weakness is a desired effect. The
portion of Grazko cited by Appellants states that "a favorable response to
botulinum toxin is often associated with some degree of muscle weakness."
Grazko, 716 (emphasis added). Grazko does not teach that a favorable
response is indicated or marked by muscle weakness. Quite the opposite, by
using the word "often," Grazko teaches that a favorable response sometimes
involves no muscle weakness. We find the Examiner has the better
interpretation of the prior art in finding that muscle weakness "is an
undesirable side effect which the prior art then offers a potential fix for (e.g.
titration; see Grazko et al.)." Final Act. 10; Ans. 13. We also agree with the
Examiner that "the dose of the botulinum toxin is a results effective
variable" and the evidence suggests a "motivation to optimize the amount to
the lowest effective dose through routine experimentation." Ans. 13. The
Examiner further supports these determinations with other evidence (e.g.,
Erbguth 7), which states expressly that muscle weakness is a side effect of
botulinum toxin administration, and that the effect is dose-dependent.
7 Frank J. Erbguth, Dose-Dependent Anhidrotic Effect of Botulinum Toxin,
30 CURRENT PROBLEMS IN DERMATOLOGY 131--40 (2002)
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Erbguth 138-39 ("[R]educing the total dose means a reduction in the risk of
development of muscle weakness (of the palm) and other side-effects, such
as induction of neutralizing antibodies .... "). Ans. 14. In sum, we are
unpersuaded that a favorable response to botulinum toxin type A is
synonymous with muscle weakness as Appellants suggest.
Appellants also argue the combination of Grazko and Brin fails to
disclose all the limitations of claim 10. According to Appellants, "Brin does
not teach targeting the sensory afferents on or within intrafusal fibers of the
muscle." App. Br. 12. Rather, Appellants contend, Brin uses "tentative
language" and states that botulinum toxin type A "might have a direct effect
on sensory afferents by blocking intrafusalfibers." Id. (quoting Brin 112)
(emphasis added by Appellants).
We remain unpersuaded. Insofar as the portion of Brin cited by
Appellants uses alleged "tentative language," Brin explains the scientific
basis behind it. For example, Brin teaches that another study in the scientific
literature "supported this hypothesis by establishing that local injections of
BTX-A directly reduce afferent la fiber traffic, and therefore exert a
modulatory effect on sensory feedback." Brin 112. And Brin further
teaches that a blocking model known in the art "supports the proposed
mechanism of afferent action with BTX-A in conditions associated with
excessive muscle contraction." Id. at 113; FF 7. Moreover, Brin must be
read from the skilled artisan's perspective against the background
knowledge and art in the field. Final Act. 11. 8 From that perspective, the
8 See Sundance, Inc. v. DeMonte Fabricating Ltd., 550 F.3d 1356, 1361 n.3
(Fed. Cir. 2008) ("What a prior art reference discloses or teaches is
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Examiner points out, it was well known that botulinum toxins target the
primary sensory afferents, including 1 a sensory afferents. Id. (citing
Foster9). Appellants provide insufficient persuasive evidence to the
contrary.
Rejection I- Claim 20
Appellants contend "claim 20 recites that and the botulinum toxin is
administered within 6 months of the occurrence of upper motor neuron
lesion." App. Br. 13. Appellants state only that "[n]one of the cited
references disclose or suggest this additional claim limitation." Id.
We are unpersuaded. We otherwise adopt the Examiner's findings
and reasoning in support of this rejection, as well as the Examiner's
conclusion that claim 20 would have been obvious. The Examiner cited the
relevant teachings in Grazko as disclosing this limitation in claim 20. See,
e.g., Final Act. 5---6; Ans. 4, 15-16. Appellants' argument is unconvincing
inasmuch as it simply recites a claim limitation and contends it is missing.
In re Lovin, 652 F.3d 1349, 1357 (Fed. Cir. 2011) (37 C.F.R. § 41.37
requires "more substantive arguments in an appeal brief than a mere
recitation of the claim elements and a naked assertion that the corresponding
elements were not found in the prior art.").
determined from the perspective of one of ordinary skill in the art."); Custom
Accessories, Inc. v. Jeffrey-Allan Indus., 807 F.2d 955, 962 (Fed. Cir. 1986)
("The person of ordinary skill is a hypothetical person who is presumed to
be aware of all the pertinent prior art.").
9 Foster et al., US 5,989,545, issued Nov. 23, 1999.
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Rejection II - Claim 1
Appellants refer to their arguments about a "teaching away" in Grazko
and Brin, which are discussed above and remain unpersuasive. App. Br. 14.
According to Appellants, "Cosgrove is merely relied on to disclose
preventing spasticity, [and] it does not cure the deficiencies of Grazco and
Brin." Id.
Appellants do not contest the Examiner's findings on Cosgrove and,
having found no "deficiencies" in the Grazko and Brin combination, we find
that the preponderance of the evidence on this record supports the
Examiner's conclusion that claim 1 would have been obvious over Grazko,
Brin, and Cosgrove.
Rejection II - Claim 19
Appellants refer to the arguments discussed above and further contend
that "[ n ]one of the cited references disclose or suggest" the limitation of
"preventing spasticity resulting from an upper motor neuron lesion," as
recited in claim 19. App. Br. 14.
The Examiner, however, has identified the relevant teachings in the
prior art and explained how this limitation is met. See, e.g., Final Act. 13-
14 (discussing Cosgrove' s teaching of injections of botulinum toxin A into
muscles to prevent spasticity in rats); see also Ans. 16. We otherwise adopt
the Examiner's findings and reasoning in support of this rejection, as well as
the Examiner's conclusion that claim 19 would have been obvious.
Appellants' argument, merely repeating a claim limitation and asserting it is
absent in the prior art, is non-substantive and unpersuasive. In re Lovin, 652
F.3d at 1357.
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Conclusion of Law
The preponderance of the evidence on this record supports the
Examiner's conclusion that claims 10 and 20 would have been obvious over
Grazko and Brin, and that claims 1 and 19 would have been obvious over
Grazko, Brin, and Cosgrove. The dependent claims were not argued
separately and thus fall with the independent claims 1, 10, 19, and 20 from
which they depend.
SUMMARY
We affirm the rejections for obviousness on appeal.
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).
AFFIRMED
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