Catherine Llorens-Cortes et al.

Patent Trials and Appeals BoardSep 4, 2019

14367408 - (D) (P.T.A.B. Sep. 4, 2019)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 14/367,408 06/20/2014 Catherine Llorens-Cortes 127489.00004 2314 29880 7590 09/04/2019 FOX ROTHSCHILD LLP PRINCETON PIKE CORPORATE CENTER 997 LENOX DRIVE BLDG. #3 LAWRENCEVILLE, NJ 08648 EXAMINER CABRAL, ROBERT S ART UNIT PAPER NUMBER 1618 NOTIFICATION DATE DELIVERY MODE 09/04/2019 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): ipdocket@foxrothschild.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte CATHERINE LLORENS-CORTES, YANNICK MARC, JI GAO-DESLIENS, FABRICE BALAVOINE, and LIONEL SEGARD __________ Appeal 2019-001625 Application 14/367,4081 Technology Center 1600 __________ Before DONALD E. ADAMS, RYAN H. FLAX, and RACHEL H. TOWNSEND, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to an oral pharmaceutical composition, which have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. STATEMENT OF THE CASE “Hypertension is an arterial disorder whose causes generally remain unknown.” (Spec. 1.) “Antihypertensive agents have been widely used for the treatment of hypertension and related diseases and conditions.” (Id.) 1 Appellants identify the real party in interest as Quantum Genomics and Institut National de la Santé et de la Recherche Médicale. (Appeal Br. 3.) Appeal 2019-001625 Application 14/367,408 2 However, blood pressure “control and its concomitant risk factors in the general population remains difficult to control.” (Id.) Appellants’ invention is directed to a composition to address the foregoing problem. (Id.) Claims 1, 3, 5, 7, 8, and 11–15 are on appeal. Claim 1 is representative and reads as follows: 1. An oral pharmaceutical composition comprising, in at least one pharmaceutically acceptable support or vehicle, a combination of (3S,3S’) 4,4’-disulfanediylbis(3-aminobutane 1- sulfonic acid) or a pharmaceutically acceptable salt or solvate thereof and a second active ingredient selected from the group consisting of enalapril, valsartan, and losartan. (Appeal Br. 16.) The following grounds of rejection by the Examiner are before us on review: Claims 1, 3, and 11–15 under 35 U.S.C. § 103 as unpatentable over Bodineau2 and Llorens-Cortes.3 Claims 5, 7, and 8 under 35 U.S.C. § 103 as unpatentable over Bodineau, Llorens-Cortes, Villaponteau,4 and Fournie-Zaluski.5 2 Laurence Bodineau et al., Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure: A New Strategy for Treating Hypertension, 51 Hypertension 1318–1325 (2008). 3 Llorens-Cortes et al., US 6,340,708 B1, issued Jan. 22, 2002. 4 Bryant Richard Villaponteau, US 2008/0014187 A1, published Jan. 17, 2008. 5 Fournie-Zaluski et al., US 2006/0135602 A1, published June 22, 2006. Appeal 2019-001625 Application 14/367,408 3 DISCUSSION Prima Facie Case of Obviousness of Claim 1 The Examiner finds that Bodineau teaches oral administration of RB150, which is (3S,3S’) 4,4’-disulfanediylbis(3-aminobutane 1-sulfonic acid) and is an inhibitor of aminopeptidase A (“APA”), but not in conjunction with a second active selected from enalapril, valsartan, and losartan. (Final Action 3.) The Examiner finds that adding a second active selected from enalapril, valsartan, and losartan would have been obvious from the disclosure of Llorens-Cortes. (Id. 3–4.) The Examiner finds that Bodineau teaches that RB150 is a dimer of EC33, which is a selective aminopeptidase APA inhibitor generated by creating a disulfide bond, which dimerization “allows [the RB150] prodrug to cross the blood-brain barrier when administered by systemic route.” (Id.at 3.) The Examiner explains that Llorens-Cortes teaches a pharmaceutical composition for lowering arterial blood pressure that includes EC33 that can be administered orally, and which composition can be used “in addition to the blockers of the systemic renin/angiotensin system” such as enaprilate6 and losartan. (Id. at 3–4.) Llorens-Cortes suggests, says the Examiner, “that cerebral APA plays a predominant role in regulating arterial pressure compared with peripheral APA, which appears to have a lesser contribution.” (Id. at 4.) The Examiner explains that Bodineau “concludes that ‘RB150 may be the prototype of a new claim of centrally active antihypertensives.’” (Id. at 3.) 6 There is no dispute that enaprilate is the metabolite of enalapril. (See, e.g., Final Action 4.) Appeal 2019-001625 Application 14/367,408 4 The Examiner finds that one of ordinary skill in the art would have been motivated to use RB150 in place of EC33 in a composition for oral administration that also includes losartan (or enaprilate) in light of Llorens- Cortes’ teaching that cerebral APA play a predominant role in regulating arterial pressure compared with peripheral APA, and because it is prima facie obvious to combine two compositions taught to be useful for the same purpose into a single composition. (Id. 4–5.) We agree with the Examiner’s factual findings and conclusion that claim 1 is prima facie obvious. “The prima facie case is a procedural tool, and requires that the examiner initially produce evidence sufficient to support a ruling of obviousness.” In re Kao, 639 F.3d 1057, 1066 (Fed. Cir. 2011). The Examiner has done that as discussed below. Bodineau teaches that the dimer of EC33, known as RB150, delivered orally reduces blood pressure and that this dimerized EC33 crosses the blood-brain barrier inhibiting brain APA activity. (Bodineau 1318 Abstract, 1323 (noting the oral administration of RB150 results in generation of EC33 in the brain blocking the formation of angiotensin III (“ANGIII”)(which is one of the main effector peptides of the brain renin-angiotensin system, exerting tonic stimulatory control over blood pressure in hypertensive rats)). Llorens-Cortes teaches that a composition that can “oppose an angiotensin III-induced increase in [arterial] pressure” (Llorens-Cortes 2:4–7), such as EC33 delivered intracerebroventricularly (i.c.v.)7, “can be advantageously 7 Llorens-Cortes indicates that cerebral APA plays a predominant role in regulating arterial pressure compared with peripheral APA (Id. at 10:49–54.) Llorens-Cortes teaches that while EC33 has “significant inhibitory activity with regard to APA” (id. at 2:55–56), the activity at decreasing arterial Appeal 2019-001625 Application 14/367,408 5 used in addition to the blockers of the systemic renin/angiotensin system” such as losartan or enaprilate (id. at 3:33–39). Llorens-Cortes also teaches, as the Examiner indicates, that a formulation that is orally administrable is contemplated. (Id. at 3:10–14.) While Llorens-Cortes notes that EC33 used i.c.v. provides arterial pressure regulation by inhibiting ANGIII production, Bodineau teaches that EC33 can be delivered across the blood-brain barrier by providing an oral dose of the dimer of EC33, RB150. Furthermore, as the Examiner explained “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. . . . [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980). In light of the foregoing, we agree with the Examiner that it would have been obvious to use RB150 in an oral composition in combination with losartan or enaprilate with a reasonable expectation that the combination product could be used in treating hypertension. Appellants’ argument that because Bodineau describes an oral composition of RB150 only, it does not provide motivation for an oral composition having both RB150 and enalapril, valsartan, or losartan (Appeal Br. 8) is not persuasive as the rejection relies on the combined teachings Llorens-Cortes and Bodineau for the reason to provide a combination pressure is significant when EC33 is injected intracerebroventricularly as compared to when administered intravenously (id. at 10:25–48). Appeal 2019-001625 Application 14/367,408 6 composition. Llorens-Cortes was relied upon for the suggestion to provide a combination therapeutic. Appellants’ argument that because Llorens-Cortes describes effects of EC33 via i.c.v. and intravenous injections and not oral administration and teaches that EC33 i.c.v. provides the inhibitory effect and does not describe a combination composition that includes enalapril or losartan, one of ordinary skill in the art would not have been motivated to use RB150 in an oral composition with enalapril or losartan (Appeal Br. 8) is also not persuasive. The argument does not consider the import of Bodineau’s teaching that RB150 can be provided orally, which will provide for EC33 to cross the blood-brain barrier and achieve inhibition of brain APA activity and reduce blood pressure. (See, e.g., Bodineau 1323.)8 It also fails to take into consideration that irrespective of whether Llorens-Cortes teaches a combination therapeutic (see Reply Br. 5–6), the fact that the reference teaches that EC33 can be used in conjunction with enalapril or losartan in reducing blood pressure and that Bodineau teaches RB150 can be provided orally and result in EC33 in the brain, is itself sufficient to suggest a prima facie combination of the RB150 with enalapril or losartan. Both RB150 and enalapril and losartan are known in the art to be used to lower blood pressure. Thus, their combination into a single formulation is prima facie obvious. Kerkhoven, 626 F.2d at 850. We disagree that the Examiner’s rejection was based impermissibly only on hindsight. (Appeal Br. 9.) “Any judgment on obviousness is in a 8 It is for this reason too, that we disagree with Appellants that the “Examiner disregarded the fact that EC33 and RB150 are not the same compounds” (Reply Br. 5). Appeal 2019-001625 Application 14/367,408 7 sense necessarily a reconstruction based upon hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971). We also do not find persuasive Appellants’ argument that, because “it was known in the art that a reducing agent or environment can break . . . a disulfide bond,” that one of ordinary skill in the art would not have had a reasonable expectation of success of combining the dimer of EC33 that is generated by creating a disulfide bond with either one of enalapril or losartan (Appeal Br. 9–10, Reply Br. 5). In making an obviousness determination, one “can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). As Appellants note, it was known in the art that a reducing agent or environment can break a disulfide bond, and it would have taken no more than ordinary skill to have appreciated that fact when combining enalapril or losartan with RB150 is such a way as to avoid such an environment in making the combined formulation. For all of the foregoing reasons, we also disagree with Appellants’ argument that the Examiner has failed to provide an articulated reasoning with a rational underpinning to establish claim 1 is prima facie obvious from the teachings of Bodineau and Llorens-Cortes or improperly relied on hindsight reasoning. (Appeal Br. 13–14.) Appeal 2019-001625 Application 14/367,408 8 Unexpected Results Appellants contend that the Examiner’s prima facie case is rebutted by unexpected results. (Appeal Br. 10–12.) We disagree for the reasons that follow. In the Declaration of Fabrice Balavoine, Ph.D., dated October 25, 2017, it is explained that RB150 targets a different receptor and system in the body than enalapril, valsartan, and losartan. (Balavoine Declaration ¶ 9.) Dr. Balavoine explains that because of the targeting of different receptors and systems, “one cannot expect any additivity or potentiation with such combination therapy.” (Id. ¶10.) Dr. Balavoine then describes the evidence in the Specification, and as provided in the Declaration, that demonstrates that a combination of RB150 and enalapril decreases blood pressure in a synergistic manner as compared to administration of those compounds alone, namely that “during the first two hours postdosing, the lowering effect observed with the combination therapy is clearly greater than the sum of the effects of each drug taken separately, which demonstrates that RB150 and enalapril act on BP levels in a synergistic manner, potentiating the effects of one by the other.” (Id. ¶ 11 (referring to Figure 1 of the Specification and Exhibit A of the Declaration.) We agree that the evidence Dr. Balavoine points to here demonstrates potentiation greater than the sum of the effects of each of those drugs taken individually, where such synergy would not be expected given that the drugs act on different systems in the body. However, we note that the claims are not limited to such a combination. Dr. Balavoine describes a similar “synergy” observation with respect to the combination of RB150 and losartan. (Id. ¶ 12 (referring to Exhibit B Appeal 2019-001625 Application 14/367,408 9 of the Declaration (“The lowering effect observed 2 hours post-dosing with the combination therapy (-20.8 mmHg) is clearly greater than the sum of the effects of each drug taken separately (-7.2 mmHg for losartan and -7.9 mmHg for RBI50), which demonstrates that RBI50 and losartan act on BP levels in a synergistic manner.”)).) We note, however, that unlike the combination of RB150 and enalapril, the synergistic result disappears after 4 hours. Thus, it is not clear that the synergism at 2 and 3 hours is a meaningful result. In order to outweigh a prima facie case of obviousness, evidence of unobviousness must show unexpected property of a significant aspect of the invention. In re Eli Lilly & Co., 902 F.2d 943, 947 (Fed. Cir. 1990) (citing In re Nolan, 553 F.2d 1261, 1267 (CCPA 1977)). Dr. Balavoine also contends that a lowering of blood pressure was observed with RB150 and valsartan alone “in a synergistic manner that was significantly improved over the administration of both RB150 and valsartan alone.” (Balavoine Declaration ¶ 11 (referring to Figure 4 of the Specification).) Notably, unlike the combination of RB150 and enalapril, Dr. Balavoine does not indicate that the lowering of blood pressure is greater than the sum of the effects of RB150 and valsartan taken separately, although this does appear to be the case at least 4 hours after dosing with 0.3 mg/kg of valsartan in combination with 100 mg/kg of RB150 and thereafter. (Spec. Figure 4.) We note, however, that the Specification demonstrates that valsartan at 1 mg/kg provides better results at lowering blood pressure at 1 and 2 hours postdosing than a combination of valsartan at 1 mg/kg with RB150 at 100 mg/kg (Figure 3) and it also demonstrates that valsartan at 0.3 mg/kg combined with RB150 at 100 mg/kg provides similar blood pressure lowering results postdosing at 2 hours compared to individual use of Appeal 2019-001625 Application 14/367,408 10 valsartan at 0.3 mg/kg and RB150 at 100 mg/kg (Figure 4). Dr. Balavoine does not address this evidence. Thus, while it may be the case that there is some evidence of synergistic effect with a combination of valsartan at 0.3 mg/kg and RB150 at 100 mg/kg, the evidence suggests that this is not a universal outcome for all combinations of this drug pairing. In re Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011) (“If an applicant demonstrates that an embodiment has an unexpected result and provides an adequate basis to support the conclusion that other embodiments falling within the claim will behave in the same manner, this will generally establish that the evidence is commensurate with [the] scope of the claims.”); In re Lindner, 457 F.2d 506, 508 (CCPA 1972) (“It is well established that the objective evidence of nonobviousness must be commensurate in scope with the claims.”). We note that Dr. Balavoine also explains that the blood pressure decrease was “achieved much more rapidly” with the co-administration of RB150 and valsartan and RB150 with losartan (just as it is with the coadministration of RB150 with enalapril). (Balavoine Declaration ¶ 13.) In particular, Dr. Balavoine states: Specifically, significant decreases were seen after 1 hour (enalapril + RB150), 2 hours (losartan + RB 150), 4 hours (valsartan + RB 150), compared to no significant decreases at any of 1, 2, or 4 hours after individual administration of any of RB 150, valspartan, lorsartan, and/or enalapril. (Id.) While Dr. Balavoine does not address Figure 3 of the Specification concerning administration of 1 mg/kg of valsartan and RB150 at 100 mg/kg, we note that the combination of 1 mg/kg of valsartan and RB150 at 100 mg/kg achieves a significant blood pressure decrease after 4 hours just as the combination of 0.3 mg/kg of valsartan and RB150 at 100 mg/kg does. However, it is not clear that this is a “significant” decrease “achieved more Appeal 2019-001625 Application 14/367,408 11 rapidly” compared to what would have been expected when administering a combination of 1 mg/kg of valsartan and RB150 at 100 mg/kg. Given that it was known these compounds address different mechanisms in lowering blood pressure and the evidence demonstrates that each compound administered separately achieves an increase in blood pressure lowering from time zero to 4 hours, we conclude one of ordinary skill in the art would have reasonably expected an increased benefit in lowering blood pressure at 4 hours when both compounds were used together as compared to the result when each compound is used individually, and the benefit does not seem to be beyond additive at any time period in Figure 3. Thus, the evidence is not commensurate in scope with the claim that does not recite a specific amount of valsartan combined with a specific amount of RB150. Moreover, it is not clear that the more rapid decrease observed after 2 hours with the combined losartan and RB 150 is a meaningful result to one of ordinary skill in the art where the reduction in blood pressure 4 hours postdosing with that combination is not synergistic and not significantly greater than the administration of losartan alone. Lilly, 902 F.2d at 947 (in order to outweigh a prima facie case of obviousness, evidence of unobviousness must show unexpected property of a significant aspect of the invention.). Appellants argue that the evidence of quick action discussed by Dr. Balavoine is not suggested by the prior art because Bodineau states the hypotensive effect with RB150 began 2 hours after administration. (Appeal Br. 12, Reply Br. 7.) While it is the case that Bodineau teaches the blood pressure lowering affect began 2 hours after administration (Bodineau 1321), Appellants evidence does not establish RB150 plus valsartan, which Appeal 2019-001625 Application 14/367,408 12 is a composition within the scope of the claims, achieves significant blood pressure lowering activity prior to 2 hours. Moreover, as just discussed, it is not clear that the quick action that is synergistic for the combination of losartan and RB150 is significant, where the combined activity is not synergistically maintained. Indeed, Appellants seem to indicate in their argument that it is the advantages of the quick action where the “significant hypotensive effect . . . is maintained in a satisfactory manner” that is the unexpected result rebutting any prima facie case of obviousness set forth by the Examiner. (Appeal Br. 11–12.) The evidence establishes that quick action that is also synergistic occurs with a combination of RB150 at 100 mg/kg and enalapril at 1 mg/kg. (Spec. Figure 1, Balavoine Declaration ¶ 13.) However, the claims are not so limited.9 9 We do not consider Appellants’ cited article and arguments based thereon submitted in the Reply Brief. “[T]he reply brief [is not] an opportunity to make arguments that could have been made in the principal brief on appeal to rebut the Examiner’s rejections, but were not.” Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative). Appellants have not demonstrated any specific Examiner findings presented for the first time in the Answer necessitating this specific new argument in rebuttal in the Reply Brief. Appellants’ suggestion that the Examiner’s position in maintaining the rejection is that “if any two agents have antihypertensive effect separately, it would be ‘logically’ obvious to combine them to obtain better therapeutic benefits” (Reply Br. 8) is a mischaracterization of the Examiner’s rejection. The Examiner states: “To make an oral composition comprising both RB 150 and enalapril or valsartan or losartan would follow logically from the oral compositions having been individually taught in the prior art” (Ans. 7), which is precisely the position taken in the Final Action (Final Action 2 (in rejecting the declaration evidence the Examiner states “the cited references teach and/or suggest the combination of components as discussed in the rejection maintained below”); Final Action 4 (“It would have been prima facie obvious to one of ordinary skill in the art to modify Appeal 2019-001625 Application 14/367,408 13 In light of the foregoing, we affirm the Examiner’s rejection of claim 1 under 35 U.S.C. § 103 as unpatentable over Bodineau and Llorens-Cortes. Claims 3, and 11–15 have not been argued separately and therefore fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv). Claims 5, 7, and 8 Appellants’ argument that claims 5, 7, and 8 are non-obvious rests on the arguments Appellants made regarding an alleged failure of Bodineau and Llorens-Cortes to render claim 1 obvious. (Appeal Br. 15.) For the reasons discussed, we disagree with Appellants that claim 1 is not rendered obvious by Bodineau and Llorens-Cortes. Thus, we affirm the Examiner’s rejection of claims 5, 7, and 8 under 35 U.S.C. § 103 as unpatentable over Bodineau, Llorens-Cortes, Villaponteau, and Fournie-Zaluski. SUMMARY We affirm the rejection of claims 1, 3, and 11–15 under 35 U.S.C. § 103 as unpatentable over Bodineau and Llorens-Cortes. the teaching of Bodineau et al. with Llorens-Cortes et al. One of ordinary skill in the art would find motivation to combine the references in that both references teaching compositions useful for treating hypertension that utilize the selective APA inhibitor, EC33. In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCP A 1980) (‘It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose)’”.) We do not find any substantial differences in the Examiner’s initial findings and the Examiner’s findings stated in the Answer that would warrant the new arguments presented in the Reply Brief for the first time, which arguments appear to be an attack of the prima facie case (although presented in the Reply Brief section addressing unexpected results) that should have been made in the appeal brief. Appeal 2019-001625 Application 14/367,408 14 We affirm the rejection of claims 5, 7, and 8 under 35 U.S.C. § 103 as unpatentable over Bodineau, Llorens-Cortes, Villaponteau, and Fournie- Zaluski 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