Ex Parte Schmitz et al

Patent Trial and Appeal BoardOct 18, 2016

11045648 (P.T.A.B. Oct. 18, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 111045,648 01/28/2005 20529 7590 10/20/2016 NATH, GOLDBERG & MEYER Joshua Goldberg 112 South West Street Alexandria, VA 22314 FIRST NAMED INVENTOR Harold H. Schmitz 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. Ml34-US 3578 EXAMINER FINN, MEGHAN R ART UNIT PAPER NUMBER 1629 NOTIFICATION DATE DELIVERY MODE 10/20/2016 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): USPTO@nathlaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte HAROLD H. SCHMITZ, CATHERINE L. KWIK-URIBE, MARK A. KELM, and JOHN F. HAMMERSTONE, JR. 1 Appeal2014-001935 Application 11/045,648 Technology Center 1600 Before DEMETRA J. MILLS, FRANCISCO C. PRATS, and JOHN G. NEW, Administrative Patent Judges. PRATS, Administrative Patent Judge. DECISION ON APPEAL This appeal under 35 U.S.C. Â§ 134(a) involves claims to methods of inducing vasorelaxation in human subjects suffering from hypertension. The Examiner rejected the claims for obviousness. We have jurisdiction under 35 U.S.C. Â§ 6(b). We affirm. STATEMENT OF THE CASE The sole rejection before us for review is the Examiner's rejection of claims 1-6, 12-18, and 22 under 35 U.S.C. Â§ 103(a) for obviousness over Bruyne2 and Schnackenberg.3 Ans. 2-5. 1 Appellants state that the "patent application in the case appealed is owned by Mars, Incorporated, who is the real party in interest." Br. 3. Appeal2014-001935 Application 11/045,648 Claim 1 is representative of the appealed claims, and reads as follows (Br. 23): 1. A method of inducing vasorelaxation in a subject suffering from hypertension comprising administering to the subject, as a regimen, a composition consisting of an effective amount to induce vasorelaxation of an A-type procyanidin composed of n monomeric units of the formula: OH OH wherein (i) the monomeric units are connected via interflavan lirJ<:ages 4~6 and/or 4~8; (ii) at least two of the monomeric units are additionally linked by an A-type interflavan linkage (4~8; 2~0~7) or (4~6; 2~0~7); (iii) n is 2 to 12; or a pharmaceutically acceptable salt thereof, and wherein the subject is a human. 2 Tess De Bruyne et al., Biological Evaluation of Proanthocyanidin Dimers and Related Polyphenols, 62 J. Nat. Prod. 954-958 (1999) ("Bruyne"). 3 Christine G. Schnackenberg and Christopher S. Wilcox, Two-Week Administration ofTempol Attenuates Both Hypertension and Renal Excretion of 8-Iso Prostaglandin F2a, 33 Hypertension 424--428 (1999) (''Schnackenberg"). 2 Appeal2014-001935 Application 11/045,648 OBVIOUSNESS The Examiner's Position Appellants do not present separate arguments as to any of the claims subject to this ground of rejection. Accordingly, we limit our analysis to claim 1. See 37 C.F.R Â§ 41.37(c)(l)(iv). The Examiner cited Bruyne as disclosing that the procyanidin Al dimer and procyanidin A2 dimer, both encompassed by the formula set forth in claim 1, were tested for superoxide scavenging activity, and both exhibited "good activity." Ans. 4 (citing Bruyne 955). The Examiner conceded that Bruyne differs from claim 1 in that the reference did "not teach treatment of hypertension, however." Id. To address that deficiency, the Examiner found that Schnackenberg "teaches that administration of a superoxide scavenger reduces blood pressure and teaches that their study suggests a role for oxygen radicals in maintenance of hypertension (see abstract)." Id. The Examiner found that, although Bruyne did not test humans as required by claim 1, "spontaneously hypertensive rats are commonly used as an animal [model] for hypertensive treatments that are designed to treat humans. They further teach that hypertensive patients have higher levels of superoxide present compared to normotensive patents (page 424, column 1, paragraph l)." Id. Based on the references' teachings, the Examiner concluded that an ordinary artisan would have considered it obvious to use the A 1 and A2 dimer procyanidins described in Bruyne to treat hypertension, "because of their activity as superoxide scavengers and there is a reasonable expectation of success because they have been shown to have good activity as 3 Appeal2014-001935 Application 11/045,648 superoxide scavengers and there is a known link between superoxide scavengers and treatment of hypertension." Id. Analysis As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992): [T]he examiner bears the initial burden ... of presenting a primafacie case ofunpatentability .... After evidence or argument is submitted by the applicant in response, patentability is determined on the totality of the record, by a preponderance of evidence with due consideration to persuasiveness of argument. We adopt the Examiner's findings of fact and reasoning regarding the scope and content of the prior art as set out in the Final Action, discussed above, and in the Examiner's Answer. Appellants' arguments do not persuade us that a preponderance of the evidence fails to support the Examiner's prima facie case of obviousness as to representative claim 1. Claim 1 is directed to a method of inducing vasorelaxation in a human subject suffering from hypertension. Br. 23. The sole step required by claim 1 is the administration of a procyanidin compound having a formula undisputedly encompassing the procyanidin A 1 and A2 dimers. As the Examiner found, Bruyne discloses that the procyanidin A 1 and A2 dimers exhibit "good" superoxide scavenging activity. Bruyne 955 ("The doubly linked proanthocyanidins Ai [compound] (8) and A2 [compound] (9) also showed a good activity, although they were not as potent as procyanidins B2 or Bs."). Although Bruyne does not describe administering those compounds to treat hypertension as required by claim 1, Schnackenberg, as the Examiner found, describes a study in which spontaneously hypertensive rats (SHR) 4 Appeal2014-001935 Application 11/045,648 were treated with a superoxide dismutase mimetic known as "tempol." Schnackenberg 424. Schnackenberg discloses that, "[b ]ecause long-term administration of a superoxide scavenger reduces blood pressure and oxidative stress in vivo, this study suggests a role for oxygen radicals in the maintenance of hypertension in SHR." Id. Schnackenberg summarizes its findings as follows: In conclusion, this study provides evidence that the SHR is a model of oxidative stress in vivo. The finding that a superoxide dismutase mimetic reduces blood pressure and oxidative stress in vivo suggests that oxygen radicals may be important in the long-term regulation of blood pressure in SHR. Although there are limitations in extrapolating data from the anesthetized state to the conscious state, this study provides a rational basis for a novel form of antihypertensive therapy based on tempo! or similar agents. Such therapy may correct the complications created by hypertension associated with oxidative stress. Id. at 427 (emphasis added). Thus, given Schackenberg's teaching that the superoxide scavenger tempol and "similar agents" would be useful for treating hypertension (id.), and given Bruyne's teaching that the procyanidin Al and A2 dimers exhibit "good" superoxide scavenging activity (Bruyne 955), we agree with the Examiner that an ordinary artisan would have had an adequate reason for administering procyanidin Al and A2 dimers to human subjects suffering from hypertension, as well as a reasonable expectation of success in the therapeutic effect of that administration. Appellants' arguments do not persuade us to the contrary. It might be true, as Appellants argue (Br. 13, 14), that tempol is structurally different from the procyanidin A 1 and A2 dimers encompassed by claim 1 and described in Bruyne. However, given Schackenberg' s 5 Appeal2014-001935 Application 11/045,648 conclusion that the superoxide scavenger tempol and "similar agents" would be useful for treating hypertension (Schnackenberg 427), and given that, similar to tempol, the procyanidin Al and A2 dimers exhibit "good" superoxide scavenging properties (Bruyne 955), Appellants do not persuade us that, based on the structural differences between the compounds of Schnackenberg and Bruyne, an ordinary artisan lacked a reason to administer the procyanidin A 1 and A2 dimers to human subjects suffering from hypertension. We acknowledge, as Appellants argue (Br. 13-15), that Schnackenberg in its background section might have suggested an initial uncertainty as to the viability of the SHR as a model for studying oxidative stress. Nevertheless, based on the results of its study, and contrary to Appellants' assertion, Schnackenberg ultimately concluded that "the SHR is a model of hypertension and renal vasoconstriction associated with oxidative stress." Schnackenberg 424. We acknowledge, but are not persuaded by, Appellants' contention that certain passages in Schnackenberg would have led an ordinary artisan to appreciate that Schnackenberg could not conclusively determine whether oxidative stress contributed to hypertension in the SHR model. Br. 15-17 (citing Schnackenberg 427). As noted above, and as the Examiner contends (Ans. 16-17), Schnackenberg expressly teaches that the superoxide scavenger tempol and "similar agents" would be useful for treating hypertension. Schnackenberg 427. Indeed, even considering the caveat upon which Appellants focus, we agree with the Examiner that when read in full text, and in context, the following sentence advanced by Appellants as suggesting a lack of 6 Appeal2014-001935 Application 11/045,648 motivation actually supports the concept of administering superoxide scavengers to treat hypertension: "Although there are limitations in extrapolating data from the anesthetized state to the conscious state, this study provides a rational basis for a novel form of antihypertensive therapy based on tempo! or similar agents. Such therapy may correct the complications created by hypertension associated with oxidative stress." Id. (emphasis added). That Schnackenberg might not have conclusively shown that such methods would produce the therapeutic outcomes suggested by the results of its study does not demonstrate nonobviousness. See In re 0 'Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988) ("Obviousness does not require absolute predictability of success .... For obviousness underÂ§ 103, all that is required is a reasonable expectation of success."); accord, In re Kubin, 561 F.3d 1351, 1359-61 (Fed. Cir. 2009). We acknowledge, but are not persuaded by, Appellants' contention that an ordinary artisan would have understood, based on Onuma, 4 that tempol reduces blood pressure by increasing nitric oxide levels, rather than through superoxide scavenging, and that an ordinary artisan therefore would not have considered superoxide scavengers to be equivalently useful to Schnackenberg' s tempol. Br. 17-8. We first note that Onuma's October 2004 publication date appears to be after Appellants' asserted priority date of January 28, 2004, and Onuma, 4 Shizuka Onuma and Kazushige Nakanishi, Superoxide Dismustase Mimetic Tempo! Decreases Blood Pressure by Increasing Renal Medullary Blood Flow in Hyperinsulinemic-Hypertensive Rats, 53 Metabolism 1305-1308 (2004) ("Onuma"). 7 Appeal2014-001935 Application 11/045,648 therefore, technically is not prior art. See Spec. 1. We note also, as the Examiner points out (Ans. 7-8), that Onuma actually suggests an interrelationship between tempol's superoxide-scavenging properties and its hypertension-lowering activity. See Onuma 1305 ("Taken together, we suggest that tempol, by scavenging superoxide in the renal medulla, increases MBF [ medullary blood flow] through a NO-mediated mechanism in FFR [fructose-hypertensive rats]."). In addition, we agree with the Examiner (see, e.g., Ans. 19-20), that, even assuming the mechanism underlying tempol's hypertension-lowering action might have been unclear, that fact does not undercut Schnackenberg' s express teaching that the superoxide scavenger tempol and "similar agents" would be useful for treating hypertension (Schnackenberg 427), nor does it undercut the fact that an ordinary artisan would have understood from Bruyne that the procyanidin A 1 and A2 dimers encompassed by claim 1 were known to possess significant superoxide scavenging activity (Bruyne 955). Indeed, the primary functional property of tempol identified in Schnackenberg is that it is a superoxide dismutase mimetic, i.e., a superoxide scavenger. Schnackenberg 424. We, therefore, agree with the Examiner that Schnackenberg's disclosure of using agents "similar" to tempol for treating hypertension (id. at 427), would have been understood by an ordinary artisan to mean using other superoxide scavengers in that treatment. To the extent an ordinary artisan might not have expected every superoxide scavenger to function equivalently to tempol, as noted above, absolute predictability is not a prerequisite to a showing of obviousness. See O'Farrell, 853 F.2d at 903-04; Kubin, 561 F.3d at 1359-61. 8 Appeal2014-001935 Application 11/045,648 We acknowledge, but are not persuaded by, Appellants' contention that, because statins are not prescribed exclusively to treat hypertension, despite being known to reduce oxidative stress (as shown by Davignon5), an ordinary artisan would not have used superoxide scavengers to treat hypertension, based on the teachings in Schnackenberg. Br. 18-19. We first note that Davignon's 2005 publication date appears to be after Appellants' asserted priority date of January 28, 2004 and Davignon, therefore, is not prior art. See Spec. 1. We note also that Appellants do not direct us to any convincing evidence to support the assertion that statins have not been used as an exclusive agent for treating hypertension. Argument by counsel is not an adequate substitute for evidence. See In re Geisler, 116 F.3d 1465, 1471 (Fed. Cir. 1997). Moreover, as the Examiner points out (Ans. 8-11 ), both Davignon and Borghi6 teach that statins have an antihypertensive effect independent of lipid lowering, thus suggesting their use in treating hypertension. Davignon 34-35 (citing Borghi). More importantly, Appellants do not explain persuasively why an ordinary artisan would have viewed prior art disclosures relating to the treatment of hypertension with statins as undercutting or dissuading an ordinary artisan from following Schnackenberg's express teachings, discussed above, suggesting the use of superoxide scavengers in the treatment of hypertension. To that end, we 5 Jean Davignon and Lawrence A. Leiter, Ongoing clinical trials of the pleiotropic effects of statins, 1 Vascular Health and Risk Management 29--40 (2005) ("Davignon"). 6 C. Borghi et al., Use of statins and blood pressure control in treated hypertensive patients with hypercholesterolemia, 35 J. Cardiovasc. Pharmacol. 549-555 (2000) ("Borghi"). 9 Appeal2014-001935 Application 11/045,648 note that Appellants do not dispute the Examiner's assertion that statins are not superoxide scavengers. See Ans. 11. We are, therefore, not persuaded that Appellants have explained persuasively why any alleged therapeutic shortcomings relating to statins would have led an ordinary artisan to doubt the teachings, discussed above, in Schnackenberg. We acknowledge, but are not persuaded by, Appellants' contention that the Examiner's theory of obviousness is undercut by the fact that oxidative stress is a result, rather than a cause, of hypertension, as shown by the fact that the antioxidant vitamin E did not reduce hypertension, whereas inhibitors of angiotensin converting enzyme (ACE) effectively treat hypertension. Br. 19-20 (citing Miinzel). 7 As the Examiner points out (Ans. 12-13), Miinzel teaches that, unlike the A 1 and A2 procyanidin dimers described in Bruyne, vitamin E has only "limited" activity against superoxide. See Miinzel 1571. Appellants, therefore, do not persuade us that any alleged inability of vitamin E to impact hypertension would be predictive of Bruyne' s A 1 and A2 procyanidin dimers. More importantly, again, Appellants identify no specific teaching in Miinzel undercutting or calling into question Schnackenberg' s express teaching, discussed above, that compounds similar to the superoxide scavenger tempol would be useful for treating hypertension. 7 Thomas Miinzel, MD and John F. Keaney, Jr., MD, Are ACE Inhibitors a "Magic Bullet" Against Oxidative Stress?, 104 Circulation 1571-1574 (2001) ("Miinzel"). 10 Appeal2014-001935 Application 11/045,648 We acknowledge, but are unpersuaded by, Appellants' contention that, based on the Kwik-Uribe Declaration,8 an ordinary artisan would not have expected the superoxide scavenging concentrations of the A 1 and A2 procyanidin dimers taught in Bruyne to be achievable in the plasma of a human recipient, without conducting experimentation. Br. 20-21. In particular, we acknowledge that Bruyne discloses "ICso" concentrations for "superoxide scavenging activity" for the procyanidin dimers Al and A2 of about 14.7 ÂµMand 17.18 ÂµM, respectively. Bruyne 955 (Table 1). As the Examiner points out, however (Ans. 14-15), Bruyne performed an in vitro analysis, and Appellants do not direct us to persuasive evidence suggesting that the amount of superoxide anion used in Bruyne' s tests would be representative of the amount present in human plasma. We acknowledge also Dr. Kwik-Uribe's testimony that administration to fasted individuals of 1 mg/kg body weight of procyanidin A 1 dimer (Kwik-Uribe Deel. ,-i 8) resulted in mean plasma concentrations of 11.42, 67.43, 132.18, 137.14, and 113.88 nmols/L, at 0, 60, 120, 180 and 240 minutes post-consumption, respectively. Id. ,-i 10. Appellants do not explain persuasively, however, whether an ordinary artisan at the time of Appellants' invention would have been aware that those were the expected plasma concentrations, nor do Appellants explain persuasively why those concentrations would have been considered unsuitable for the therapeutic effect, discussed above, expressly suggested by Schnackenberg. To the extent that an ordinary artisan might have expected that experimentation would be required to determine a suitable 8 Declaration by Dr. Catherine Kwik-Uribe, dated June 17, 2008. 11 Appeal2014-001935 Application 11/045,648 dosage, Appellants do not dispute, nor do we discern error in, the Examiner's assertion (Final Action 5; Ans. 15), that an acceptable dosage would be determined routinely. In sum, for the reasons discussed, Appellants' arguments do not persuade us that the evidence of record fails to support the Examiner's prima facie case of obviousness as to claim 1. Because Appellants have not advanced secondary evidence of nonobviousness sufficient to outweigh the evidence of prima facie obviousness advanced by the Examiner, we affirm the Examiner's rejection of claim 1 over the cited references. Because they were not argued separately, claims 2-6, 12-18, and 22 fall with claim 1. SUMMARY For the reasons discussed, we affirm the Examiner's rejection of claims 1-6, 12-18, and 22 under 35 U.S.C. Â§ 103(a) for obviousness over Bruyne and Schnackenberg. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. Â§ l.136(a). AFFIRMED 12