Ex Parte Horiuchi et alDownload PDFPatent Trial and Appeal BoardMar 16, 201811484132 (P.T.A.B. Mar. 16, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 111484, 132 07/11/2006 65989 7590 03/20/2018 KING & SPALDING 1185 A VENUE OF THE AMERICAS NEW YORK, NY 10036-4003 FIRST NAMED INVENTOR Masatsugu Horiuchi 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. 17620-105001US1 7300 EXAMINER SZNAIDMAN, MARCOS L ART UNIT PAPER NUMBER 1628 NOTIFICATION DATE DELIVERY MODE 03/20/2018 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): usptomailnyc@kslaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte MASATSUGU HORIUCHI, MASARU IWAI, TOSHIO SADA, and MAKOTO MIZUNO Appeal 2016-003023 Application 11/484, 132 1 Technology Center 1600 Before JEFFREY N. FREDMAN, TIMOTHY G. MAJORS, and DEVON ZASTROW NEWMAN, Administrative Patent Judges. NEWMAN, Administrative Patent Judge. DECISION ON APPEAL This appeal under 35 U.S.C. § 134 involves claims to a pharmaceutical composition. The Examiner entered final rejections for obviousness. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 Appellants identify Daiichi Sankyo Company, Limited as the real party in interest. App. Br. 2. Appeal 2016-003023 Application 11/484, 132 STATEMENT OF THE CASE Background Currently, calcium channel blockers and inhibitors of the renin-angiotensin system are widely used clinically for the prophylaxis and treatment of hypertension. Various types of calcium channel blockers are used, and among them 1,4- dihydropyridine derivatives .... Furthermore, as inhibitors of the renin-angiotensin system, clinical use of angiotensin II receptor antagonists is growing larger and larger since, first, angiotensin II receptor antagonists lack side effects such as cough, which has been a cause of troubles elicited by angiotensin converting enzyme (ACE) inhibitors, and second, they exert protective effects on the cardiovascular and renal systems. However, the blood pressure of patients with hypertension cannot be fully controlled by only one kind of these drugs in many cases. Spec. 1-2. The Specification discloses "medicaments to prevent or to inhibit the proliferation of vascular smooth muscles and neointima formation in blood vessels [and] that effectively inhibit remodeling of vessels and prevent progression of arteriosclerosis as well as restenosis of vessels following [percutaneous coronary intervention (PCI)]." Id. at 5. Claims 1 and 8-11 are on appeal. 2 App. Br. 3. Claim 1, the only independent claim, is illustrative and reads as follows: 1. A pharmaceutical composition consisting of pharmaceutically effective amounts of the following active ingredients: 2 Claims 2-7 and 12 are cancelled. App. Br. 3. 2 Appeal 2016-003023 Application 11/484, 132 (A) an angiotensin II receptor antagonist which is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy- l-methylethyl)-2-propyl-l-[[2 '-(IH-tetrazol-5- yl)biphenyl-4-yl]methyl]imidazol-5-carboxylate and (B) a calcium channel blocker which is amlodipine or amlodipine besylate, and optionally a pharmacologically acceptable carrier. Appellants seek our review of the rejection of claims 1 and 8-11 under 35 U.S.C. § 103(a) as being unpatentable over Norwood, 3 Faulkner,4 Sato, 5 MacGregor, 6 Webb, 7 and Gaviraghi. 8 Ans. 2. We select claim 1 as representative of the claims on appeal. 37 C.F.R. § 41.37(c)(l)(iv). 3 Daryl Norwood, et al.,Olmesartan Medoxomilfor Hypertension: A Clinical Review, 27: Drug Forecast, P&T, 611-618 (2002) (hereinafter "Norwood"). 4 Michele A. Faulkner et al., Amlodipine/benazepril: fixed dose combination therapy for hypertension, 2, 1: EXPERT OPINION ON PHARMACOLOGY, 165-178 (2001) (hereinafter "Faulkner"). 5 Keiichiro Sato, et al., 18(5): CLIN. AND EXPER. HYPERTENSION 607---624 (1996) (hereinafter "Sato"). 6 Graham A. MacGregor, et al., Efficacy of Candesartan Cilexetil Alone or in Combination With Amlodipine and Hydrochlorothiazide in Moderate-to- Serve-Hypertension, 36: HYPERTENSION JOURNAL OF THE AMERICAN HEART ASSOCIATION, 454--460 (2000) (hereinafter "MacGregor"). 7 Webb et al., US 6,204,281 Bl, issued March 20, 2001 (hereinafter "Webb"). 8 Gaviraghi, et al., WO 00/27396 Al, published May 18, 2000 (hereinafter "Ga viraghi "). 3 Appeal 2016-003023 Application 11/484, 132 DISCUSSION The Examiner finds that Norwood, teaches "a method of treating hypertension comprising administering a pharmaceutical composition comprising the ARB [angiotensin (AT) receptor antagonist] Olmesartan Medoxomil." Ans. 3 (emphasis omitted). The Examiner finds that Faulkner teaches "a method of treating hypertension comprising administering a pharmaceutical composition comprising the CCB [calcium channel blocker] Amlodipine or Amlodipine besylate." Id. (emphasis omitted). The Examiner finds that Sato and MacGregor each teach that "combinations of ARBs and CCBs are effective in treating hypertension," and that Gaviraghi teaches that "a combination of the ARB telmisartan and the DHP-CCB lacidipine is effective in treating cardiovascular disorders such as hypertension, atherosclerosis and ischemic heart disease." Id. at 3, 5 (emphasis omitted). The Examiner finds that Gaviraghi discloses that "f! synergistic antihypertensive effect is achieved" by combining lacidipine and telmisartan, and suggest that the combined use would provide "synergistic antihypertensive effects, antihypertensive effect over a longer period and/or allow a better management of any potential drug-related side effects." Id. at 5. The Examiner finds that Webb teaches a method of treating hypertension comprising "the administration of an ARB (or AT 1 receptor antagonist) like Valsartan and a CCB, wherein the preferred CCB is Amlodipine or Amlodipine besylate." Id. at 4, 5. The Examiner finds that Webb discloses motivation for combining "different and complementary mechanics" to control hypertension and the "surprising ... experimental finding that the combined administration of the ARB valsartan and a CCB 4 Appeal 2016-003023 Application 11/484, 132 results not only in a synergistic therapeutic effect but also in additional benefits resulting from combined treatment such as a surprising prolongation of efficacy and a broader variety of therapeutic treatment." Id. at 4--5. The Examiner finds that Webb discloses that "combination therapy with valsartan and a CCB results in a more effective antihypertensive therapy through improved efficacy as well as greater respon[se] rate." Id. at 5. The Examiner finds that Norwood teaches: Although the ARBs have some structural and pharmacokinetic differences, few pharmacological differences separate these agents from one another[.] In fact, the order of binding affinity to the ATl receptor, compared with the AT2 receptor for ARBs appears to be as follows: valsartan > olmesartan > candesartan > irbesartan > telmisartan > losartan > eprosartan. Id. at 6 (citation and emphasis omitted). The Examiner further finds that Norwood teaches that "all the ARBs including valsartan, candesartan, telmisartan and olmesartan have very similar pharmacological properties, with olmesartan being more effective than valsartan in reducing blood pressure." Id. The Examiner concludes that the skilled artisan would have found it obvious "to treat hypertension [by] combining two compositions (Olmesartan Medoxomil and Amlodipine) each of which is taught by the prior art to be useful for the same purpose (treating hypertension), in order to form a third composition to be used for the very same purpose." Id. (citing In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980)). 5 Appeal 2016-003023 Application 11/484, 132 Principles of Law "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Prima facie obviousness may be rebutted with evidence of secondary considerations, and, when such evidence is submitted, all of the evidence is considered anew. In re Piasecki, 745 F.2d 1468, 1472-73 (Fed. Cir. 1984). Secondary considerations include, inter alia, long-felt but unsolved needs, failure of others, and unexpected results. In re Rouffet, 149 F.3d 1350, 1355 (Fed. Cir. 1998). Analysis We agree with the Examiner that, based on the cited references, it would have been prima facie obvious to treat hypertension by administering an ARB and a CCB in combination. The references cited by the Examiner disclose the use of ARBs and CCBs for treatment of hypertension, disclose that multiple types of ARBs and CCBs are known in the art, and specifically disclose use of a combination of both an ARB and a CCB to achieve an added benefit of combination therapy resulting in a more effective antihypertensive therapy. See Norwood 611-12; Faulkner 165, 167-8; Sato 615; MacGregor 454, 459; Webb 1:8-57, 21-5, 34--61; 3:12-16; 7:25-32; and Gaviraghi 1 :26-2:9. Thus, we agree with the Examiner that the skilled artisan would have found it prima facie obvious to treat hypertension using the claimed combination of an ARB and a CCB, olmesartan medoxomil and 6 Appeal 2016-003023 Application 11/484, 132 amlodipine, or amlodipine besylate, in a composition as taught by these references, to achieve the benefit of combination therapy. To respond to the prima facie case of obviousness, Appellants advance the Declaration of Nigel John Michael Birdsall, 9 which Appellants argue shows "that Appellants' claimed method of treating hypertension comprising administering olmesartan medoxomil and amlodipine or amlodipine besylate provides a synergistic response, and furthermore that this superior efficacy was in fact unexpected by one skilled in the art as of the priority date of January 31, 2003." App. Br. 8. Appellants argue that "[b ]y providing evidence of unexpected results based on the observations of synergy confirmed in the Birdsall Declaration, Appellants have rebutted the prima facie basis of obviousness that was lacking in Kerkhoven, therefore making the Examiner's continued reliance on Kerkhoven improper." Id. With regard to the application of Kerkoven, the Examiner responds that "reliance on in re Kerkhoven is appropriate, since in re Kerkhoven provides the motivation to combine two compositions, each of which was taught by the prior art to be useful for the same purpose" and that demonstration of unexpected properties is a separate issue unrelated to the application of Kerkoven. Ans. 12-13. We agree with the Examiner that the application of Kerkoven is a separate issue from whether evidence of unexpected results, when considered with the prima facie case, results in a conclusion of nonobviousness, and further agree that the Examiner properly applied 9 Declaration of Dr. Nigel John Michael Birdsall under 37 C.F.R. § 1.132, executed October 17, 2013 (hereinafter "Birdsall Deel."). 7 Appeal 2016-003023 Application 11/484, 132 Kerkoven in reasoning that the skilled artisan would have been motivated to substitute a known ARB or CCB for another such known compound, based on the knowledge in the art that the known compounds are useful for the same purpose. Kerkoven, 626 F .2d at 850. We agree with the Examiner that Kerkoven supports a conclusion that the claimed invention, which claims an ARB and a CCB known in the art at the time of the invention, is prima facie obvious. However, as we discuss in greater detail below, Appellants provided persuasive and countervailing objective evidence of nonobviousness, particularly the analysis provided by Dr. Birdsall that the composition provided synergistic effects to recipients that were significantly greater than would have been expected from adding the known effects of the respective individual compounds, and the Examiner has not provided an adequate basis to show that the increased effect would have been expected. When this evidence is considered along with the teachings of the applied prior art, the decision tilts in Appellants' favor. In the Birdsall Declaration submitted by Appellants, Dr. Birdsall opines, among other points, that "the combination of olmesartan medoxomil and amlodipine provide[s] unexpected synergy" and that as of the time of the invention, because of different targets of both ARBs and especially CCBs, one skilled in the art could not have predicted whether the olmesartan medoxomil and amlodipine would be synergistic because one skilled in the art could not predict whether the combination of any ARB and any CCB not previously combined would provide a synergistic beneficial effect. 8 Appeal 2016-003023 Application 11/484, 132 Birdsall Deel. i-f 9(C), (G). Dr. Birdsall opines that the prior art contained evidence that the combination of certain ARBs and CCBs "did not give synergy." Id.i-f 9(A). With regard to identifying synergy, Dr. Birdsall opines that the preferred analysis is the "Chou-Talalay method [of statistical analysis, which] provides a mathematical means of quantitating the synergism (and distinguishing it from additive or inhibitory effects) of drug combinations when there are dose response-curves for the individual actions of the drugs." Id. at i-f 11.4. With regard to the Examiner's findings that Webb discloses a synergistic effect of a valsartan (ARB) and CCB combination, Dr. Birdsall reports that he attempted to obtain the data in Webb to analyze the results, but reported he was unable to do so, and that the experimental data that was reported in Webb "relates to survival rates for the combination of valsartan and verapamil in an experimental model of diabetes" and does not relate to hypertension. Id. at i-f 12.5. Dr. Birdsall opines that "one skilled in the art can give no credibility to the claim of synergy made in Webb in the absence of data to support the claim" and provides "[e]xperimental evidence that contradicts the Webb's claims of synergy." Id. ,-r 12.11 . Dr. Birdsall opines that he applied the Chou-Talalay method to data published in Davis, 10 which "describe[d] the disparate effects of angiotensin II antagonists and channel blockers on hypertension and albuminuria in an 10 Davis et al., Disparate Effects of Angiotensin II Antagonists and Calcium Channel Blockers on Albuminuria in Experimental Diabetes and Hypertension: Potential Role of Nephrin, 21: J. HYPERTENS. 209--216 (2003) (hereinafter "Davis"). 9 Appeal 2016-003023 Application 11/484, 132 experimental model of diabetes in spontaneously hypertensive (SHR) rats." Id. i-f A. I. Dr. Birdsall opined that his analysis of Davis' "experimental results for the combination valsartan with either of two CCBs that have different mechanisms of action are in direct opposition to the statements in Webb that are not supported by experimental data" and that the "analysis ... shows a strong, less than additive effect" when a combined therapy of valsartan with either amlodipine or verapramil was administered. Id. i-fi-1 A.6, A.11. From this analysis, Dr. Birdsall opines that "one skilled in the art would not have been able to infer the activity of the combination of olmesartan medoxomil and amlodpine from the activity of a different sartan, valsartan, with a different CCB, verapamil, having a different mechanism of action than amlodipine," and that "[t]he experimental data of Davis contradict the statements in Webb that valsartan combined with amlodipine or verapamil exhibit synergy in their antihypertensive actions or their effects on renal disease." Id. i-fi-1 A.13, A.15. Dr. Birdsall further opines that because of these results and others, the skilled artisan "would not have expected a combination of olmesartan medoxomil and amlodipine would impart more than a 'less than additive' effect (e.g., a synergistic or an additive benefit) in reducing blood pressure." Id. i-f A.16. The Examiner responds that "the synergistic properties of the instant combination ... for reducing hypertension cannot be considered unexpected since the prior art already teaches several cases of synergistic combinations of ARBs and CCBs that were already mentioned in the above 103 rejection." Ans. 15-16 (emphasis omitted) (citing Webb (disclosing the use of "ARB Valsartan and the DHP-CCB Amlodipine besylate.")) (citing Gaviraghi 10 Appeal 2016-003023 Application 11/484, 132 (disclosing use of "the ARB tehnisartan and the DHP-CCB lacidipine.")) 11 The Examiner further responds that Appellants have failed to compare the claimed composition to the closest prior art, Webb and MacGregor. Id. at 17 (citing MacGregor's use of "ARB candesartan and CCB amlodipine")), but concedes later in the Answer that "MacGregor ... is silent regarding whether the combination of the ARB candesartan and the CCB amlodipine is synergistic or not." Id. at 29. With regard to Dr. Birdsall's claim that no testing data were available from Webb regarding co-administered Valsartan and Amlodipine, the Examiner cites Webb's description of the testing (Webb 4:36-66) and finds these statements "clearly indicate[] that experimental data was provided for the combination of valsartan and amlodipine for the treatment of hypertension in hypertensive rats, and that the combination shows unexpected synergistic effects." Ans. 31. The Examiner further responds that the Davis reference is completely irrelevant to the current discussion, since the Davis reference studied the effect of mixtures of the ARB valsartan with either the CCB amlodipine or the CCB phenylalkylamine on the progression of renal disease and the expression of the podocyte slit pore protein, nephrin in an accelerated model of diabetic nephropathy, which is a different study than the one 11 The Examiner further cites post-filing references "wherein studies show that the valsartan-amlodipine combination, not only is effective for the treatment of hypertension, it is also safe and synergistic." Ans. 17. The prohibition against post-filing date art applies to "the impermissible application of later knowledge about later art-related facts ... which did not exist on the filing date." In re Hogan, 559 F.2d 595, 605 (CCPA 1977). Because we confine our review to the record before us as viewed by the skilled artisan at the time of the invention, we do not address this issue. 11 Appeal 2016-003023 Application 11/484, 132 disclosed by Webb, which measured blood pressure in spontaneously hypertensive rats. Ans. 31-32 (emphasis omitted). The Examiner concludes that the data of Davis "cannot be correlated with the effect on blood pressure that will result by administering the same mixture in the SHR (spontaneously Hypertensive Rats) rats as disclosed by Webb" and reiterates that Webb's statements are "not a denial that synergy occurred" and "leaves the door open that synergy might exist." Id. at 32-33. In reply, Appellants note that "Webb doesn't provide any experimental data for the valsartan and amlodipine combination," and that the Examiner's interpretation of the Webb data as "meaning that there could be more than an additive effect," is error. Reply Br. 2-3. Appellants additionally argue that the Examiner does not accurately differentiate between the types of improvements disclosed in the various references. Id. at, e.g., 4--5. Appellants argue that the prima facie burden has been overcome because "Birdsall provides substantial objective factual evidence of non-equivalence of the various ARBs and various CCBs," which overcomes the Examiner's presumption that the claimed combination of olmesartan medoxomil and amlodipine, as an ARB and CCB, would be expected to provide a synergistic effect. Id. at 7; see also Ans. 40-41 (regarding the Examiner's presumption that "the expectation is that some or all mixtures of ARBs and CCBs could also be synergistic, or in other words, it should be expected that any future mixtures of ARBs and CCBs could be synergistic."). We find this to be a close case. As discussed above, the Examiner has established a prima facie case that combining an ARB and a CCB for the purpose of achieving a combined beneficial effect is obvious. However, we 12 Appeal 2016-003023 Application 11/484, 132 are persuaded by Dr. Birdsall's opinion that the synergistic effect of the combination of olmesartan medoxomil and amlodipine in reducing symptoms of hypertension was an unexpected result at the time of the invention. See, e.g., Birdsall Deel. i-f 9A (referencing Annex 3). In particular, we are persuaded by Dr. Birdsall's analysis of the best available data, from Davis, which combined the claimed compound amlodopine and valsartan, another sartan compound with a similar structure to the claimed ARB, olmesartan medoxomil, and found no synergistic effect. Id.AI (see Opinion A). We therefore agree with Appellants that there is factual evidence of non-equivalence of the ARBs and CCBs, undermining the Examiner's Kerkoven rationale. We acknowledge but are unpersuaded by the Examiner's opinion that any combination of an ARB and CCB would have been expected to provide a synergistic effect at the time of the invention. Ans. 40-41. Although we agree that a skilled worker would have reasonably expected the combination of an ARB and CCB to be more effective than either compound alone, we conclude that the Examiner has not provided a reasonable basis for concluding that the observed synergy as calculated by the Chou-Talalay method would have been expected for every such claimed combination, including the claimed composition. Birdsall Deel. i-f E. l-E.13 (Section D, Annex 3). In particular, we agree with Appellants that although Webb describes testing of the valsartan and amlodipine combination, no data are provided in Webb to permit analysis, and Dr. Birdsall' s sworn statement indicates the data were not obtainable. Birdsall Deel. i-f 12.6. We are further unpersuaded that the data analyzed in Davis are irrelevant as the data measured are "the disparate effects of angiotensin II antagonists and channel 13 Appeal 2016-003023 Application 11/484, 132 blockers on hypertension and albmninuria in an experimental model of diabetes in spontaneously hypertensive (SHR) rats." Id. i-f A. I. As such, the data are comparable to those in Webb for purposes of analysis of the subject composition. When the Examiner's prima-facie case is considered anew, in light of all the evidence of record, we are unpersuaded that claim 1 would have been obvious over Norwood, Faulkner, Sato, MacGregor, Webb, and Gaviraghi. Appellants have provided persuasive argument and objective evidence of nonobviousness that outweighs the evidence of obviousness. Mintz v. Dietz & Watson, Inc., 679 F.3d 1372, 1379 (Fed. Cir. 2012) ("Obviousness requires ... walk[ing] a tightrope blindfolded (to avoid hindsight}-an enterprise best pursued with the safety net of objective evidence.") This is not a case where the prima facie case is so strong that it controls the obviousness determination. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007). We thus reverse the rejection of claim 1 and its dependent claims. In re Fritch, 972 F.2d 1260, 1266 (Fed. Cir. 1992) ("[D]ependent claims are nonobvious if the independent claims from which they depend are nonobvious.") Because the arguments pertaining to the proposed combination of olmesartan medoxomil and amlodipine or its salt apply equally to claims 8-11, we likewise reverse the rejection of under 35 U.S.C. § 103 over claim 1 and its dependent claims 8-11. Conclusion of Law The preponderance of the evidence of record does not support the Examiner's conclusion that claims 1 and 8-11 would have been obvious. 14 Appeal 2016-003023 Application 11/484, 132 SUMMARY We reverse the rejection of all claims. REVERSED 15 Copy with citationCopy as parenthetical citation