THE UNIVERSITY OF BIRMINGHAMDownload PDFPatent Trials and Appeals BoardMar 23, 20212020004240 (P.T.A.B. Mar. 23, 2021) Copy Citation 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. 14/431,534 03/26/2015 Zsuzsanna Nagy UB-02-US 2010 50446 7590 03/23/2021 HOXIE & ASSOCIATES LLC 75 MAIN STREET SUITE 203 MILLBURN, NJ 07041 EXAMINER CHONG, YONG SOO ART UNIT PAPER NUMBER 1627 NOTIFICATION DATE DELIVERY MODE 03/23/2021 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): HoxiePatentMail@gmail.com HoxiePatentMail@hoxpat.com file@hoxpat.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte ZSUZSANNA NAGY and TIMOTHY BARRETT Appeal 2020-004240 Application 14/431,534 Technology Center 1600 ____________ Before ULRIKE W. JENKS, JOHN G. NEW, and RYAN H. FLAX, Administrative Patent Judges. JENKS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s decision to reject claims directed to a method of treating Wolfram Syndrome-related neurodegeneration as 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 real party-in-interest as University of Birmingham, United Kingdom. Appeal Br. 2. Herein we refer to the Final Office Action mailed March 25, 2019 (“Final Act.”), Appeal Brief filed October 11, 2019 (“Appeal Br.”), Examiner’s Answer mailed March 17, 2020 (“Ans.”), and Reply Brief filed May 18, 2020 (“Reply Br.”). Appeal 2020-004240 Application 14/431,534 2 BACKGROUND According to the Specification, Wolfram Syndrome is a rare autosomal recessive disorder characterized by neurodegeneration and diabetes mellitus (caused by gene “WFS1”, which encodes WFS1 protein). Spec. 1. The Specification acknowledges that the precise function of the WFS1 protein is unknown, but “WFS1 protein deficiency affects the unfolded protein response, intracellular ion homeostasis, cell cycle progression, and granular acidification.” Id. In “WFS1 depleted neuronal cells increased levels of p21 (CIP1/WAF1) is able to prevent neuronal apoptosis and reverse the cell cycle disturbance caused by the WFS1 depletion.” Id. at 2. According to the Specification, p21 is a protein that in humans is primarily known from investigations into its role in cell cycle regulation. Id. at 1. “Its clinical importance is associated mainly with cancer and resistance against HIV infection.” Id. Experimental evidence shows that “WFS1 depleted cells that retain their p21 expression are protected against cell death (apoptosis).” Id. at 3, 17 (“an increased p21 expression and/or functional activity leads to a reduced neuronal apoptosis (i.e. reduced neurone cell death) and correction of the cell cycle deficiency in WFS1 depleted cell lines.”). STATEMENT OF THE CASE Claims 14 and 21–26 are on appeal, and can be found in the Claims Appendix of the Appeal Brief. Claim 14 is representative of the claims on appeal, and reads as follows: 14. A method of treating Wolfram Syndrome (WS)-related neurodegeneration, comprising administering to a patient in need thereof a compound selected from one or more of the group Appeal 2020-004240 Application 14/431,534 3 consisting of valproic acid and a salt thereof, wherein the (WS)- related neurodegeneration is caused by or linked to loss of function mutations in WFS1 genes, and wherein the compound is administered at an amount effective to increase the expression, increase the binding, increase the activation, increase the accumulation and/or increase the induction of p21. Appeal Br. 11 (Claims Appendix). REJECTION Appellant requests review of Examiner’s rejection of claims 14 and 21–26 under 35 U.S.C. § 103 as obvious over Glimcher2 in view of Shang3 and Kakiuchi.4 ANALYSIS Examiner finds that Glimcher teaches “the treatment of neurodegenerative disease” (abstract), for example Wolfram Syndrome, where there is a mutation in the WFS1 protein of the ER membrane (paragraph 0186). Ans. 4. “An example of an art recognized agent useful in the treatment of a neurodegenerative disease associated with protein aggregation is valproate (paragraph 0369).” Id. Examiner, however, acknowledges that Glimcher does not “disclose a single embodiment of treating Wolfram Syndrome (WS)-related neurodegeneration by administering valproate.” Id. Examiner looks to the teachings of Shang and Kakiuchi to make up for this deficiency in Glimcher. Examiner relies on Shang for teaching that 2 Glimcher et al., US 2011/0142799 A1, published June 16, 2011 (“Glimcher”). 3 Shang et al., WO 2013/055834 A2, published Apr. 18, 2013 (“Shang”). 4 Kakiuchi et al., Valproate, a Mood Stabilizer, Induces WFS1 Expression and Modulates Its Interaction with ER Stress Protein GRP94, 4 PLOS ONE e4134 (1–6) (January 2009) (“Kakiuchi”). Appeal 2020-004240 Application 14/431,534 4 “WFS1 deficiency leads to activation of the unfolded protein response (UPR) components, which coordinates protein-folding capacity with transcriptional regulation and protein synthesis to mitigate ER stress.” Ans. 4. Shang teaches that failure to deal with the UPR results in cell death by apoptosis. Id. at 5; Shang ¶ 5. Therefore, Examiner finds that Shang “confirms that Wolfram Syndrome (WS)-related neurodegeneration is caused by [a] deficiency in the WFS1 gene, which leads to upregulation of ER stress markers, and ultimately loss of cellular functionality or cell death by apoptosis.” Ans. 5. Examiner finds that Kakiuchi “teaches that valproate modulates the ER stress response through regulation of WFS1, an important component for mitigating ER stress. . . . [V]alproate induce expression of WFS1 mRNA and activate the WFS1 promoter.” Ans. 5. Based on the combined teaching of Glimcher, Shang, and Kakiuchi, Examiner concludes that one of ordinary skill in art at the time the invention was made would have reasonably expected to treat Wolfram Syndrome-related neurodegeneration in a patient in need thereof by administering valproate. Id. at 6. Appellant contends that (1) Examiner has not presented a prima facie case of obviousness, (2) Examiner’s claim interpretation does not give the preamble proper weight, and (3) Examiner ignores the “wherein clause” of the claim. See generally Appeal Br. We address these arguments below. According to Appellant, Glimcher teaches the use of valproate as a secondary compound that functions as a mood stabilizer, but was not shown to affect XBP-1 (a polypeptide), which is the focus of the Glimcher reference. See Reply Br. 4; Appeal Br. 4. Appellant contends that Kakiuchi does not provide motivation for one of ordinary skill in the art to administer Appeal 2020-004240 Application 14/431,534 5 valproate to a patient population that is homozygous for the defective WFS1 gene, because increasing expression of a defective protein would not be expected to provide any benefit. See Reply Br. 6; Appeal Br. 7 (“increased expression of a dysfunctional protein would not be expected to improve the [Wolfram Syndrome] condition.” (emphasis removed)). In other words, Appellant contends that there is no reasonable expectation of success in administering valproate to a patient population that has Wolfram Syndrome “caused by or linked to loss of function mutations in WFS1 genes” as claimed, because Wolfram Syndrome is an autosomal recessive disorder meaning that both forms of the gene are non-functional (the gene does not express the protein, rather than functioning to express a dysfunctional protein). Reply Br. 6; see Spec. 1. On this record, we find that Appellant has the better position. Glimcher teaches: XBP-1 activation is known to control expression of several other genes. . . . [Such as e]xpression of WFSl protein, an ER resident membrane protein, is up-regulated by ER stress-inducing agents and is a component of the IREI and PERK signaling pathways. In addition, mutations in the gene encoding this protein are responsible for Wolfram syndrome. Glimcher ¶ 186. Glimcher suggests the administration of a compound that modulates an XBP-1, IRE-I alpha, and/or EDEM signal transduction pathway (e.g., by directly modulating XBP-1 activity) in conjunction with another compound known in the art to be useful in treatment of a particular condition or disease, such as, for example, mood-stabilizers (lithium, valproate, carbamazepine). Id. ¶ 369. Glimcher teaches that XBP-1 deficiency protects against neurodegenerative disease associated with protein aggregation. Id. ¶ 11. Glimcher teaches the use of inhibitory Appeal 2020-004240 Application 14/431,534 6 compounds, which inhibit the expression and/or activity of spliced XBP-1, in the prevention and/or treatment of disorders associate with aberrant protein aggregation. Id. ¶ 372. Glimcher provides a list of diseases that can be treated with these XBP-1 inhibitors, and that list does not include Wolfram Syndrome. Id. Glimcher does disclose that Wolfram Syndrome exists and that it is caused by mutation in the WFS1 gene; however, the reference does not connect administration of valproic acid with treating this disease. Id. ¶ 186. Shang teaches that “WFS1 deficiency leads to the activation of the unfolded protein response (UPR) components, such as GRP78 (Bip) and XBP-1 and decreases the ubiquitination of ATF6a. The unfolded protein response coordinates protein-folding capacity with transcriptional regulation and protein synthesis to mitigate ER stress.” Shang ¶ 5. Shang teaches that Wolfram Syndrome is associated with intracellular ER stress. Id. ¶ 8. Shang explains that when WFS1 levels are deficient this leads to activation of the unfolded protein response, which includes increasing levels of XBP-1. Shang ¶ 5. The teachings of Glimcher and Shang, therefore, suggest keeping XBP-1 expression at low levels in order to avoid protein aggregation leading to neurodegeneration via cell death. At most, the combination Glimcher and Shang would suggest that the ordinary artisan administer XBP-1 inhibitors in order to prevent neurodegeneration, including in patients with Wolfram Syndrome. Glimcher’s additional teaching of co-administering valproate with XBP-1 modulators does not specifically address which conditions could be treated in this manner (other than mood-instability). Glimcher ¶ 369. We agree with Appellant that Glimcher’s long list of neurodegenerative diseases Appeal 2020-004240 Application 14/431,534 7 that could be treated with the XBP-1 inhibitors does not include Wolfram Syndrome. See id. ¶ 372. Examiner, however, does not rely solely on the combination of Glimcher and Shang, Examiner also looks to Kakiuchi to provide motivation to administer valproate to patients. Kakiuchi teaches that “[v]alproate activates the WFS1 promoter and induces WFS1 mRNA expression in neuronal cells. Under normal conditions, WFS1 forms a complex with GRP94 and valproate enhances its dissociation from GRP94” allowing for higher expression. Kakiuchi 2. Figure 4 of Kakiuchi, reproduced below, provides model of action of valproate and XBP-1 in regulating WFS1. Figure 4, shows a model of action of valproate on the regulation of WFS1. Id. at 5. Specifically, Kakiuchi suggests that transcription factor XBP-1 as well as valproate activates the WFS1 promoter in neuronal cells. Id. 3 (“Collectively, these results indicate that valproate can strongly activate the WFS1 promoter together with XBP-1 specifically in neuronal cells.”). Thus, Kakiuchi suggests that both XBP-1 and valproate activate the same WFS1 promoter leading to an increase in WFS1 protein expression. Appellant contends that, at best, Kakiuchi teaches that valproate can increase expression of WFS1 in a heterozygous patient population, i.e. those Appeal 2020-004240 Application 14/431,534 8 suffering from bipolar disorder. Reply Br. 5. However, this patient population has one functional gene and increasing expression using valproate would increase both functional and non-functional proteins in this patient population. Id. Patients with Wolfram Syndrome only carry defective WFS1 genes. Appellant contends that increasing the expression of a dysfunctional protein from a defective gene, however, would not be expected to improve the Wolfram Syndrome condition, therefore, there is no reason to administer valproate to this patient population. See Appeal Br. 7; Reply Br. 5. We agree with Appellant, Kakiuchi teaches that valproate activates the WFS1, and Examiner has not articulated why increasing the expression of a defective protein would reasonably result in a method of treating Wolfram Syndrome-related neurodegeneration. In other words, having more protein that does not function would result in increased intracellular ER stress, which then leads to an increase in XBP-1 levels, a condition which is implicated in the development neurodegenerative disease. See Shang ¶ 8; Glimcher ¶ 11 (“XBP-1 deficiency in motor neurons in an animal model of neurodegenerative disease associated with protein aggregation, increases the life span of the animals and reduces motor neuron apoptosis.”). The record, therefore, supports the position that one of ordinary skill in the art would want to reduce XBP-1 expression in order to reduce neurodegeneration. Glimcher ¶ 372. Kakuichi, however, teaches that both XBP-1 and valproate activate the WFS1 promoter. Activation of the gene leading to the production of a dysfunctional WFS1 protein would further increase the levels XBP-1 in response to ER stress. Shang ¶ 5. Adding valproate into this cycle would Appeal 2020-004240 Application 14/431,534 9 lead to the accumulation of more dysfunctional WFS1 protein in the system. See Kakiuchi 5 (Figure 4). Because valproate and XBP-1 activate the same promoter on the WFS1 gene this would lead to the accumulation of more dysfunctional WFS1 protein in patients having Wolfram Syndrome resulting in increased ER stress because the cells still experience this as a WFS1 deficiency. Therefore, based on the teaching of Kakiuchi and Shang one of ordinary skill in the art would not be motivated to add valproate to a system, because to do so would increase the level of dysfunctional WFS1 protein, leading to ER stress. See Kakiuchi 5 (Figure 4); Shang ¶ 5. Taken together, the combination Glimcher, Shang, and Kakiuchi does not support Examiner’s conclusion that the claims are obvious, because Examiner has not articulated why in the Wolfram Syndrome patient population one of ordinary skill in the art would want to simultaneously decrease XBP-1 while administering valproate. Here, both XBP-1 and valproate are known to activate the WFS1 promoter leading to the production of dysfunctional protein which is bad. Accordingly, we agree with Appellant that Examiner has not provided a sufficiently articulated rationale based on the teachings in the art that suggests administering valproate to patients suffering from Wolfram Syndrome. Appellant also contends that Examiner is not giving weight to the preamble of “treating Wolfram Syndrome (WS)-related neurodegeneration” and instead is solely focusing on similarity in the prior art based on the “neurodegeneration” aspect of the claim preamble. Appellant contends that in this case the preamble should be treated like a claim limitation because the phrase “to a patient in need thereof” would otherwise not have proper antecedent basis in the body of the claim. See Appeal Br. 8 (citing Jansen v. Appeal 2020-004240 Application 14/431,534 10 Rexall Sundown, 342 F.3d 1329, 1333-34 (Fed. Cir. 2003); Rapoport v. Dement, 254 F.3d 1053, 1060-61 (Fed. Cir. 2001)). Our reviewing court in both Rapoport and Jansen considering similarly structured claims determined that these claims should be interpreted to require that the method be practiced with the “intent to achieve the objective stated in the preamble.” Jansen, 342 F.3d 1333. “The preamble is therefore not merely a statement of effect that may or may not be desired or appreciated. Rather, it is a statement of the intentional purpose for which the method must be performed.” Id. Applying the same claim interpretation to the present claims requires that the combination of references suggests treating neurodegeneration in patients having Wolfram Syndrome. Given this construction, we agree with Appellant that the combination of references does not disclose treating patients having Wolfram Syndrome-related neurodegeneration with valproate. See e.g. Glimcher ¶ 372 (providing a list of neurodegenerative disorder that can be treated with the inhibitors - Wolfram Syndrome is notably missing from that list). Appellant also contends that Examiner is not giving weight to the last clause of the claim: “wherein the compound is administered at an amount effective to increase the expression, increase the binding, increase the activation, increase the accumulation and/or increase the induction of p21.” Appeal Br. 7–8 (citing In re Wilson, 424 F.2d 1382, 1385 (CCPA 1970); CFMT, Inc. v. Yieldup Intern. Corp., 349 F.3d 1333, 1342 (Fed. Cir. 2003)) (citing In re Royka, 490 F.2d 981, 985 (CCPA 1974)); MPEP 2143.03). The issue is whether the combination of references as applied by Examiner treats the same patient population — those suffering from neurodegeneration due to Wolfram Syndrome — with valproate in order to Appeal 2020-004240 Application 14/431,534 11 reach the conclusion that the effect on p21 would be expected to be the same. See Ans. 6. Examiner reasons that “the cited prior art references teach the same patient population and the same active agent, it is obvious to one of ordinary skill in the art that the same mechanism of action [on p21] will obviously occur.” Ans. 8. Examiner’s position, therefore, is if there is a reason to administer valproate to the same patient population, those suffering from neurodegeneration, then the mode of action on the p21 would occur regardless of whether the art recognizes this compound to be a target of action. Here, the problem is that the art does not suggest administering valproate to the claimed patient population. Kakiuchi suggests that both valproate and XBP-1 activate the same promoter leading to an increase WFS1 expression. See Kakiuchi 5 (Figure 4). The bipolar patient population of Kakiuchi is a different patient population from those suffering from Wolfram Syndrome. Here, there is no evidence in the record that Kakiuchi’s bipolar patient population also suffer from neurodegeneration, let alone neurodegeneration due to Wolfram Syndrome. Thus, administration of valproate to a bipolar patient population does not teach treating patients having Wolfram Syndrome. It also does not explain why one of ordinary skill in the art would want to decrease transcription factor XBP-1 that interacts with the same WFS1 promoter as valproate while simultaneously administering a compound — valproate — that activates transcription from the same promoter. Because Examiner has not established that the art suggests treating the same patient population with the same compound, we do not need to address whether the mode of action is expected to be the same. Appeal 2020-004240 Application 14/431,534 12 We conclude that the preponderance of the evidence of record does not support Examiner’s conclusion that the combination of Glimcher, Shang, and Kakiuchi teaches a method having all the limitations of claims 14 and 21–26. We therefore reverse the rejection under 35 U.S.C. § 103(a) that relies on the teachings of Glimcher, Shang, and Kakiuchi. DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Basis/References Affirmed Reversed 14, 21–26 103 Glimcher, Shang, Kakiuchi 14, 21–26 REVERSED Copy with citationCopy as parenthetical citation