INSERM (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE) et al.

Patent Trials and Appeals Board

Jan 25, 2022

2021002359 (P.T.A.B. Jan. 25, 2022)

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. 15/765,756 04/04/2018 Francine BEHAR-COHEN 11450493US 6232 30743 7590 01/25/2022 W&C IP 11491 SUNSET HILLS ROAD SUITE 340 RESTON, VA 20190 EXAMINER RODRIGUEZ, RAYNA B ART UNIT PAPER NUMBER 1628 MAIL DATE DELIVERY MODE 01/25/2022 PAPER 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. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte FRANCINE BEHAR-COHEN and MIN ZHAO ____________ Appeal 2021-002359 Application 15/765,7561 Technology Center 1600 ____________ Before JEFFREY N. FREDMAN, DEBORAH KATZ, and DAVID COTTA, Administrative Patent Judges. COTTA, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a method of treating choroidal neovascularization in a subject who is refractory to treatment with an anti-vascular endothelial growth factor (VEGF). The Examiner rejected the claims on appeal as obvious under 35 U.S.C. § 103. A hearing was held on October 7, 2021, a transcript from which has been entered into the record. (“Tr.”). We affirm. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. According to Appellant, the real parties in interest are Inserm (Institut National de la Sante et de la Recherche Medicale), Universite Paris Descartes, Sorbonne Universite, Universite Paris Diderot - Paris 7, and Fondation Asile Des Aveugles. Appeal Br. 3. Appeal 2021-002359 Application 15/765,756 2 STATEMENT OF THE CASE The Specification states that “[c]horoidal neovascularization (CNV) may cause visual loss due to exudation of intraretinal or subretinal fluid, hemorrhage, or fibrosis at the macula.” Spec. 1. According to the Specification, “VEGF [vascular endothelial growth factor] is the main growth factor responsible for development and progress of new [vascular] vessels [in the eye].” Id. The Specification discloses that the “idea of inhibiting the activities of VEGF with anti-VEGF drugs has been investigated in the management of ocular neovascular disorders” however, “current anti-VEGF treatments do not induce a total regression of the CNV requiring repeated injections to maintain vision.” Id. Accordingly, there is “a need for alternative medicines for the treatment of CNV.” Id. The Specification discloses “a method of treating choroidal neovascularisation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a mineralocorticoid receptor antagonist.” Id. at 2. Claims 1-3, 7, 8, 10-14, and 16-20 are on appeal. Claims 1, 2, 8, and 13 read as follows: 1. A method of treating choroidal neovascularisation in a subject who is refractory to treatment with an anti-vascular endothelial growth factor (VEGF) treatment comprising administering to the subject a therapeutically effective amount of a mineralocorticoid receptor (MR) antagonist, thereby treating the choroidal neovascularisation in the subject who is refractory to treatment with the anti-VEGF treatment, wherein the step of administering is performed by intraocular or periocular administration. 2. The method of claim 1 wherein the subject suffers from a disease selected from the group consisting of age-related macular degeneration, myopic choroidal neovascularization, Appeal 2021-002359 Application 15/765,756 3 idiopathic choroidal neovascularization, polypoidal chorioretinopathy associated or not with central serous chorioretinoapthy and an inflammatory condition. 8. The method of claim 1 wherein the MR antagonist is administered to the subject in combination with an anti-VEGF agent. 13. The method of claim 2, wherein the subject suffers from dry age-related macular degeneration. Appeal Br. 22-23 (Claims App.). In response to a restriction requirement, Appellant elected spironolactone as the elected MR antagonist, age-related macular degeneration as the elected disease species, and ranibizumab as the elected anti-VEFG agent species (recited in claim 8). Final Act. 2.2 The claims stand rejected as follows: The Examiner rejected claims 1-3, 7, 10-12, 14, and 16-20 under 35 U.S.C. § 103 as being obvious over the combination of Behar-Cohen3 and Oliveira Dias.4 The Examiner rejected claim 8 under 35 U.S.C. § 103 as being obvious over the combination of Behar-Cohen, Oliveira Dias, and Naveed.5 The Examiner rejected claim 13 under 35 U.S.C. § 103(a) as being obvious over the combination of Behar-Cohen, Oliveira Dias, and Boyd.6 2 Office Action, mailed July 17, 2020 (“Final Act.”). 3 Behar-Cohen, International Patent Publication No. WO 2011/141456 A1, published Nov. 17, 2011 (“Behar-Cohen”). 4 Oliveira Dias et al., Cytokines in Neovascular Age-Related Macular Degeneration: Fundamentals of Targeted Combination Therapy, 95 Br. J. Ophthalmol 1631-1637 (May 5, 2011) (“Oliveira Dias”). 5 Naveed, International Patent Publication No. WO 2008/063932 A2, published May 29, 2008 (“Naveed”). 6 Boyd, US Patent Publication No. 2013/0295014 A1, published Nov. 7, 2013 (“Boyd”). Appeal 2021-002359 Application 15/765,756 4 FINDINGS OF FACT FF1 Oliveira Dias discloses: The application of anti-VEGF drugs for CNV-therapy has markedly enhanced standards in terms of improvements in the control of disease. . . . Greater benefits may be achieved if angiogenesis, scarring and inflammation are simultaneously targeted. Inflammatory and angiogenic pathways become more numerous and redundant as disease [CNV] progresses. . . . The fact that inflammation appears early in AMD pathology may explain why anti-inflammatory agents are beneficial as preventive or adjunctive therapies for patients who do not respond to conventional anti-VEGF therapy. However, more studies are required to test the efficacy and safety of systemic, periocular and intravitreal applications of each anti-inflammatory agent. Combination approaches may not only increase overall efficacy but also reduce the potential for side effects by allowing relatively low doses to yield a greater level of efficacy than higher doses of a single agent. Oliveira Dias 1635 (internal citation omitted). FF2 Behar-Cohen discloses “a minelarocorticoid [sic mineralocorticoid] receptor (MR) antagonist for use in the treatment of fluid accumulation in and/or under the retina associated with . . . the exudative forms of age related macular degeneration.” Behar-Cohen 4. Among the MR antagonists disclosed are “spirolactone-type steroidal compounds.” Id. at 5; see also, id. at 12 (“Of particular interest is the compound spirolactone.”). FF3 Behar-Cohen discloses that “[h]igh doses of corticosteroids are currently injected into the vitreous cavity of patients with macular edema because of their anti-inflammatory and anti-edematous effects on the retina, but are associated with frequent and sometimes severe side effects.” Id. at 34. Appeal 2021-002359 Application 15/765,756 5 FF4 Behar-Cohen discloses: [T]he inventors believe that anti-edematous effects of corticosteroid on the retina are mainly explained by an action via MR pathway, more than by an action on GR pathway. The inventors have indeed observed that administration of a glucocorticoid (e.g. triamcinolone acetonide) provides the same effect as a MR antagonist on AQP4 expression. Accordingly, MR antagonists would synergize the effects of glucocorticoids in the treatment of fluid accumulation in and/or under the retina, but also would prevent the severe side effects of glucocorticoids. Id. at 22. FF5 Behar-Cohen discloses that although “aldosterone per se did not promote retinal angiogenesis, MR antagonism reduced the pathological angiogenesis associated with inflammation and oxidative stress in this model.” Id. at 43. FF6 Amoaku7 discloses: “Poor or nonresponse to anti-VEGF treatments requires re-evaluation of diagnosis and if necessary switch to alternative therapies including other anti-VEGF agents and/or with photodynamic therapy (PDT).” Amoaku 721. FF7 Tachyphylaxis is defined as “a decreasing therapeutic response to a pharmacological agent following repeated administration over time” and was “thought to occur in 2% when treatment was given for recurrent CNV.” Id. at 726. Amoaku discloses that “some cases of alleged tachyphylaxis may represent poor or suboptimal response to treatment, rather than true tachyphylaxis.” Id. In such cases, “eyes may respond favourably to a 7 Amoaku et al., Defining Response to Anti-VEGF Therapies in Neovascular AMD, 29 Eye 721-731 (Apr. 17, 2015) (“Amoaku”). Amoaku was cited by the Examiner as evidence that it was “known in the art to switch from one anti-VEGF therapy to another.” Ans. 12. Appeal 2021-002359 Application 15/765,756 6 change of in the anti-VEGF agent used.” Id. According to Amoaku, “there is emerging evidence that switching from one anti-VEGF therapy to another may result in increased response.” Id. FF8 Han8 studied “[t]he effect of spironolactone on renal inflammation and renal function . . . in type 2 diabetic rats.” Han Abstr. Han discloses: “[W]e have provided evidence that spironolactone treatment decreases urinary albumin excretion and mitigates the glomerulosclerosis that is associated with attenuation of the renal inflammatory process in an animal model of type 2 diabetic nephropathy.” Han 1368. FF9 Han discloses: “In this study, we found that spironolactone treatment down-regulated many of the genes that are involved in the inflammatory process, such as MCP-1, MIF, the TNF receptor, and IL and its receptor.” Id. at 1369. FF10 Miura9 studied “the effect of . . . spironolactone on the production of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) in cultured human peripheral blood mononuclear cells stimulated with angiotensin (Ang) II.” Miura Abstr. Miura discloses that “spironolactone may contribute to ameliorate the prognosis of patients with cardiovascular diseases by reducing Ang II- 8 Han et al., Spirolactone Prevents Diabetic Nephropathy through an Anti- Inflammatory Mechanism in Type 2 Diabetic Rats, 17 J. Am. Soc. Nephrol. 1362-1372 (2006) (“Han”). Han was cited by the Examiner as evidence that it was “well known in the art at the effective filing date of the instant application that spironolactone is an anti-inflammatory agent.” Ans. 12. 9 Miura et al., Anti-Inflammatory Effect of Spironolactone on Human Peripheral Blood Mononuclear Cells, 101 J. Pharmacol. Sci. 256-259 (2006) (“Miura”). Miura was cited by the Examiner as evidence that it was “well known in the art before the effective filing date of the claimed invention that spironolactone was an anti-inflammatory agent.” Ans. 12. Appeal 2021-002359 Application 15/765,756 7 induced inflammation, although further exploration including determining the mechanisms would be required.” Id. FF11 Lai10 studied “the pathway by which aldosterone regulates VEGF expression” by administering spironolactone to “cultured cortical collecting duct epithelial cells (M-1 cell line)” that had been “incubated with aldosterone.” Lai Abstr. Lai discloses that “[a]fter aldosterone (10-7 M) incubation for 48 h, the mRNA level of VEGF164 and VEGF120 showed 1.8- and 1.7-fold increases.” Id. Lai discloses that “[t]his upregulation was almost completely blocked by spironolactone as shown both by mRNA levels and cytosolic protein levels.” Id. OBVIOUSNESS OVER THE COMBINATION OF BEHAR-COHEN AND OLIVEIRA DIAS Appellant argues claims 1-3, 7, 10-12, 14, and 16-20 together. We designate claim 1 as representative. In rejecting claim 1 as obvious, the Examiner found that Behar-Cohen disclosed “a mineralocorticoid receptor [MR] antagonist for use in the treatment of exudative forms of age related macular degeneration,” and identified spironolactone as a MR antagonist compound “of particular interest.” Ans. 4-5. The Examiner found that Behar-Cohen disclosed all of the elements of claim 1 except that it did not disclose that the subject to whom the MR antagonist - spironolactone - was administered was refractory to anti-VEGF treatment. Id. at 5. 10 Lai et al., Aldosterone Upregulates Vascular Endothelial Growth Factor Expression in Mouse Cortical Collecting Duct Epithelial Cells Through Classic Mineralocorticoid Receptor, 81(7) Life Sci. 570-576 (2007) (“Lai”). Lai was cited by Appellant as evidence that “it was thought that mineralocorticoids, such as aldosterone, were a part of the same signaling pathway as VEGF.” Appeal Br. 13. Appeal 2021-002359 Application 15/765,756 8 To address this deficiency, the Examiner relied on the teachings of Oliveira Dias and Behar-Cohen as well as evidence of what was known in the art, as reflected in the teachings of Han, Miura, and Amoaku. The Examiner found that Oliveira Dias taught that “anti-inflammatory agents are beneficial as preventive or adjunctive therapies for patients who do not respond to conventional anti-VEGF therapy.” Id. at 11-12. The Examiner tied the teaching that anti-inflammatory agents are useful in VEGF refractory patients to evidence that MR antagonists generally, and spironolactone specifically are “anti-inflammatory agents.” In this regard, the Examiner found that Behar-Cohen taught that “mineralocorticosteroid antagonists are anti-inflammatory agents.” Id. at 5. The Examiner also found that Han and Miura provided evidence that it was “well known in the art . . . that spironolactone was an anti-inflammatory agent.” Id. at 12. Finally, the Examiner found that in cases where a patient does not respond to anti-VEGF treatment, it was “known in the art to switch from one anti- VEGF therapy to another as evidenced by Amoaku.” Id. at 12-13. Based on the cited art, the Examiner concluded that it would have been obvious to treat age-related macular degeneration [the elected disease species] in a subject that is refractory to anti-VEGF treatment with spironolactone [the elected MR antagonist] with an expectation of success because the prior art establishes that spironolactone is a mineralocorticoid receptor antagonist useful for treating age-related macular degeneration, mineralocorticoid receptor antagonist[s] have anti-inflammatory properties[,] and anti-inflammatory agents are beneficial as preventive or adjunctive therapies for patients who do not respond to conventional anti-VEGF therapy. Id. at 12. Appeal 2021-002359 Application 15/765,756 9 We agree with the Examiner that claims 1-3, 7, 10-12, 14, and 16-20 would have been obvious over the combination of Behar-Cohen and Oliveira Dias as evidenced by Han, Miura, and Amoaku. We address Appellant’s arguments below. Appellant argues that, “before the filing of the present application, it was thought that mineralocorticoids, such as aldosterone, were a part of the same signaling pathway as VEGF.” Appeal Br. 13. As support, Appellant points to Lai, which Appellant characterizes as teaching that “aldosterone upregulated VEGF expression while spironolactone almost completely blocked this upregulation.” Id.; see also, FF11. According to Appellant, the ordinary artisan “would not have predicted that a MR antagonist such as spironolactone would be effective for treating CNV and that such an effect would be independent of VEGF.” Appeal Br. 13-14. Instead, Appellant argues, the ordinary artisan “would presume that spironolactone would block VEGF expression and thus have an identical effect as an anti-VEGF agent.” Id. at 14. Thus, according to Appellant, it would not be obvious to treat a population of patients refractory to anti-VEGF treatment with an MR antagonist because the ordinary artisan would expect the MR antagonist to “provide the same [ineffective] result as an anti-VEGF treatment.” Id. We are not persuaded. Even if we accept the premise of Appellant’s argument - i.e, that it was thought that anti-VEGF agents and MR antagonists were part of the same signaling pathway - Amoaku teaches that it was known to switch to another anti-VEGF agent where a first anti-VEGF treatment provides a poor response. FF6, FF7. Accordingly, we find the alleged expectation that VEGF and MR antagonists share the same signaling pathway would not have discouraged an ordinary artisan from using an MR antagonist in Appeal 2021-002359 Application 15/765,756 10 patients that were refractory to anti-VEGF. To the contrary, as supported by Amoaku, it would have been obvious to treat an anti-VEGF refractory patient with a MR antagonist, like spironolactone, that was known to be useful to treat AMD. FF2. Appellant argues that Behar-Cohen teaches that MR agonists, like aldosterone, have anti-inflammatory effects, not that MR antagonists are anti-inflammatory. Appeal Br. 14. Appellant explains: “Behar-Cohen does not teach that MR antagonism reduced inflammation, but that MR antagonism reduced angiogenesis associated with inflammation.” Id. According to Appellant, “it would not be logical . . . to suggest that MR agonists and antagonists have the same effect.” Id. at 15. We are not persuaded. Behar-Cohen teaches that “MR antagonism reduced the pathological angiogenesis associated with inflammation and oxidative stress.” FF5. We acknowledge that angiogenesis is different from inflammation and that Behar-Cohen’s teaching expressly states only that MR antagonism reduced angiogenesis. However, the angiogenesis that MR antagonism was taught to reduce was “associated with inflammation.” Id. And Behar-Cohen teaches that, at least in some respects, MR antagonists provide the same effects as glucocorticoids (which are MR agonists). FF4; Appeal Br. 14 (identifying corticosteroids as MR agonists). More importantly, the current record, as evidenced by Han and Miura, supports that spironolactone was known to have anti-inflammatory properties. FF8-FF10. Accordingly, we agree with the Examiner that it would have been obvious to administer spironolactone to patients refractory for anti-VEGF in view of the teaching in Oliveira Dias that “anti-inflammatory agents are beneficial as preventative or adjunctive Appeal 2021-002359 Application 15/765,756 11 therapies for patients who do not respond to conventional anti-VEGF therapy.” FF1. At oral argument, Appellant argued that Han and Miura were not relevant because they were not directed to the eye or retina. Tr. 6-8. This argument is waived because it was not included in the Appeal Brief. 37 C.F.R. § 41.37(c)(1)(iv) (2020) (“Except as provided for in §§ 41.41, 41.47 and 41.52, any arguments or authorities not included in the appeal brief will be refused consideration by the Board for purposes of the present appeal.”). But even if this argument were properly before us, we would not find it persuasive. Although we recognize the possibility that spironolactone may have different effects on cells in the eye than on peripheral blood cells (as studied in Miura (FF10)) or on renal cells (as studied in Han (FF8, FF9)), the law does not require absolute predictability. Absent persuasive evidence to the contrary,11 the fact that spironolactone has anti-inflammatory effects in peripheral blood cells and in renal cells, and that MR agonists reduce angiogenesis associated with inflammation in the eye, is sufficient to support a reasonable expectation that they would have similar effects in the eye or retina. In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988) (“Obviousness does not require absolute predictability of success. . . . For obviousness under § 103, all that is required is a reasonable expectation of success.”). Appellant argues that the ordinary artisan would not have had a reasonable expectation of success in administering spironolactone to patients refractory to anti-VEGF treatment. Appeal Br. 15. As support, Appellant 11 Attorney argument is not evidence. Johnston v. IVAC Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989); In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974). Appeal 2021-002359 Application 15/765,756 12 points to the statement in Oliveira Dias that “more studies are required” (see FF1) and to two articles published subsequent to the filing of the present application,12 both of which Appellant characterizes as demonstrating that “the administration of an anti-inflammatory agent (dexamethasone) with an anti-VEGF agent (ranibizumab) in patients with persistent or recurrent neovascular AMD provided no benefit.” Id. (emphasis omitted). We acknowledge that the existence of an anti-inflammatory agent that provides no benefits to the claimed patient population somewhat diminishes the expectation that the claimed patient population could successfully be treated with an anti-inflammatory agent. However, evidence of a single anti- inflammatory agent - dexamethasone - that did not work, is insufficient to overcome the reasonable expectation that other anti-inflammatory agents would work in view of the teaching in Oliveira Dias that “anti-inflammatory agents are beneficial as preventive or adjunctive therapies for patients who do not respond to conventional anti-VEGF therapy.” FF1. This is particularly true given the teaching in the art that treatment with one anti- VEGF agent may work even where treatment with another anti-VEGF agent failed. FF6, FF7. Appellant argues that claim 1 requires “intraocular or periocular administration” and that this feature is “not taught or referred to by the cited references.” Appeal Br. 16. We do not find this persuasive because, Behar- 12 The two references are, Rezar-Dreindl et al., The Intraocular Cytokine Profile and Therapeutic Response in Persistent Neovascular Age-Related Macular Degeneration, 57 Invest. Ophthalmol. Vis. Sci. 4144-4150 (2016) (“Rezar-Dreindl”) and Chaudhary et al., Ozurdex in Age-Related Macular Degeneration as Adjunct to Ranibizumab (The OARA Study), 51(4) Can. J. Ophthalmol. 302-305 (2016) (“Chaudhary”). Appeal 2021-002359 Application 15/765,756 13 Cohen teaches “[p]referably, local ocular routes should be used such as intravitreous, topical, periocular injections.” Behar-Cohen 26. Appellant argues that Oliveira Dias “does not mention or allude to subjects who are refractory to anti-VEGF treatment” but “does discuss that anti-VEGF therapy is not always sufficient to treat this disease.” Appeal Br. 16. Appellant asserts that, in such cases: Oliveira Dias provides two recommendations for further improvement in treatments “probably to be used in combination with anti-VEGF”: 1) “Further studies should evaluate the efficacy of other types of VEGF inhibitors such as VEGF Trap or tyrosine kinase inhibitors”. . . ; and 2) “Molecular targeting of the inflammatory cytokines TNF [tumor necrosis factor], PDGF [platelet derived growth factor] or FGF [fibroblast growth factor] is possible via targeted biological therapies and these cytokines are the most likely targets for effective combination treatments of wet-AMD.” Id. According to Appellant, “Oliveira Dias thus teaches that therapies that target specific inflammatory cytokines are the therapies that should be pursued for treating subjects together with an anti-VEGF treatment.” Id. at 16-17. Appellant then explains that Oliveira Dias’ references to targeted therapy “is referring to therapy with antibodies” not the use of non-targeted therapies, like spironolactone. Id. at 17. We are not persuaded. For the reasons discussed above, the cited art suggests treating patients who are refractory to anti-VEGF treatment with spironolactone. Even if we credit Appellant’s argument that Oliveira Dias suggests treating patients for whom anti-VEGF therapy is not sufficient with a combination of another type of anti-VEGF inhibitor and an antibody, that does not diminish the suggestion to treat VEGF refractory patients with spironolactone. “[J]ust because better alternatives exist in the prior art does not mean that an inferior combination is inapt for obviousness purposes.” In re Mouttet, 686 Appeal 2021-002359 Application 15/765,756 14 F.3d 1322, 1334 (Fed. Cir. 2012); See, DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1364 (Fed. Cir. 2006) (“We will not read into a reference a teaching away from a process where no such language exists.”). Accordingly, we affirm the Examiner’s rejection of claim 1. Because they were not argued separately, claims 2, 3, 7, 10-12, 14, and 16-20 fall with claim 1. OBVIOUSNESS OVER THE COMBINATION OF BEHAR-COHEN, OLIVEIRA DIAS, AND NAVEED Claim 8 depends from claim 1 and further requires that “the MR antagonist is administered to the subject in combination with an anti-VEGF agent.” The Examiner rejected claim 8 as obvious over the combination of Behar-Cohen, Oliveira Dias, and Naveed. Appellant argues that the cited art does not disclose co-administering an anti-VEGF agent to a patient refractory to anti-VEGF treatment. Appeal Br. 18. Appellant contends that the Examiner’s reliance of Naveed for this requirement is misplaced because, although “Naveed teaches a method of treating AMD with a VEGF antagonist in a patient who has had previous VEGF antagonist therapy[,] . . . such patients were not refractory to the initial VEGF antagonist therapy.” Id. In addition, Appellant notes that Naveed is “silent regarding MR antagonists and thus, even if combined with Behar-Cohen and Oliveira Dias, does not teach or suggest the claimed invention.” Id. We are not persuaded. The Examiner finds, and Appellant does not dispute, that “anti-VEGF agents were known as the standard of care for neovascular age-related macular degeneration.” Ans. 23-24; see also, Naveed claim 10 (claiming a method of treating wet AMD with the anti-VEGF agent, ranibizumab). As discussed above, spironolactone, an MR antagonist, was also known to treat Appeal 2021-002359 Application 15/765,756 15 AMD. See, FF2. Accordingly, we agree with the Examiner that it would have been obvious to treat AMD by combining two compositions (spironolactone and an anti-VEGF agent), each of which was known to be useful for the same purpose - treating AMD. In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980). Accordingly, we affirm the Examiner’s rejection of claim 8. OBVIOUSNESS OVER THE COMBINATION OF BEHAR-COHEN, OLIVEIRA DIAS, AND BOYD Claim 13 ultimately depends from claim 1 and further requires that the subject suffer from dry age-related macular degeneration. The Examiner rejected claim 13 as obvious over the combination of Behar-Cohen, Oliveira Dias, and Boyd. Appellant argues that Behar-Cohen and Oliveira Dias both relate to “the wet (or exudative) form of AMD.” Appeal Br. 18. Appellant argues that Boyd does not solve this problem because “Boyd is silent with respect to treating subjects who are refractory to anti-VEGF treatment.” Id. at 18- 19. We are not persuaded. The Examiner finds, and Appellant does not dispute, that “dry AMD can progress to treat wet AMD” and thus “dry AMD is [an] early stage [of] AMD.” Ans. 10, 25. The Examiner also finds, and Appellant also does not dispute, that Boyd teaches treating dry age-related macular degeneration with spironolactone. Id. at 10. We agree with the Examiner that “since Boyd establishes that dry AMD can progress to wet AMD and that spironolactone and anti-VEGF agents are suitable agents for treating dry AMD . . . it would have been prima facie obvious . . . to utilize the method suggested by Behar-Cohen and Oliveira Dias to treat dry age-related macular degeneration in a subject that is refractory to anti-VEGF treatment Appeal 2021-002359 Application 15/765,756 16 with spironolactone with an expectation of success.” Id. at 10. Accordingly, we affirm the Examiner’s rejection of claim 13. CONCLUSION In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/ Basis Affirmed Reversed 1-3, 7, 10- 12, 14, 16-20 103(a) Behar-Cohen, Oliveira Dias 1-3, 7, 10-12, 14, 16-20 8 103(a) Behar-Cohen, Oliveira Dias, Naveed 8 13 103(a) Behar-Cohen, Oliveira Dias, Boyd 13 Overall Outcome 1-3, 7, 8, 10-14, 16-20 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). See 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED