University of Maryland, Baltimore

Patent Trials and Appeals BoardJan 1, 2021

2020002828 (P.T.A.B. Jan. 1, 2021)

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. 15/300,984 09/30/2016 Scott Thompson UOMD.P0021US-11611089 5572 26271 7590 01/01/2021 NORTON ROSE FULBRIGHT US LLP 1301 MCKINNEY SUITE 5100 HOUSTON, TX 77010-3095 EXAMINER LEE, ANDREW P ART UNIT PAPER NUMBER 1628 NOTIFICATION DATE DELIVERY MODE 01/01/2021 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): hoipdocket@nortonrosefulbright.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte SCOTT THOMPSON, MARK D. KVARTA, and ADAM VAN DYKE Appeal 2020-002828 Application 15/300,984 Technology Center 1600 Before JASON V. MORGAN, DEBORAH KATZ, and JOHN E. SCHNEIDER, Administrative Patent Judges. SCHNEIDER, Administrative Patent Judge. DECISION ON APPEAL STATEMENT OF THE CASE Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims 1, 2, 5, 10–12, 19, and 24–32. See Final Act. 1. We have jurisdiction under 35 U.S.C. § 6(b). We Reverse 1 We use the term “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as the real parties in interest are UNIVERSITY OF MARYLAND, BALTIMORE; NATIONAL INSTITUTES OF HEALTH (NIH); U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT. Appeal Br. 4. Appeal 2020-002828 Application 15/300,984 2 CLAIMED SUBJECT MATTER The claims are directed to a method of using negative modulators of GABA receptors containing alpha 5 subunits as fast acting antidepressants. Claim 1, reproduced below, is illustrative of the claimed subject matter: 1. A method of treating or ameliorating at least one symptom of a medical condition in an individual, comprising the step of providing to the individual a therapeutically effective amount of one or more negative modulators of GABAA receptors, wherein the medical condition is selected from the group consisting of depression having anhedonia as a symptom; major depressive disorder (MDD); suicidality; and a combination thereof, wherein the negative modulator of GABAA receptor is a partial inverse agonist of a GABAA receptor comprising an α5 subunit, said modulator selected from the group consisting of ethyl (13aS)-7-methoxy-9-oxo-11,12,13,13a-te[t]rahydro-9H- imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate (L-655,708), 3-bromo-10-(difluoromethyl)-9H-benzo[f]imidazo [1,5-a] [1,2,4]triazolo[1,5-d][1,4]diazepine (RO4938581), N- benzyl-6-ethoxy-4-oxo-1H-1,5-naphthyridine-3-carboxamide (CP-457,920), 3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1- methyl-1H-1,2,4triazol-5-ylmethoxy)pyrazolo(1,5-d)(l ,2,4) triazine (MRK-016), RG-1662, and a combination thereof. Appeal Br. 13 (Claims Appendix). Appeal 2020-002828 Application 15/300,984 3 REFERENCES The prior art relied upon by the Examiner is: Name Reference Date Jones Jones et al., Pharmacokinetics and metabolism studies on (3-tert-butyk-7-(5- methylisoxazol-3-yl)-2- (1-methyl-1H-1,2,4- triazol-5-ylmethoxy) pyrazolo[-1,5d]triazine, a functional selective GABAA α5 inverse agonist for cognitive dysfunction, 16 BIOORG. MED. CHEM. LETT. 872– 75 (2006) 2006 MöhlerMöhler Möhler, The GABA system in anxiety and depression and its therapeutic potential, 62 NEUROPHARMACOLOGY 42–53 (2012) 2012 REJECTION Claims 1–2, 11, 24–26, 28, and 33–35 are rejected under 35 U.S.C. § 103 as being unpatentable over Jones in view of Möhler. OPINION Issue The issue on appeal is whether a preponderance of the evidence supports the Examiner’s conclusion that the subject matter of claims 1, 2, 5, Appeal 2020-002828 Application 15/300,984 4 10–12, 19, and 24–32 would have been obvious to one of ordinary skill in the art over Jones combined with Möhler. The Examiner finds that Jones teaches that use of (3-tert-butyk-7-(5- methylisoxazo(1-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy) pyrazolo[1,5-d]triazine (“MRK-016”) as a “functionally selective inverse agonist of the GABAA α5 receptor.” Final Act. 5. The Examiner finds that while Jones does not teach the use of MRK-016 to treat a depression disorder, Möhler teaches that GABA receptor modulators can be used to treat central nervous system disorders such as depression and suicidality. Id. at 6. The Examiner concludes It would have been obvious to one of ordinary skill in the art at the time the invention was made to treat a depression disorder by administering M[R]K-016 and to also administer another therapy, as suggested by [Möhler], and produce the instant invention. One of ordinary skill in the art would have been motivated to do so since MRK-016 is an effective inverse agonist of the GABAA α5 receptor as taught by Jones, which can be modulated for the treatment of depression as taught by [Möhler], with a reasonable expectation of success absent evidence of criticality of the particular steps. One of ordinary skill in the art would have been motivated to do so since it is prima facie obvious to combine components known for the same purpose for their combined additive effects, with a reasonable expectation of success absent evidence of criticality of the particular formulation. Additionally, “ [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). In the instant case, it would have been obvious to combine MRK-016 and TPA023 cojointly [sic] in order to treat depression disorders. Id. Appeal 2020-002828 Application 15/300,984 5 Appellant contends that modulators of α2 receptor subtypes and α5 receptor subtypes have non-overlapping functions and receptors for each subtype are localized to different regions of the brain. Appeal Br. 6–7. Appellant contends that Jones teaches that MRK-016 is a GABAA receptor α5 receptor partial inverse agonist that can be used to treat cognitive dysfunction. Id. at 7. Appellant contends that Möhler teaches that the GABAA modulators are positive modulators of the α2 and α3 subtypes. Id. Appellant contends that given that MRK-016 is a negative modulator of an α5 subtype, one skilled in the art would not consider using MRK-016 to treat depression. Id. at 8–9. Legal Principles “[T]he examiner bears the initial burden, on review of the prior art or on any other ground, of presenting a prima facie case of unpatentability. . . . If that burden is met, the burden of coming forward with evidence or argument shifts to the applicant.” In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). “It is well-established that before a conclusion of obviousness may be made based on a combination of references, there must have been a reason, suggestion, or motivation to lead an inventor to combine those references.” Pro-Mold and Tool Co. v. Great Lakes Plastics Inc., 75 F.3d 1568, 1573 (Fed. Cir. 1996). Analysis We have considered the arguments presented by the Examiner and Appellant and the evidence of record and conclude that Appellant has the better argument. Jones teaches that MRK-016 is a “functionally selective, inverse agonist at the BZ site of GABAA α5 receptors which enhances performance Appeal 2020-002828 Application 15/300,984 6 in animal models of cognition.” Jones, 872. Möhler also teaches that “partial inverse agonists, which diminish selectively as GABAA receptor function, displayed enhanced spatial and temporal memory in various paradigms.” Möhler, 45. Thus both references cited by the Examiner teach that compounds such as MRK-016 act to improve cognitive ability. This is also consistent with the testimony of Dr. Thompson. Thompson Decl. II2, ¶ 7. The evidence of record also shows that GABA receptors composed of α2 and α5 subunits are localized to different of the regions brain producing different effects. Thompson Decl. I3, ¶¶ 8–9, Möhler Fig. 1. For example, Figure 1 of Möhler, reproduced below, shows the different regions affected by α2 and α5 receptors and discussed the different effects of the receptors. 2 Declaration Under 37 C.F.R. § 1.132, filed Jan. 11, 2019. (“Thompson Decl. II”). 3 Declaration Under 37 C.F.R. § 1.132, filed June 19, 2018 (Thompson Decl. I”). Appeal 2020-002828 Application 15/300,984 7 Figure 1 of Möhler showing roles of different GABAA receptors. Specifically, it depicts [t]he domain-specific innervation of principle cells by GABA interneurons supports temporal dynamics, network oscillations, selection of cell assemblies and implementation of brain states. A diversity of GABAA receptors is required to accommodate the diverse temporal requirements in interneuron signal transduction. On a systems level, α1 GABAA receptors mediate benzodiazepine-induced sedation, anti-convulsant activity and, largely, dependence liability. α2 GABAA receptors mediateanxiolysis. α3 GABAA receptors mediate anxiolysis at high receptor occupancy and control dopaminergic activity. α5 GABAA receptors, located mainly in hippocampus extrasynaptically, modulate memory performance. PV and CCK indicate parvalbumin- and cholecystokinin-containing interneurons respectively (from Möhler, 2011). Möhler 43. Möhler teaches that α2/α3 GABAA modulators “may serve as novel antidepressants.” Möhler, Abstr. Dr. Thompson testifies that the compounds identified by Möhler in Table 1 as having an antidepressant effect are positive allosteric modulators, in contrast with MRK-016 which is a negative modulator. Thompson Decl. II ¶ 6. Given the different activity and effect of MRK-016 as compared with the GABAA agonists disclosed in Möhler, we agree with Dr. Thompson that one skilled in the art would not use MRK-016 to treat depression. Thompson Decl. II ¶¶ 4–6. The rejection is based on the Examiner’s contention that Möhler teaches the use of GABAA receptor modulators in general can be used to treat depression and that the claimed method merely substitutes one modulator for another. Ans. 4. We agree with Appellant that this is an over broad interpretation of Möhler. Reply Br. 3. Möhler teaches that only α2 and α3 receptor modulators have an antidepressant effect. Möhler, Abstr. Both Appeal 2020-002828 Application 15/300,984 8 Möhler and Jones teach that MRK-016 is effective for cognitive dysfunction. Möhler, 45; Jones, 872. The Examiner has not pointed to nor have we discerned any teaching in the references that a receptor modulator that improves cognitive function would also have an effect on depression. See Ans. 5–8. We therefore conclude that the Examiner has failed to state a proper reason having a rational underpinning for combining the references. The Examiner contends that the claims do not require a specific mechanism of action such that the modulator can operate by other mechanisms. Ans. 5–7. While this may be true, the claims still requires that the recited modulator be a partial inverse agonist of a GABAA receptor comprising a α5 subunit. As discussed above we do not find anything in the record to show why one skilled in the art would be motivated to use such a modulator to treat depression. Conclusion We conclude that a preponderance of the evidence does not support the Examiner’s conclusion that the subject matter of claims 1, 2, 11, 24–26, 28, and 33–35 would have been obvious over Jones combined with Möhler. CONCLUSION The Examiner’s decision to reject claims 1–2, 5, 10–12, 19, and 24– 32 under 35 U.S.C. § 103 as unpatentable over Jones combined with Möhler is reversed. Appeal 2020-002828 Application 15/300,984 9 DECISION SUMMARY Claims Rejected 35 U.S.C. § References Affirmed Reversed 1–2, 11, 24–26, 28, 33–35 103 Jones, Möhler 1–2, 11, 24–26, 28, 33–35 Reversed