Abraham Palmer et al.

Patent Trials and Appeals BoardJun 24, 2021

2020005871 (P.T.A.B. Jun. 24, 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. 14/774,886 02/01/2016 Abraham Palmer PALMP0002US/1000354721 7603 32425 7590 06/24/2021 NORTON ROSE FULBRIGHT US LLP 98 SAN JACINTO BOULEVARD SUITE 1100 AUSTIN, TX 78701-4255 EXAMINER KASSA, TIGABU ART UNIT PAPER NUMBER 1619 NOTIFICATION DATE DELIVERY MODE 06/24/2021 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): aoipdocket@nortonrosefulbright.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte ABRAHAM PALMER, MARGARET DISTLER, and KATHERINE M.J. MCMURRAY Appeal 2020-005871 Application 14/774,886 Technology Center 1600 Before DONALD E. ADAMS, JENNIFER MEYER CHAGNON, and RACHEL H. TOWNSEND, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims to a method of treating a depressive disorder as being obvious. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42(a). Appellant identifies the inventors as the real party in interest. (Appeal Br. 1.) Appeal 2020-005871 Application 14/774,886 2 STATEMENT OF THE CASE Appellant’s Specification states that “recent estimates indicate that more than 19 million Americans over the age of 18 years experience a depressive illness each year.” (Spec. ¶ 4.) The Specification further notes that “[s]ince the introduction of selective serotonin reuptake inhibitors (SSRIs) . . . many patients have been effectively treated with anti-depressant medication.” (Id. ¶ 5.) But, the Specification further explains that “an estimated 10 to 30 percent of depressed patients taking an antidepressant are partially or totally resistant to the treatment.” (Id.) The Specification states that there is, therefore, “a need to develop alternative treatments for these patients.” (Id.) Appellant’s invention is directed to such a treatment which involves administration of an inhibitor of glyoxalase 1 (GLO1). (Id. ¶¶ 13, 15.) CLAIMED SUBJECT MATTER Claims 77–79, 81–84, and 86 are on appeal. Claims 87–92 remain pending but are withdrawn from consideration as being directed to a nonelected species. (Final Action 2.) Claim 77, reproduced below, is illustrative of the claimed subject matter: 77. A method of treating a condition in a subject, comprising treating the condition by administering to the subject a composition comprising a Glo1 inhibitor, wherein the condition is a depressive disorder. Appeal 2020-005871 Application 14/774,886 3 The prior art relied upon by the Examiner is: Name Reference Date Akil et al. US 2006/0051786 A1 2006 Paul J. Thornalley et al. Antitumor Activity of S-(p- Bromobenzyl)glutathione Diesters in Vitro: A Structure—Activity Study, 39 J. Med. Chem. 3409– 11 1996 Iiris Hovatta et al. Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice, 438 Nature 662–66 2005 Cristina S. Benton et al. Evaluating genetic markers and neurobiochemical analytes for fluoxetine response using a panel of mouse inbred strains, 221 Psychopharmacol. 297– 315 2012 The following ground of rejection by the Examiner is before us on review: Claims 77–79, 81–84, and 86 under 35 U.S.C. § 103(a) as unpatentable over Benton, Hovatta, Thornalley, and Akil.2 2 In the final rejection, the Examiner also relied on the teachings of Michiko Fujimoto et al, Reduced expression of glyoxalase-1 mRNA in mood disorder patients, 438 Neuroscience Letters 196–99 (2008). (Final Action 3, 5, 9.) The Examiner withdrew reliance on this reference in the Examiner’s Answer. (See Ans. 3.) Appeal 2020-005871 Application 14/774,886 4 DISCUSSION Non-Obviousness The Examiner found that Benton teaches “[i]dentification of biomarkers that establish diagnosis or treatment response is critical to the advancement of research and management of patients with depression.” (Final Action 4.) The Examiner found that Benton states that “[o]ur goal was to identify biomarkers that can potentially assess fluoxetine response and risk to poor treatment outcome (see abstract Objective).” (Id.) The Examiner noted that Benton teaches that GLO1 and GNB1 were measured, among a number of other neurobiochemical analytes, in genetically diverse mouse inbred lines after chronic treatment with water or fluoxetine. (Final Action 4.) The Examiner found that Benton teaches that GLO1 and GNB1 “mostly account for baseline anxiety-like and depressive- like behavior, indicating a common biological link between depression and anxiety” and that “[h]igher levels of GLO1 and GNB1 associated with higher anxiety-like and depressive-like behavior.” (Id. (emphasis omitted).) The Examiner noted Benton’s study included measuring immobility which is a measure of hopelessness of depressive-like behavior in mice. (Id. at 5.) Benton noted that lower immobility scores following fluoxetine treatment was linked with higher levels of GLO1, among other analytes. (Id.) The Examiner further found that Benton teaches GLO1 is “linked within a cellular growth/proliferation pathway, suggesting the involvement of cellular genesis in fluoxetine response.” (Id.) The Examiner found that Hovatta teaches GLO1 overexpression in inbred mice brain resulted in increased anxiety-like behavior, “while local Appeal 2020-005871 Application 14/774,886 5 inhibition of [GLO1] expression by RNA interference decreased the anxiety- like behavior.” (Final Action 6 (emphasis omitted).) The Examiner also found that Hovatta teaches GLO1 is “involved in oxidative stress metabolism, linking this pathway with anxiety-related behavior” and that “[o]xidative stress has also been implicated in the pathogenesis of other neuropsychiatric diseases, including . . . major depressive disorder.” (Id. at 6–7 (emphasis omitted).) The Examiner found that Thornalley teaches S-(p-Bromobenzyl) glutathione is a competitive inhibitor of GLO1 as determined in an in vitro human leukemia cell growth investigation. (Final Action 7.) “The most potent derivative was S-(p-bromobenzyl)glutathione cyclopentyl diester.” (Final Action 6–7 (emphasis omitted).) The Examiner found that it would have been obvious to one having skill in the art to modify the teachings of Benton and Hovatta by using S-(p- bromobenzyl)glutathione cyclopentyl diester as the inhibitor of GLO1 instead of the RNA interference because Thornalley teaches that it was the most potent inhibitor and all of the references are concerned with GLO1. (Final Action 9.) We do not agree with the Examiner’s conclusion of obviousness. We, instead, agree with Appellant that one of ordinary skill in the art would have had “no reasonable expectation [from the relied upon prior art] that administering a Glo1 inhibitor to a subject would serve to treat a depressive disorder.” (Appeal Br. 2.) We recognize that Benton teaches that there is an association between GLO1 and depression. Indeed, Benton states: “GLO1 is an antioxidant enzyme that catalyzes the detoxification of methylglyoxal and has been Appeal 2020-005871 Application 14/774,886 6 linked with various psychiatric disorders including depression.” (Benton 308.) Benton also teaches that from its experiments it was determined that “[l]ower immobility scores following fluoxetine treatment were linked with higher levels of . . . GLO1.” (Benton 305, see also Fig. 1.) And Benton teaches that the immobility score is a measure of hopelessness or depressive- like behavior. (Benton 304, Fig. 1.) However, Benton states that the results of its study finding GLO1 is “correlated with increased baseline immobility in the TST” is “discordant with other studies that have found higher expression of GLO1 in less anxious and depressed mice.” (Benton 308; see Appeal Br. 3–4.) Benton recognizes a few reasons that there may be inconsistent findings, including the strain of the mouse and protein quantification methods. (Benton 308.) Benton then states: “Therefore, functional and metabolic assessment of GLO1 through measurement of methylglyoxal-mediated glycation is required for clarification.” (Id.) Benton does not describe having performed such testing. The only conclusion that Benton drew from its study results, and which seems consistent with the uncertainty of whether GLO1 is upregulated or downregulated in depression, is: the association of GLO1 and GNB1 with baseline behavioral despair and anxiety-like behavior offers a novel possibility in which these proteins can be targeted to modulate both [anxiety and depressive] disorders and improve treatment outcomes in patients who suffer from comorbid anxious depressive symptoms. (Benton 309.) It did not suggest in which direction modulation should occur to improve treatment outcomes. Nor do we think one of ordinary skill in the art would have determined from Benton that it would have been reasonable Appeal 2020-005871 Application 14/774,886 7 to expect inhibition would improve treatment outcomes given the teaching that Benton’s results regarding GLO1 were discordant with other results and that further testing should be done. None of the other prior art references relied on by the Examiner provide any suggestion with respect to depressive disorders either. (See Appeal Br. 4.) Hovatta is concerned with anxiety. It is true, as the Examiner noted, that Benton indicates a “common biological link between depression and anxiety” where GLO1 and GNB1 “mostly account for baseline anxiety-like and depressive-like behavior.” (Benton 297; Reply Br. 5.) However the mere fact that GLO1 has been identified as a biological compound that is affected in both anxiety and depression does not provide one of ordinary skill in the art with a reasonable basis to conclude from Hovatta’s teaching that inhibiting GLO1 expression decreased anxiety-like behavior in certain inbred mice strains (Hovatta 662) that inhibiting GLO1 expression would be expected to similarly decrease depressive-like behavior. That is because identifying a biochemical compound that is implicated in two different disorders does not tell one of ordinary skill in the art that the pathways in which the biochemical functions are the same in both disorders or that the biochemical that is a “common . . . link” between them is modulated in the same manner in the body no matter what pathway it is implicated in. Although Hovatta states that its study suggests “that free radicals may have a role in the pathogenesis of anxiety disorders,” and that “[o]xidative stress has also been implicated in the pathogenesis of other neuropsychiatric diseases, including . . . major depressive disorder” (Hovatta 663), that also does not tell one of ordinary skill in the art that the pathways in which GLO1 Appeal 2020-005871 Application 14/774,886 8 functions are the same in both disorders. Nothing in Hovatta suggests that the free radicals that may play a role in both anxiety and depressive disorders interact with GLO1 or other cofactors which GLO1 interacts with (id.) in these disorders in the same way. Moreover, the Examiner has not provided any other evidence to establish the foregoing. Consequently, there is not sufficient evidence from the prior art to correlate findings regarding anxiety and inhibition of GLO1 with what would be expected regarding depression and inhibition of GLO1. In light of the foregoing, we conclude that the Examiner’s contrary conclusion is founded on an impermissible obvious to try reasoning because the disclosure of Benton, while piquing scientific curiosity in modulating GLO1, does not provide “sufficient teaching of how to obtain the desired result, or that the claimed result would be obtained if certain directions were pursued.” In re Eli Lilly & Co., 902 F.2d 943, 945 (Fed. Cir. 1990). Moreover, even if one were not convinced of uncertainty of what could be expected from the teachings of Benton alone, we note that patentability determinations are based on a preponderance of the evidence. “After evidence or argument is submitted by the applicant in response, patentability is determined on the totality of the record, by a preponderance of evidence with due consideration to persuasiveness of argument.” In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992) (“[T]he ultimate determination of patentability is made on the entire record.”) Appeal 2020-005871 Application 14/774,886 9 In response to the rejection, Appellant provided the Yang3 article which post-dates Benton, and also assessed GLO1 in a depression model. The model was the CUMS rat model, which is a model for major depressive disorder. The Yang study determined that GLO1 was significantly decreased in CUMS rats relative to control rats. (Yang 195.) Yang recognized the Benton study, as well as the study reported in Fujimoto, which the Examiner had previously relied on in rejecting the claims on appeal. (Yang 198.) Yang notes that Fujimoto measured mRNA expression in peripheral white blood cells of MDD patients and found “state-dependent downregulation” but that Benton found that cortical GLO1 expression has been “positively correlated with depression-like behavior.” (Id. (emphasis added).) Yang noted that its study “findings support the hypothesis that cortical GLO1 downregulation is associated with [Major Depressive Disorder,] MDD.” (Id.) As noted above, Benton suggests further analysis is necessary to confirm whether its findings of elevation of GLO1 in mice with increased baseline mobility in the TST testing is in fact an accurate determination of GLO1 baseline levels in depression, given contrary findings in the art. Given that uncertainty expressed by Benton, coupled with the Yang evidence, we conclude that the preponderance of the evidence does not support a conclusion from the prior art of a reasonable expectation of success for treating depression by using an inhibitor of GLO1. 3 Y. Yang et al., Proteomics reveals energy and glutathione metabolic dysregulation in the prefrontal cortex of a rat model of depression, 247 Neuroscience 191–200 (2013). Appeal 2020-005871 Application 14/774,886 10 Consequently, we reverse the Examiner’s rejection of claims 77–79, 81–84, and 86 under 35 U.S.C. § 103(a) as unpatentable over Benton, Hovatta, Thornalley, and Akil. DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 77–79, 81– 84, 86 103(a) Benton, Hovatta, Thornalley, Akil 77–79, 81– 84, 86 REVERSED