Ex Parte Chvatchko et alDownload PDFPatent Trials and Appeals BoardJun 25, 201910275341 - (D) (P.T.A.B. Jun. 25, 2019) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 10/275,341 02/25/2003 50828 7590 06/27/2019 DAVIDS. RESNICK NIXON PEABODY LLP Exchange Place, 53 State Street BOSTON, MA 02109 FIRST NAMED INVENTOR Yolande Chvatchko 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. 057878-12 5854 EXAMINER JIANG,DONG ART UNIT PAPER NUMBER 1646 NOTIFICATION DATE DELIVERY MODE 06/27/2019 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): bostonpatent@nixonpeabody.com ipairlink@nixonpeabody.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte YOLANDE CHVATCHKO, ALAIN TEDGUI, and ZIAD MALLAT 1 Appeal2017-008185 Application 10/275,341 Technology Center 1600 Before DEMETRA J. MILLS, JOHN G. NEW, and TA WEN CHANG, Administrative Patent Judges. CHANG, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134(a) involving claims to a method of treating loss of elasticity of arteries due to atheroma, which have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 Appellants identify the Real Party in Interest as Merck Serono SA and Yeda Research and Development Company Ltd. (Appeal Br. 3.) Appeal2017-008185 Application 10/275,341 STATEMENT OF THE CASE Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by progressive accumulation of lipids, like cholesterol, cells, like macrophages, T lymphocytes or smooth muscle cells, and extracellular matrix . . . . Larger accumulations are called atheromas or plaques . . . . The fatty tissue can erode the wall of the artery, diminish the elasticity of the artery, and interfere with the blood flow. Eventually, clots may form around the plaque deposits, further interfering with blood flow, which may lead to a total occlusion of the blood vessel. . . . It is the major cause of organ ischemia like e.g. myocardial infarction. (Spec. 1.) According to the Specification, "the invention relates to the use of IL-18 inhibitors for treatment and/or prevention of atherosclerosis." (Id.) Claims 49-54, 63---66, 75-86, and 96-98 are on appeal. Claim 49 is illustrative: 49. A method of treating loss of elasticity of arteries due to atheroma in a human individual affected with non- ischemic or ischemic heart failure comprising identifying a non-ischemic or ischemic human heart failure patient having atherosclerotic plaques and having an elevated level of IL-18 as compared with an asymptomatic human individual free of ischemic signs, and administering to the human heart failure patient a plasma IL-18 level reducing amount of a pharmaceutical composition comprising an isoform a or c of human IL-18BP, and a pharmaceutically acceptable carrier; wherein the isoform a or c of the human IL-1 8BP binds IL-18 to neutralize the IL-18 thereby reducing the circulating amount of IL-18, and wherein the treatment results in reduced apoptosis within the atheroma, decreased ulceration at the site of the atheromatous plaque, increased collagen synthesis within the atheroma, and/or increased stability of the atheroma thereby treating loss of elasticity of arteries. (Appeal Br. 27 (Claim App'x).) 2 Appeal2017-008185 Application 10/275,341 The Examiner rejects claims 49-54, 63---66, 81-86, and 96-98 under pre-AIA 35 U.S.C. § I03(a) as being unpatentable over Gabel2 and Novick. 3 (Ans. 2.) The Examiner rejects claims 75-80 under pre-AIA 35 U.S.C. § I03(a) as being unpatentable over Gabel, Novick, and Beers. 4 (Ans. 6.) The Examiner rejects claims 49-54, 81-86, and 96-98 under pre-AIA 35 U.S.C. § I03(a) as being unpatentable over Torigoe. 5 (Ans. 7.) The Examiner rejects claims 63-66 under pre-AIA 35 U.S.C. § I03(a) as being unpatentable over Torigoe and Novick. (Ans. 10.) The Examiner rejects claims 75-80 under pre-AIA 35 U.S.C. § I03(a) as being unpatentable over Torigoe and Beers. (Ans. 11.) I. Issue The Examiner has rejected claims 49-54, 63-66, 81-86, and 96-98 as obvious over Gabel and Novick. The Examiner has rejected claims 75-80 as obvious over Gabel, Novick, and Beers. The same issues are dispositive for both rejections; we therefore discuss the rejections together. The Examiner finds that Gabel teaches "two diarylsulfonylurea ... binding proteins (DBPs) that mediate ... cytokine inhibitory activity" and further teaches that "agents binding to DBP-31/32 have utility as inhibitors 2 Gabel et al., US 6,461,822 B2, issued Oct. 8, 2002 ("Gabel"). 3 Novick et al., WO 99/09063, published Feb. 25, 1999 ("Novick"). 4 THE MERCK MANUAL OF DIAGNOSIS AND THERAPY (Mark H. Beers and Robert Berkow, eds., 17th ed. 1999) ("Beers"). 5 Torigoe et al., WO 00/12555, published Mar. 9, 2000. The citations to Torigoe herein are to Torigoe et al., US 2005/0191303 Al, published Sept. 1, 2005, which serves as an English translation ("Torigoe"). 3 Appeal2017-008185 Application 10/275,341 of the overproduction of inflammatory cytokines such as IL- I and IL-18 [] and can be used to treat disorders characterized by the overproduction of the cytokines [such as] atherosclerosis." (Ans. 2.) The Examiner finds that Gabel "does not teach the use [ of] IL-18BP for treating atherosclerosis in a patient having heart failure (ischemic heart failure, for example)." (Id.) However, the Examiner finds that Novick discloses an IL-18BP, and teaches that the IL-18BP is capable of blocking the biological activity of IL-18, and IL-18BP inhibited in a dose-dependent manner the INF-y inducing activity of human and mouse IL-18 in murine splenocytes, PBMC and the human KG-I cell line. Additionally, Novick teaches that the pharmaceutical composition of the IL-18BP can be used for the treatment of diseases or conditions requiring modulation or blocking ofIL-18 activity, such as, among others, ischemic heart disease including acute heart attacks. (Ans. 2-3 (citations omitted).) The Examiner concludes that it would have been obvious to a skilled artisan to "identify a human patient having atherosclerotic plaques (atherosclerosis) and elevated level of IL-18 ( with or without ischemic heart failure), and to treat such a patient by inhibiting IL-18 with Novick' s IL- 18BP." (Id. at 3.) The Examiner finds that a skilled artisan would have been motivated to do so for treating atherosclerosis ( with or without ischemic heart failure) as over time it causes accumulation of atherosclerotic plaques/atheroma, which is the underlying pathology/cause of ischemic heart disease leading to ischemic heart failure; and reasonably would have expected success because Gabel teaches inhibition if IL- I and IL-18 for treating atherosclerosis, and Novick teaches the IL-I8BP, the fusion protein and the functional derivative thereof that are capable of neutralizing IL-18 activities, and have increased half- life of the IL-18BP in plasma. 4 Appeal2017-008185 Application 10/275,341 (Id. at 3--4.) The Examiner concludes that the "treating" limitations in the preamble of the claims "merely state the purpose or the intended use of the invention" and are non-limiting and/or are inherently met by treating arteriosclerosis with hIL-18BPa as suggested by the combination of Gabel and Novick. (Id. at 4.) Appellants contend that the combination of Gabel and Novick does not teach that "IL-18 inhibition can be an effective treatment of atherosclerosis" and that, in any event, "treatment of atherosclerosis ... is not synonymous with a method of stabilizing atherosclerotic plaques[] as recited in the pending claims." (Appeal Br. 10, 13.) Appellants also contend that "the cited art fails to teach or suggest a step of selecting patients with elevated circulating IL-18 levels." (Id. at 14.) Appellants further contend that a skilled artisan would not have had a reasonable expectation of success of arriving at the claimed invention based on Gabel and Novick. (Id. at 14--15.) Appellants do not separately argue claims 49-54, 63---66, 81-86, and 96-98. Accordingly, we limit our analysis to claim 49 as representative with respect to the rejection over Gabel and Novick. Appellants also do not make any additional arguments with respect to the rejection of claims 75-80 over Gabel, Novick, and Beers. Therefore, the issue with respect to these rejections is whether a preponderance of the evidence of record supports the Examiner's conclusion that a skilled artisan would have reason to combine Gabel and Novick to arrive at the invention of claim 49, with a reasonable expectation of success. 5 Appeal2017-008185 Application 10/275,341 Findings of Fact 1. Gabel teaches that "[i]nflammatory diseases such as rheumatoid arthritis are characterized by an excessive production of cytokines that promote and/or maintain the inflammatory state" and that "[p ]rominent among [ these cytokines] are IL- I ... , tumor necrosis factor alpha (TNF a), and IL-18." (Gabel 1:15-19.) 2. Gabel teaches that, for certain cytokines such as IL- I and IL-18, stimulus-coupled posttranslational processing enhances the release of mature cytokines from producing cells. (Id. at 1:28-2:26, 11:26-29.) 3. Gabel teaches that, [b ]ecause IL-I and IL-18 are important mediators of inflammation and inhibitors of their function provide therapeutic relief in animal models of disease ... , it is anticipated that agents that disrupt the process of stimulus-coupled posttranslational processing will be useful for the treatment in man and animals of disorders that are sustained by inflammatory mediators. These include rheumatoid arthritis, osteoarthritis, asthma, inflammatory bowel disease, ulcerative colitis, neurodegeneration, atherosclerosis, and psoriasis. (Id. at 2:32--46, italicized emphasis added.) 4. Gabel teaches that diarylsulfonylureas (DASUs) have been identified as "potent inhibitors of stimulus-coupled posttranslational processing." (Id. at 2:27-29.) 5. Gabel teaches DASU binding proteins (DBPs) that "mediate the cytokine inhibitory activity of [DASUs]." (Id. at 2:47-50.) Gabel teaches that "DBPs may be used to screen for structurally unique drugs that disrupt stimulus-coupled posttranslational processing" and further teaches that "[ c ]ompounds that bind to the DBPs also may be used as therapeutics in the treatment of inflammatory disorders." (Id. at 2 :4 7-54.) 6 Appeal2017-008185 Application 10/275,341 6. In particular, Gabel teaches that [a]gents that bind to DBP-31/32 have utility as inhibitors of the production of cytokines such as IL- I and IL-18 that are externalized by non-traditional stimulus-coupled posttranslational processing. Administration of these agents to mammals thus constitutes a method to treat disorders characterized by the overproduction of inflammatory cytokines. These disorders include rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, neurodegeneration, stroke, sepsis, atherosclerosis, and asthma. (Id. at 11 :26-35, italicized emphasis added.) 7. Novick teaches IL-18 binding proteins (IL-I8BP) capable of binding IL-18 and/or modulating and/or blocking IL-18 activity. (Novick Abstract; see also id. at 4:4--7, 6:21-23.) 8. Novick teaches that IL-I8BP isolated from urine "inhibits human as well as murine IL-18 activity as measured by co-induction of IFN- y in human and murine mononuclear cells." (Id. at 37:28-29; see also id. at 46:14--47:8 (stating that "IL-I8BPa inhibited in a dose dependent manner the IFN-y inducing activity of human and mouse IL-18 in murine splenocytes, PBMC and the human KG-I cell line" and that, "[t]herefore, it is concluded that deglycosylated IL-18BP is biologically active as a modulator ofIL-18 activity").) Novick further teaches that "[t]he concentration of IL-18BP which reduced IL-18 activity by >90% was comparable to that of IL-18 itself, suggesting a high affinity interaction between these two proteins." (Id. at 38:1-2.) 9. Novick teaches therapeutic use ofIL-I8BPs by modulating and/or blocking IL-18 activity. (Id. at 1:11-13; see also id. at 3:14--16, 4:11-14.) 7 Appeal2017-008185 Application 10/275,341 10. In particular, Novick teaches that IL-18BPs "may be employed in the treatment and alleviation of conditions in which IL-18 is involved or caused by an excess of ... IL-18" and that "[s]uch conditions are, e.g., autoimmune diseases, type I diabetes, rheumatoid arthritis, graft rejections, inflammatory bowel disease, sepsis, multiple sclerosis, ischemic heart diseases (including heart attacks), ischemic brain injury, chronic hepatitis, psoriasis, chronic pancreatitis, acute pancreatitis and the like." (Id. at 7:25- 31; see also id. at 24:19-25, 25:15-21.) 11. Atherosclerosis is "a chronic inflammatory disease of the arterial wall characterized by progressive accumulation of lipids, ... cells, ... and extracellular matrix." (Spec. 1.) Analysis Unless otherwise noted, we adopt the Examiner's findings of fact and reasoning regarding the Examiner's rejection of claim 49 (Final Act. 3-6; Ans. 2-5, 13-20) and agree that claim 49 is obvious over Gabel and Novick. Only those arguments timely made by Appellants in the Appeal Brief (no Reply Brief was submitted) have been considered; arguments not so presented in the Brief are waived. See 37 C.F.R. § 4I.37(c)(l)(iv) (2015); see also Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative) ("Any bases for asserting error, whether factual or legal, that are not raised in the principal brief are waived."). We address Appellants' arguments below. Appellants first contend that the combination of Gabel and Novick does not teach treating atherosclerosis by inhibiting IL-18. Appellants assert that 8 Appeal2017-008185 Application 10/275,341 Gabel contemplates the use of molecules that they believe to target both IL- I and IL-18 production. Thus, they logically speculate that their molecules can be used to treat any disease in which either IL- I or IL-18 is implicated. Gabel provides no basis for a belief that IL-18 in particular ( as opposed to IL- I) is implicated in atherosclerosis. Thus, without making impermissible use of hindsight bias, Gabel's disclosure relative to atherosclerosis must be limited to indicating that IL- I may be a therapeutic target in atherosclerosis and that as DASUs can act indirectly to inhibit IL- I, they may have some utility in the treatment of atherosclerosis. There is nothing in Gabel that points to the use of inhibition of IL-18 in a subject with atherosclerosis. (Appeal Br. 12.) Appellants further assert that none of the art cited in Gabel supports a role ofIL-18 in atherosclerosis. (Id. at 10-11.) We are not persuaded that the cited combination suggests that only IL- I may be a therapeutic target in atherosclerosis. As the Examiner points out, Gabel teaches that agents that inhibit production of cytokines such as IL- I and IL-18 "constitute[ ] a method to treat disorders characterized by the overproduction of inflammatory cytokines," including atherosclerosis. (Ans. 16; FF6.) As the Examiner also points out, atherosclerosis, an inflammatory disease, is an underlying pathology of ischemic heart disease, and Novick teaches that IL-18BP can be used to treat diseases caused by an excess of IL- 18, including ischemic heart diseases. (Ans. 15-16; FFIO; FFI 1.) We agree with the Examiner that the combination of these teachings would give a skilled artisan reason to administer to "a non-ischemic or ischemic human heart failure patient having atherosclerotic plaques and ... an elevated level of IL-18" a "pharmaceutical composition comprising ... IL-18BP," as recited by claim 49. 9 Appeal2017-008185 Application 10/275,341 Appellants next contend that, even if Gabel teaches treating atherosclerosis by inhibiting IL-18, "the treatment of atherosclerosis (by any means)[ ] is not synonymous with a method of stabilizing atherosclerotic plaques, as recited in the pending claims," and certain patients with atherosclerosis "can best be treated by methods that remove and/or reduce the size of a plaque" rather than methods that stabilize the plaque. (Appeal Br. 13.) Appellants contend, therefore, that (Id.) the recitation that the present methods are directed to methods of stabilizing plaques has a very real meaning which identifies a specific group of patients to which the treatment should be administered. Additionally, the claims are further limited to the treatment of patients who also have elevated levels of IL-18, restricting the method only to those patients who will have the appropriate target for the therapy to act upon. This is the same as any recitation of a target group of patients, clearly excludes patients not falling within the recited group( s ), and is well established to carry weight when evaluating the relevance of the prior art. Accordingly, Appellant's claims are directed not to the treatment of atherosclerosis per se, but to the treatment of the subpopulation of patients who are 1) in need of stabilization of atherosclerotic plaques and 2) have increased IL-18. We are not persuaded. As the Examiner points out, claim 49, as written, does not "positively recite any active method step that allows identifying or distinguishing [the] specific group of patients ... in need of stabilization of atherosclerotic plaques" as opposed to, e.g., removal of such plaques. (Ans. 17.) Instead, the claim merely recites administering certain human isoforms of IL-18BP to "a non-ischemic or ischemic human heart failure patient having atherosclerotic plaques and having an elevated level of IL-18," while the limitation of "increased stability of the atheroma" is part of a wherein clause that recites an intended result. (Appeal Br. 27 (Claims 10 Appeal2017-008185 Application 10/275,341 App.).) "A where[in] clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited." Minton v. Nat 'l Ass 'n of Secs. Dealers, Inc., 336 F.3d 1373, 1381 (Fed. Cir. 2003) ( citation omitted). In addition, Gabel teach the treatment of atherosclerosis with IL- 18BP. (FF3, FF6.) "From the standpoint of patent law, a compound and all of its properties are inseparable; they are one and the same thing." In re Papesch, 315 F.2d 381,391 (CCPA 1963). Therefore, the IL-18BP used in the treatment of atherosclerosis in Gabel would inherently treat any symptom of atherosclerosis associated with inflammation. Appellants' recognition that IL-18BP reduces apoptosis within the atheroma, decreases ulceration at the site of the atheromatous plaque, increases collagen synthesis within the atheroma, and/or increases stability of the atheroma thereby treating loss of elasticity of arteries, is tantamount to the recognition of a newly-discovered property of IL-18BP. "The general principle that a newly-discovered property of the prior art cannot support a patent on that same art is not avoided if the patentee explicitly claims that property." Abbott Labs. v. Baxter Pharm. Products, Inc., 471 F.3d 1363, 1368 (Fed. Cir. Nov. 9, 2006). "Newly discovered results of known processes directed to the same purpose are not patentable because such results are inherent." Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1376 (Fed. Cir. 2001). "An inherent structure, composition or function is not necessarily known. . . . Insufficient prior understanding of the inherent properties of a known composition does not defeat a finding of anticipation." Compare, Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1349 (Fed. Cir. 11 Appeal2017-008185 Application 10/275,341 1999). Therefore, the prior art need not specifically recognize Appellants' claimed inherent properties for IL-18BP used to treat atherosclerosis. As to Appellants' apparent argument that the cited combination of prior art does not render obvious the identification of a non-ischemic or ischemic human heart failure patient having atherosclerotic plaques "and having an elevated level ofIL-18," we are also not persuaded. Gabel teaches that atherosclerosis is a disorder "characterized by the overproduction of inflammatory cytokines" such as IL-I and IL-18. (FF6.) Novick similarly teaches that ischemic heart disease is a condition "in which IL-18 is involved or caused by an excess of ... IL-18" and that IL-18BPs may be used in the treatment and alleviation of such conditions. (FFIO.) We agree with the Examiner that it would have been obvious to a skilled artisan to administer IL-18BPs to a non-ischemic or ischemic human heart failure patient having atherosclerotic plaques and an elevated level of IL-18 in light of these disclosures. Finally, Appellants contend that a skilled artisan would not have had a reasonable expectation of success of arriving at the claimed method based on the combination of Gabel and Novick. (Appeal Br. 14--15.) Appellants contend that neither Gabel nor the references cited in Gabel "have any actual demonstration of a role for IL-18 in any aspect of atherosclerosis nor any 12 Appeal2017-008185 Application 10/275,341 reason to suspect the same." (Id. at 14.) Appellants points to the Chvatchko Declaration 6 and the Aderka Declaration 7 as further support. We are not persuaded. We have already discussed above why the combination of Gabel and Novick suggests that IL-18 inhibition would be useful in atherosclerosis. In addition, it is not necessary for reasonable expectation of success that the prior art explicitly demonstrates that IL-18 inhibitors would be effective in treating atherosclerosis, as Appellants appear to suggest: "Obviousness does not require absolute predictability of success .... For obviousness under§ 103, all that is required is a reasonable expectation of success." In re O 'Farrell, 853 F.2d 894, 903---04 (Fed. Cir. 19 88) ( citation omitted). The Chvatchko and Aderka Declarations also do not persuade us that a skilled artisan would not have had a reasonable expectation of success in combining Gabel and Novick to arrive at the invention of claim 49. The Aderka Declaration explains that atherosclerosis and heart failure are distinct diagnoses, that "[h ]eart failure is also a distinct diagnosis from the generalized term of 'heart disease,"' and that "patients with no hear[t] failure symptoms but affected with atherosclerosis are [ not merely] part of a continuum of a heart disease population." ( Aderka Deel. ,r,r 8, 14, 17.) Neither the declaration nor the Appeal Brief, however, explain why these 6 Declaration of Yolande Chvatchko under 37 C.F.R. § 1.132 (Mar. 17, 2008). Appellants state that the Chvatchko Declaration was previously submitted on June 11, 2008; however, the declaration appears to have been submitted on March 24, 2008. 7 Declaration of Dan Aderka under 37 C.F.R. § 1.132 (Sept. 9, 2009). Appellants state that the Aderka Declaration was previously submitted on February 19, 2010; however, the declaration appears to have been submitted on September 22, 2009. 13 Appeal2017-008185 Application 10/275,341 statements, if true, shows that a skilled artisan would not have had a reasonable expectation of success, based on the combination of Gabel and Novick, of treating heart failure patients having atherosclerotic plaques and elevated level of IL-18 with IL-18BP. The Chvatchko Declaration states that "Gabel does not describe anywhere that inhibiting IL-18 alone will be useful for the treatment of atherosclerosis." (Chvatchko Deel. ,r 10.) However, claim 49 does not require that IL-18BP be administered alone. See Crystal Semiconductor Corp. v. TriTech Microelectronics Int'!, Inc., 246 F.3d 1336, 1348 (Fed. Cir. 2001) (holding that: "Use of the transition 'comprising' in the language of a claim creates a presumption ... that the claim does not exclude additional, unrecited elements." Therefore, the prior art does not need to provide a reasonable expectation of successfully treating atherosclerosis by inhibiting IL-18 alone. The Chvatchko Declaration also asserts that Gabel does not teach IL- 18 specific inhibitors and that "even an inference that anything other than inhibition of mature IL- I a and IL- I B expression can be expected from the use of the Gabel compounds is a stretch due to lack of any experimental showing." (Chvatchko Deel. ,r,r 11-12.) However, the rejection relies on Novick rather than Gabel to teach IL-I8BP, and "[n]on-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references. . . . [The reference] must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole." In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). 14 Appeal2017-008185 Application 10/275,341 Finally, the Chvatchko Declaration states that the cited prior art does not suggest inhibiting IL-18 to stabilize atherosclerotic plaques. ( Chvatchko Deel. ,r,r 10, 13-14.) However, as already discussed, "increas[ing] stability of the atheroma" is merely an intended result of the claim. A claim does not become obvious merely by recognizing additional advantages or latent properties present in a prior art method. Abbott Labs., 471 F.3d at 1368. Accordingly, we affirm the Examiner's rejection of claim 49. Claims 50-54, 63-66, 81-86, and 96-98, which are not separately argued, fall with claim 49. 37 C.F.R. § 4I.37(c)(l)(iv). Appellants do not make any additional arguments with respect to the rejection of claims 75-80 as obvious over Gabel, Novick, and Beers, and we affirm the rejection for the same reasons discussed with respect to claim 49. II. Issue The Examiner has rejected claims 49-54, 81-86, and 96-98 as obvious over Torigoe. The Examiner has rejected claims 63---66 as obvious over Torigoe and Novick. The Examiner has rejected claims 75-80 as obvious over Torigoe and Beers. The same issues are dispositive for both rejections; we therefore discuss the rejections together. The Examiner finds that Torigoe teaches that excessive amounts of IL-18 "may disturb the balance of immune system." ( Ans. 7.) The Examiner finds that Torigoe teaches IL-18 binding proteins (IL-18BP), including human IL-18BPa (isoform a). (Id.) The Examiner finds that Torigoe teaches that IL-18BP suppresses the physiological activities ofIL- 18 and may be useful in treating and/or preventing diseases, especially "immunopathies and disorders in circulatory and nerve systems ... , 15 Appeal2017-008185 Application 10/275,341 wherein disorders in circulatory system include ischemia, ischemic cardiomyopathy, and arteriosclerosis." (Id. at 8.) The Examiner cites the Specification as disclosing that atherosclerosis is also known as arteriosclerosis. (Id.) The Examiner finds that "Torigoe does not explicitly teach identifying an ischemic heart failure patient having atherosclerotic plaques and having an elevated level ofIL-18." (Id.) However, the Examiner finds that it would have been obvious to a skilled artisan to identify such a patient for treatment with human IL-18BPa in light of Torigoe, because it is well established that atherosclerotic plaques/atheroma is the underlying pathology/cause of ischemic heart disease leading to ischemic heart failure; and Torigoe teaches excessive amounts of IL-18 in these pathological disorders .... The person of ordinary skill in the art would have been motivated to do so for disease treatment, and reasonably would have expected success because Torigoe has indicated the association of excessive amounts ofIL- 18 and the pathological disorders including ischemic cardiomyopathy (ischemic heart failure) and arteriosclerosis, and demonstrated that IL-18BPa is capable of binding and neutralizing IL-18. (Id. at8-9.) The Examiner further concludes that the "treating" limitations in the preamble of the claims "merely state[ ] the purpose or the intended use of the invention" and are thus non-limiting. (Id. at 9.) Similarly, the Examiner concludes that "effectively treating ischemic cardiomyopathy/ischemic heart failure and arteriosclerosis/atherosclerosis with the hIL-18BPa following the teachings of Torigoe would have inherently treated those conditions recited in the preamble in such a patient, and would have inherently resulted in the effect recited" in the wherein clauses of the claims. (Id.) 16 Appeal2017-008185 Application 10/275,341 Appellants contend that Torigoe fails to provide a reasonable expectation of success and does not suggest the step of "identifying a non- ischemic or ischemic human heart failure patient having atherosclerotic plaques and ... an elevated level ofIL-18." (Appeal Br. 17-22.) Appellants do not separately argue claims 49-54, 81-86, and 96-98. Accordingly, we limit our analysis to claim 49 as representative with respect to the rejection over Torigoe. Appellants also do not make any additional arguments with respect to the rejection of claims 63---66 over Torigoe and Novick and the rejection of claims 75-80 as obvious over Torigoe and Beers. Therefore, the issue with respect to these rejections is whether a preponderance of the evidence of record supports the Examiner's conclusion that a skilled artisan would have reason to combine the teachings in Torigoe to arrive at the invention of claim 49, with a reasonable expectation of success. Findings of Fact 12. Torigoe teaches "an IL-18 binding protein ... and an IL-18- suppressor as well as agent for susceptive diseases containing as an effective ingredient this IL-18-binding protein." (Torigoe Abstract; see also id. ,r 24 (stating that "[t]he IL-18-binding protein of [the] invention, when acting on IL-18, suppresses the representative physiological activity of IL-18, inducing IFN-y production by immunocompetent cells" and "may suppress the enhancement of cytotoxicity of killer cells and the induction of killer cell generation by the action ofIL-18"), ,r,r 41--42, claims 1 and 2.) 13. Torigoe teaches that its IL-18-binding protein "has an efficacy to alleviate or prevent disorders in circulatory system" such as ischemia, ischemic cardiomyopathy, and arteriosclerosis. (Id. ,r 28.) 17 Appeal2017-008185 Application 10/275,341 14. The Specification states that Atheroma is the commonest lesion in arteries, which may be further complicated by thrombo-embolism. Atheromatous plaques often narrow the lumen of arteries causing ischemia and sometimes atrophy of tissues in the hypoperfused territory. Serious consequences include the symptom of angina due to myocardial ischemia, heart failure due to ischemia or non- ischemic events, and hypertension due to renal artery narrowing and hypoperfusion of a kidney which responds physiologically by increased renin secretion. Sometimes atherosclerosis and arteriosclerosis are referred to as separate pathological conditions, and in this case, atherosclerosis is defined as implying hardening (sclerosis) or loss of elasticity of arteries due specifically to atheroma, whilst arteriosclerosis is hardening or loss of elasticity of arteries from any cause. Atherosclerosis is also called arteriosclerosis or hardening of the arteries. Within the context of the present invention, the term atherosclerosis encompasses all diseases or diseased conditions of arteries usually described as atherosclerosis, in which fatty material is deposited in the vessel wall, eventually resulting in narrowing and impairment of blood flow as well as rupture and/ or erosion with thrombus formation. In accordance with the present invention, atherosclerosis is meant to comprise both sclerosis or loss of elasticity of arteries due to atheroma (atherosclerosis) and due to any other cause (arteriosclerosis). The pathological conditions of atherosclerosis, as well as the complications or consequences of atherosclerosis, which are intended to be included in the term "atherosclerosis" as used herein, have been described in detail in the "background of the invention" above. (Spec. 1-2, 8.) 18 Appeal2017-008185 Application 10/275,341 Analysis Unless otherwise noted, we adopt the Examiner's findings of fact and reasoning regarding the Examiner's rejection of claim 49 (Final Act. 6-8; Ans. 7-9, 21-26) and agree that claim 49 is obvious over Torigoe. Only those arguments timely made by Appellants in the Appeal Brief (no Reply Brief was submitted) have been considered; arguments not so presented in the Brief are waived. See 37 C.F.R. § 4I.37(c)(l)(iv) (2015); see also Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative) ("Any bases for asserting error, whether factual or legal, that are not raised in the principal brief are waived."). We address Appellants' arguments below. Appellants contend Torigoe does not provide a reasonable expectation of success for the claims. Appellants contend that Torigoe "contains absolutely no demonstration that IL-18BP has a therapeutic effect in any context whatsoever." (Appeal Br. 17 .) We are not persuaded. As we have discussed, it is not necessary for reasonable expectation of success that the prior art explicitly demonstrate the therapeutic effect ofIL-18BP. 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.). Appellants acknowledge that lack of demonstration of therapeutic effect in Torigoe "does not in and of itself disqualify the reference as prior art." (Appeal Br. 17.) However, Appellants contend that Torigoe "makes statements which are known to be directly contrary to what was known in the art," i.e., that diabetes can be treated by administration ofIL-18BP 19 Appeal2017-008185 Application 10/275,341 polypeptide and also refers to arteriosclerosis "within the context of an extensive laundry list of conditions." (Id. at 18.) Appellants contend that, [w]here Torigoe makes statements which are known to be directly contrary to what was known in the art and provides absolutely no demonstration any of therapeutic efficacy itself, one of skill in the art would have every reason to view assertions made by T origoe with skepticism and require more than a mere statement in order to rely upon any such assertion for an expectation of success. (Id.) We are not persuaded. Assuming, for argument's sake, that T origoe contains a misstatement relating to the treatment of diabetes, a reference is prior art for all that it teaches even if it discloses something inoperative. Beckman Instruments, Inc. v. LKB Produkter AB, 892 F.2d 1547, 1551 (Fed. Cir. 1989). Appellants have cited no persuasive authority, only attorney argument, supporting their contention that any misstatement in a prior art reference would render other statements in the reference suspect such that they may not be relied upon for an expectation of success absent further demonstration of their accuracy. As to Appellants' complaint that Torigoe refers to arteriosclerosis only in the context of "an extensive laundry list of conditions" that may be treated with IL-18BP, we note that a claimed invention is not nonobvious merely because the prior art also made obvious products other than what is claimed. Cf Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (where the prior art patent disclosed genus of 1,200 effective combination of compounds, including the claimed combination, that "disclos[ing] a multitude of effective combinations does not render any particular formulation less obvious"). 20 Appeal2017-008185 Application 10/275,341 Appellants next contend that Torigoe would not have provided a person of ordinary skill with a reasonable expectation of success with respect to the claims because, atherosclerosis, which is claimed, and arteriosclerosis, which is disclosed in Torigoe, are not equivalent. (Appeal Br. 19.) Appellants contend that, therefore, [ e ]ven if a treatment was effective in improving arteriosclerosis, there is no underlying biological reason for one of skill in the art to have a reasonable expectation that the same treatment would be efficacious in modulating plaque phenotypes, as recited in the present claims. Additionally, as described above, the present claims relate specifically to stabilizing plaques, and in some patients, removal or disruption of a plaque might be therapeutic. Thus, a treatment for atherosclerosis cannot be assumed to inherently have the recited activity and a treatment for arteriosclerosis ( a condition which need not even include the presence of plaques) can certainly not be assumed to have the recited activity. (Id. at 20.) We are not persuaded. As we discussed earlier, claim 49 recites (1) identifying non-ischemic or ischemic human heart failure patients having atherosclerotic plaques and an elevated level of IL-18 and (2) administering hIL-18BPa or hIL-18BPc to these patients, while the limitations relating to "reduced apoptosis within the atheroma, decreased ulceration at the site of the atheromatous plaque, increased collagen synthesis within the atheroma, and/or increased stability of the atheroma" are simply intended results. Thus, for purposes of obviousness it is not necessary for a skilled artisan to have had a reasonable expectation that administering IL-18BP to the recited patient group would result in "efficacious ... modulati[ on ofJ plaque phenotypes." 21 Appeal2017-008185 Application 10/275,341 As for Appellants' argument that T origoe does not provide a reasonable expectation of success with respect to the claims because it teaches treating arteriosclerosis, rather than atherosclerosis, with IL-18BP, we note that the Specification states that "[a]therosclerosis is also called arteriosclerosis or hardening of the arteries." (FF14.) Moreover, although the Specification states that sometimes atherosclerosis and arteriosclerosis are referred to as separate pathological conditions - i.e., arteriosclerosis refers to "hardening or loss of elasticity of arteries from any cause" andatherosclerosis refers to "hardening (sclerosis) or loss of elasticity of arteries due specifically to atheroma" -the Specification expressly states that for purposes of the invention the term atherosclerosis "is meant to comprise both sclerosis or loss of elasticity of arteries due to atheroma (atherosclerosis) and due to any other cause (arteriosclerosis)," as well as "pathological conditions" and "complications or consequences" of atherosclerosis (id.). 8 See Phillips v. AWH Corp., 415 F.3d 1303, 1319 (Fed. Cir. 2005) (holding that appellants may act as their own lexicographers as long as they have clearly set forth an explicit definition of the term). Torigoe teaches that IL-18BP suppresses the activity of IL-18 and may be used to treat disorders including ischemia, ischemic cardiomyopathy, and arteriosclerosis. Even if a skilled artisan did not understand Torigoe as teaching use of IL-18BP to treat atherosclerosis, therefore, Torigoe teaches use of IL-18BP to treat conditions closely related to (ischemic, ischemic cardiomyopathy) and/or encompassing atherosclerotic plaque 8 The Specification explains that atheromatous plaques often cause ischemia, angina due to myocardial ischemia, and heart failure due to ischemia or non- ischemic events. (FF14.) 22 Appeal2017-008185 Application 10/275,341 (arteriosclerosis) and provides a skilled artisan reason to administer IL-18BP to non-ischemic or ischemic human heart failure patients having atherosclerotic plaques and an elevated level of IL-18, with a reasonable expectation of success. Appellants further argue that Torigoe does not suggest the claim limitation relating to "identifying a non-ischemic or ischemic human heart failure patient having atherosclerotic plaques and having an elevated level of IL-18" for administration of the recited IL-18BP composition. ( Appeal Br. 21.) Appellants argue that "Torigoe fails to mention atherosclerosis in any context." (Appeal Br. 22.) Appellants argue that "elevated IL-18 is not inherent in all patients with plaques, much less all patients with atherosclerosis ... or even arteriosclerosis." (Id.) We are not persuaded. We have explained above why Torigoe would suggest the claim limitation relating to atherosclerotic plaques. As to the limitation relating to elevated IL-18, we note that Torigoe teaches that its IL- 18 binding protein suppresses the activity ofIL-18. (FF12.) We find that this would suggest to a skilled artisan to administer IL-18BP to patients having an elevated level of IL-18, so as to suppress the activity of the excess IL-18. Finally, Appellants contend that Appellant has discovered that IL-18 contributes to certain plaque phenotypes that relate to, e.g. its stability, and that this contribution can be modulated by administering the claimed IL- 18BP polypeptides. This permits unexpected and surprising results in the treatment of this specific group of patients. Accordingly, Appellant's claims are directed not to the treatment of arteriosclerosis, but to the treatment of the subpopulation of patients with 1) atherosclerotic plaques and 2) increased IL-18 23 Appeal2017-008185 Application 10/275,341 who can benefit from plaque stabilization by means of IL-18BP administration. (Appeal Br. 22.) We are not persuaded for the reasons already discussed above in connection with the rejection over Gabel and Novick: Claim 49 as written does not positively recite any method step that allows identifying or distinguishing "the specific group of patients ... who can benefit from plaque stabilization," as Appellants contend; instead, the claim only requires identifying "non-ischemic or ischemic human heart failure patient having atherosclerotic plaques and having an elevated level of IL-18," while limitations relating to "increased stability of the atheroma" are part of a wherein clause reciting an intended result and do not distinguish the claim over the prior art. We have also already explained why Torigoe renders obvious administration of IL-18BP to patients having atherosclerotic plaques and elevated level of IL-18. Finally, to the extent Appellants contend that the claimed subject matter exhibits unexpected results, we are not persuaded -Appellants point to no evidence that their results are, in fact, unexpected. In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997) ("[I]t is well settled that unexpected results must be established by factual evidence."). Accordingly, we affirm the Examiner's rejection of claim 49 as obvious over Torigoe. Claims 50-54, 81-86, and 96-98, which are not separately argued, fall with claim 49. 37 C.F.R. § 4I.37(c)(l)(iv). Appellants do not make any additional arguments with respect to the rejection of claims 63---66 as obvious over Torigoe and Novick or the rejection of claims 75-80 as obvious over Torigoe and Beers, and we affirm these rejections for the same reasons discussed with respect to claim 49. 24 Appeal2017-008185 Application 10/275,341 SUMMARY For the reasons above, we affirm the Examiner's decision rejecting claims 49-54, 63---66, 75-86, and 96-98. 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). AFFIRMED 25 Copy with citationCopy as parenthetical citation