Ex Parte Carmichael et alDownload PDFPatent Trial and Appeal BoardMay 9, 201812793607 (P.T.A.B. May. 9, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 121793,607 06/03/2010 Stanley T. Carmichael 13307 7590 05/11/2018 Foley & Lardner LLP 3000 K STREET N.W. SUITE 600 WASHINGTON, DC 20007-5109 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. 099676-0150 7035 EXAMINER CORNET, JEAN P ART UNIT PAPER NUMBER 1628 NOTIFICATION DATE DELIVERY MODE 05/11/2018 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): ipdocketing@foley.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte STANLEY T. CARMICHAEL, ISTVAN MODY, ANDREW CLARKSON, JUSTINE J. OVERMAN, and BEN HUANG Appeal2017-000237 Application 12/793,607 1 Technology Center 1600 Before ULRIKE W. JENKS, JENNIFER MEYER CHAGNON, and DEVON ZASTROW NEWMAN, Administrative Patent Judges. NEWMAN, Administrative Patent Judge. DECISION ON APPEAL This appeal under 35 U.S.C. § 134 involves claims to a method of treating a pathological injury to the central nervous system in a subject. The Examiner entered final rejections for obviousness. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 Appellants identify the real party in interest as The Regents of the University of California. App. Br. 1. Appeal2017-000237 Application 12/793,607 STATEMENT OF THE CASE Background Injuries to the brain or spinal cord from stroke, trauma or neurodegenerative disease produce loss of behavioral function and limited recovery. Damage to the brain or spinal cord produces loss of function in two ways. First, the injury causes complete damage at the center of the insult to neural circuits that control a bodily function, like movement, sensation or language. Second, the injury causes partial damage to neural circuits that are adjacent to the injury site (termed peri-infarct tissue), and disables the function of these circuits. Most therapies in CNS injury and stroke have been directed toward the first mechanism of damage: preventing the initial injury or cell death (an approach termed neuroprotection). No therapies have been directed at stabilizing partially damaged circuits in the brain, and promoting their function. Spec. 1: 11-20. The Specification discloses "[ m ]ethods for treating a central nervous system (CNS) injury in a subject ... [that] include administering to the subject an effective amount of gamma aminobutyric acid (GABA) receptor signaling inhibitor to treat the subject for the CNS injury." Id. at 3: 12-15. The Claims Claims 1, 3, 5, 12-14, 18, 19, 21, and 26 are on appeal. App. Br. 4. Claim 1 is illustrative and reads as follows: 1. A method of treating one or more pathological injuries from the group of a central nervous system (CNS) injury, stroke, trauma, or ischemic brain damage in a subject, the method consisting of: administering to the subject an effective amount of a gamma aminobutyric acid (GABA) receptor signaling inhibitor that inhibits signaling from an a5 subunit containing GABA 2 Appeal2017-000237 Application 12/793,607 receptor or that inhibits signaling from a 8 subunit containing GABA receptor, wherein the pathological injury is characterized by the presence of physically damaged or altered CNS tissue and wherein the administration does not begin until three days after the pathological injury occurs. App. Br. 12 (Claims Appendix). Appellants have selected "[ s ]troke as the central nervous system (CNS) injury characterized by physical damage[] or altered CNS tissue and L-655,708 as the elected GABA receptor inhibitor." Ans. 2. Independent claim 14 additionally recites that the subject is a human patient and is diagnosed as "having the pathological injury" prior to administration of the compounds. Appeal Br. 13. Independent claim 21 additionally recites that the subject is a human patient and recites "assessing the subject for peri-infarct tissue repair" prior to administration of the compounds. Id. at 14. 3 Appeal2017-000237 Application 12/793,607 The Issues The following rejections are before us to review: Claims 1, 3, 5, 12-14, 18, 19, and 26 are rejected under pre-AIA 35 U.S.C. § 103(a) as obvious over Barlow2 in view ofBraun. 3 Ans. 3. Claim 21 is rejected underpre-AIA 35 U.S.C. § 103(a) as obvious over Barlow, Braun, and Carmichael. 4 Id. at 6. I - OBVIOUSNESS OVER BARLOW AND BRAUN The Examiner finds that Barlow teaches a method of "treating central nervous system disease/conditions, cellular trauma/injury in a patient comprising administering a GABA agent to produce an improvement in said disorder in said patient ... wherein the central nervous system disorder is related to trauma or injury . .. [and] wherein the patient is human." Ans. 3--4. The Examiner finds Barlow discloses an embodiment wherein "the GABA agent referred to as GABA modulator is L-655,708 ... and the central nervous system disorder includes ischemic stroke" which is 'a specie of stroke."' Id. at 4. The Examiner finds Barlow teaches that "the GABA agent stimulate[ s] or activate[ s] neurogenesis" and may be used on a subject diagnosed as having had a stroke. Id. 2 U.S. 2007/0112017 Al, published May 17, 2007 ("Barlow"). 3 Johann S. Braun et al., Spatiotemporal relationship of apoptotic cell death to lymphomonocytic infiltration in photochemically induced focal ischemia of the rat cerebral cortex 92: ACTA NEUROPATHOL. 255-263 (1996) ("Braun"). 4 S. Thomas Carmichael, Cellular and Molecular Mechanisms of Neural Repair after Stroke: Making Waves, 59: ANNNEUROL. Assoc. 735-742 (2006) ("Carmichael"). 4 Appeal2017-000237 Application 12/793,607 The Examiner finds that Barlow discloses L-655-708 "the elected GABA receptor signaling inhibitor that inhibits signaling from an a5 subunit containing GABA receptor" and that the Specification "discloses L-655-708 as a GABA receptor signaling inhibitor that inhibits signaling from an a5 subunit containing GABA receptor or an inverse agonist.'' Id. The Examiner finds that Barlow therefore teaches "a GABA receptor signaling inhibitor that inhibits signaling from an a5 subunit containing GABA receptor." Id. The Examiner finds that [ w ]hile the prior art does not specifically teach ischemic stroke is characterized by increased GABA receptor signaling in peri- infarct tissue as recited in claim 19, there does not appear to be a manipulative difference between the patient population of the prior art and that of the claim since the instant specification teaches ... ischemic stroke is characterized by increased GABA receptor signaling in peri-infarct tissue. Id. at 4--5. The Examiner finds that Barlow does not teach commencing administration of the GABA agent three days after the injury occurs. Id. at 5. The Examiner finds that Braun teaches a model of induced focal cerebral ischemia (a model for ischemic stroke) used to study the time course of apoptotic cell death following ischemia. Id. The Examiner finds that Braun discloses that ischemic stroke causes "a profound inflammatory response with lymphomonocytic infiltration," that "apoptotic cell death after photothrombosis is a prolonged process continuing for several days after ischemia and is spatially related to the presence of inflammatory cells in the boundary zone of the infarcts," and that "3 days, 6 days and 14 days after stroke show the period of most cell death in this stroke model." Id. The Examiner further finds that Braun teaches "programmed cell death leads to 5 Appeal2017-000237 Application 12/793,607 elimination of infiltrating T cells and macrophages, a mechanism considered important for the induction of clinical recovery" and that "there is good evidence that excitatory amino acids, acidosis, increases in calcium concentration and production of free radicals are critically involved," which are neurotoxic factors that are known to contribute to death by necrosis and apoptosis. Id. The Examiner concludes that the ordinarily skilled artisan would have found it obvious to modify the method taught by Barlow et al by administering L-655-708 until three days after the stroke occurs to give Applicants' 'claimed invention. One would have been motivated to do so because Braun et al teach days 3, days 6 and days 14 are periods of time where most cell death in stroke, which is a mechanism considered important for the induction of clinical recovery. One would have reasonable expected administration after three (3) days of stroke to provide an effective therapy to stimulate or activate the formation of nerve cells that exhibit apoptotic cell death at that period of time. Id. at 6. Appellants argue, among other points, that the rejection should be reversed because the cited references do not teach commencing treatment with a GABA agent at three days post injury. App. Br. 5-10. According to Appellants, use of a GABA agent as claimed "too early after stroke onset increases stroke damage .... compared to administration of the same 3 days after stroke in mice models" and "waiting 3 days after the pathological injury to administer an inhibitor of a GABA receptor containing an a5 subunit or a 8 subunit is crucial for a therapeutic effect." Id. at 9. Appellants argue that the neurogenesis is believed to be effective at this time frame because "dampening tonic GABA inhibition is therapeutically 6 Appeal2017-000237 Application 12/793,607 effective only after the majority of cell death has already occurred." Id. Appellants argue that at the time of the invention, "there was no information on the role of GABA manipulation in stroke recovery, so a skilled artisan would [have been] motivated to administer a stroke therapy as soon as the injury occurs in order to prevent cell death." Id. Appellants further argue given that Braun teaches that most cell death occurs 3, 6, and 14 days after stroke, a skilled artisan would [have been] motivated to administer a GABA agent of Barlow prior to 3, 6, and 14 days after stroke. Specifically, based on Braun's teaching that CNS injury post stroke is a dynamic process that begins at day 2, a skilled artisan would [have been] motivated to administer a GABA agent of Barlow at least as early as day 2 post-stroke instead of waiting until day 3, after most cell death has already occurred. If cell death ha[d] already occurred by day 3 as taught by Braun, a skilled artisan would have [had no] reasonable expectation of success in administering a GABA agent of Barlow because the damage to the CNS has already occurred. Id. Appellants argue that "when considered as a whole, the provided art establishes that cell death continues post-stroke anywhere from 24 hours post-stroke until at least 21 days post-stroke" and would have motivated the artisan "to administer [the GABA agent] prior to 24 hours post-stroke."5 The Examiner responds on this issue that "Braun ... is the reference used in Applicants' specification, Example 3 to show that the time period (three days of after the injury occurs) was chosen because it is after the period of most cell death in this stroke model .... The Examiner cites Braun 5 Appellants cite Exhibits A---G, prior art publications, as evidence of the uncertainty of the prior art with regard to the timeline of cell death. See e.g., Reply Br. 7. We do not address these exhibits based on our finding that the cited references do not establish a prima facie case of obviousness. 7 Appeal2017-000237 Application 12/793,607 for the same reasons disclosed in the Application." Ans. 12. The Examiner further responds that because Braun teaches that three days after the stroke is the period of most cell death in stroke ... , the skilled artisan would have been motivated to apply the method taught by Barlow et al until three days after the stroke occurs so that the GABA agent can induce neurogenesis. The skilled artisan would not administer the compound prior to three days after stroke because neuronal cells are continuously dying. If neuronal cells are continuously dying, administering the compound, i.e. the GABA agent would not be efficacious, i.e. neurogenesis would not be effective. Id. at 14--15. In reply, Appellants argue the Examiner ignored the conflicted teachings of the prior art with regard to the timeline of cell death following a stroke, "and impermissibly used the Appellant's own specification as a guide to selectively rely solely on Braun's teaching that the most amount of cell death occurs 3 days post-stroke." Reply Br. 7. Appellants further argue the Examiner's selection of three days as the peak of cell death ignores the full scope of the cited references. Id. The issue with respect to this rejection is whether the teachings of Barlow and Braun would have provided the ordinarily skilled artisan with a reasonable expectation of success in practicing the claimed method. Where claimed subject matter has been rejected as obvious in view of a combination of prior art references, a proper analysis under § 103 requires, inter alia, consideration of two factors: (1) whether the prior art would have suggested to those of ordinary skill in the art that they should make the claimed composition or device, or carry out the claimed process; and (2) whether the prior art would also have revealed that in so making or carrying out, those of ordinary skill would have had a reasonable expectation of success. Both the suggestion and 8 Appeal2017-000237 Application 12/793,607 the reasonable expectation of success must be founded in the prior art, not in the applicant's disclosure. In re Vaeck, 947 F.2d 488, 493, (Fed. Cir. 1991) (citation omitted). A "finding of a reasonable expectation of success is a question of fact." Medichem S.A. v. Rolabo S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006). While we agree that the Examiner's findings are based in fact and view this as a close case, on balance we are persuaded by Appellants that on the record before us, an ordinarily skilled artisan would not have held a reasonable expectation of success in achieving the claimed method based on the rationale advanced by the Examiner. In particular, we are persuaded by Appellants' argument that the Examiner's articulation of the teachings of Braun and Barlow would not have motivated the skilled artisan to commence treatment with a GABA agent at three days post-injury. Braun discloses a study of the time course of apoptotic cell death in a rat model of focal ischemia induced by photochemical means. Braun at 255. As stated by the Examiner, Braun discloses that "apoptotic cell death after photothrombosis is a prolonged process continuing for several days after ischemia and is spatially related to the presence of inflammatory cells in the boundary zone of the infarcts." Ans. 5, citing Braun at 255. Braun identified apoptotic cells through in situ labeling of fragmented DNA confirmed by DAPI staining to reveal nuclear morphology. Braun at 259. Braun's description of the location of apoptosis during the 14-day time frame is a fluid recitation of the progression of incorporation of the labeling and the morphological location of the staining: Braun notes that significant apoptotic cell death was detected at 1 day after photothrombosis; the number of cells with nuclei positive for in situ labeling had decreased at 2 days post 9 Appeal2017-000237 Application 12/793,607 thrombosis; the number of markers was lower yet again at 3 days out; the labeling was more localized in certain areas at 6 days and "the proportion of nuclei showing fragmentation was lower than that seen on day 3"; and the labeling "virtually absent" in the lesion area by 14 days. Id. at 261. While we agree with the Examiner that Braun describes a detectable decrease in the progression nuclei positive for markers of apoptosis at day 3, we do not read Braun to clearly identify day 3 as the concrete end of apoptosis as would be necessary to provide a factual basis to support the Examiner's rationale that "Braun et al teach three days of the stroke is the period of most cell death in stroke," which is the Examiner's statement advanced in the rejection. Ans. 15. See also Ans. 6 ("Braun et al teach days 3, days 6 and days 14 are periods of time where most cell death in stroke."). While we agree with the Examiner that Appellants cited Braun in the Specification as the precise reason for selecting three days post-injury as a time for treatment (Spec. 34), our reviewing court has held that "[b ]oth the suggestion and the reasonable expectation of success must be founded in the prior art, not in the applicant's disclosure." Vaeck, 947 F.2d at 493. The Examiner has not established why the ordinarily skilled artisan, reading Barlow and Braun, would have selected three days as a time frame for commencing treatment with a GABA receptor, given that Braun describes that markers of cell death are detectable for several days following photothrombosis, until they are "virtually absent" by day 14 of the 14-day time period studied by Braun. See Braun at 260-261. Rather, the Examiner's rationale is quoted from Appellants' Specification ("This time 10 Appeal2017-000237 Application 12/793,607 period was chosen because it is after the period of most cell death in this stroke model," citing Braun). Spec. 34. "An examiner bears the initial burden of presenting a prima facie case of obviousness." In re Huai-Hung Kao, 639 F.3d 1057, 1066 (Fed. Cir. 2011 ). As we find the Examiner has not established that the ordinarily skilled artisan would have found a suggestion in Braun and Barlow to practice the claimed method or had a reasonable expectation of success in doing so based on these references, we reverse the rejection under 35 U.S.C. § 103. II The Examiner finds that claim 21 is obvious over Barlow, Braun, and Carmichael. Ans. 6. This rejection, however, relies upon the Examiner's rationale, discussed above, that Braun and Barlow would have suggested treating a patient having a CNS injury with a GABA agent commencing three days post-injury, which we have found is not supported by a preponderance of the evidence, as discussed above. Id. The Examiner does not cite Carmichael to teach this claim element. See id. at 6-7. Accordingly, we reverse this rejection for the same reasons discussed above. SUMMARY We reverse both rejections on appeal. REVERSED 11 Copy with citationCopy as parenthetical citation