Ex Parte Blumenfeld et alDownload PDFPatent Trial and Appeal BoardMay 8, 201812578518 (P.T.A.B. May. 8, 2018) Copy Citation 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. Appeal2017-006686 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. 2 Appeal2017-006686 Application 12/578,518 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 3 Appeal2017-006686 Application 12/578,518 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). 4 Appeal2017-006686 Application 12/578,518 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 5 Appeal2017-006686 Application 12/578,518 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 6 Appeal2017-006686 Application 12/578,518 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." 7 Appeal2017-006686 Application 12/578,518 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 .... "). 8 Appeal2017-006686 Application 12/578,518 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 9 Appeal2017-006686 Application 12/578,518 "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" 10 Appeal2017-006686 Application 12/578,518 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) 11 Appeal2017-006686 Application 12/578,518 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 12 Appeal2017-006686 Application 12/578,518 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. 13 Appeal2017-006686 Application 12/578,518 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. 14 Appeal2017-006686 Application 12/578,518 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 15 Copy with citationCopy as parenthetical citation