In Re COUVARAS

• Court: Court of Appeals for the Federal Circuit
• Decided: June 14, 2023
• Docket: 22-1489
• Status: Published

Opinion

Case: 22-1489 Document: 45 Page: 1 Filed: 06/14/2023

United States Court of Appeals for the Federal Circuit ______________________

IN RE: JOHN L. COUVARAS, Appellant ______________________

2022-1489 ______________________

Appeal from the United States Patent and Trademark Office, Patent Trial and Appeal Board in No. 15/131,442. ______________________

Decided: June 14, 2023 ______________________

LAURENCE M. SANDELL, Mei & Mark LLP, Washington, DC, argued for appellant John L. Couvaras. Also repre- sented by GUANG-YU ZHU.

MAUREEN DONOVAN QUELER, Office of the Solicitor, United States Patent and Trademark Office, Alexandria, VA, argued for appellee Katherine K. Vidal. Also repre- sented by KAKOLI CAPRIHAN, THOMAS W. KRAUSE, AMY J. NELSON, FARHEENA YASMEEN RASHEED. ______________________

Before LOURIE, DYK, and STOLL, Circuit Judges. LOURIE, Circuit Judge. John L. Couvaras appeals from a decision of the U.S. Patent and Trademark Office Patent Trial and Appeal Board (“the Board”) affirming an Examiner’s rejection of the pending claims of U.S. Patent Application 15/131,442 Case: 22-1489 Document: 45 Page: 2 Filed: 06/14/2023

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as unpatentable as obvious in view of the asserted prior art. In re: John L. Couvaras, No. 2022-001037, 2021 WL 6124743 (P.T.A.B. Dec. 24, 2021) (“Decision”). For the fol- lowing reasons, we affirm. BACKGROUND The pending claims of the ’422 application literally re- cite methods of increasing prostacyclin release in the sys- temic blood vessels of a human with essential hypertension to improve vasodilation. That increased prostacyclin re- lease is achieved by co-administering two well-known types of antihypertensive agents: a GABA-a agonist and an An- giotensin II Receptor Blocker (“ARB”). In reality, the claims relate to combatting hypertension with known anti- hypertensive agents and claiming their previously unap- preciated mechanism of action. Representative claim 11 is presented below: 11. A method of increasing prostacyclin re- lease in systemic blood vessels of a human in- dividual with essential hypertension to improve vasodilation, the method comprising the steps of: providing a human individual expressing GABA-a receptors in systemic blood vessels due to essential hypertension; providing a composition of a dosage of a GABA-a agonist and a dosage of an ARB com- bined into a deliverable form, the ARB being an Angiotensin II, type 1 receptor antagonist; delivering the composition to the human indi- vidual’s circulatory system by co-administer- ing the dosage of a GABA-a agonist and the dosage of the ARB to the human individual orally or via IV; synergistically promoting increased release of Case: 22-1489 Document: 45 Page: 3 Filed: 06/14/2023

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prostacyclin by blockading angiotensin II in the human individual through the action of the dosage of the ARB to reduce GABA-a re- ceptor inhibition due to angiotensin II pres- ence during a period of time, and activating the uninhibited GABA-a receptors through the action of the GABA-a agonist dur- ing the period of time; and relaxing smooth muscle of the systemic blood vessels as a result of increased prostacyclin release. J.A. at 981–82 (emphases added). Other independent claims recite similar methods but state that the GABA-a receptors are expressed in smooth muscle and the endothe- lium. Id. at 984–85. Dependent claims include limitations drawn to dosing amounts and time-release formulations, and those drawn to relaxing smooth muscle through in- creased prostacyclin release as well as reducing blood pres- sure due to said relaxation. Id. at 982–87. All of the claims stand or fall based on the arguments presented and evalu- ated here. During prosecution, Couvaras conceded that GABA-a agonists and ARBs “have been known as essential hyper- tension treatments for many, many decades.” J.A. at 998. The Examiner agreed, citing ten references establishing that GABA-a agonists and ARBs lower blood pressure, and thereby treat hypertension. The Examiner also found that the claimed results of the compounds’ administration (i.e., increased prostacyclin release, activation of uninhibited GABA-a receptors, and smooth muscle relaxation) were not patentable because they naturally flowed from the claimed administration of the known antihypertensive agents. Id. at 1011–18. Couvaras appealed to the Board, asserting that the prostacyclin increase was unexpected, and therefore Case: 22-1489 Document: 45 Page: 4 Filed: 06/14/2023

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should be patentable. Couvaras also asserted that objective indicia overcame any existing prima facie case of obvious- ness. Unpersuaded, the Board affirmed the rejection. De- cision at *9. In particular, the Board held that the claimed result of an increased prostacyclin release was inherent in the obvious administration of the two known antihyperten- sion agents. Id. at *3–4, *7. The Board also found that Couvaras’s objective indicia arguments did not overcome the prima facie case of obviousness, namely, because no ev- idence existed to support a finding of any objective indi- cium. Id. at *4–9. Couvaras appealed the Board’s decision. We have ju- risdiction under 28 U.S.C. § 1295(a)(4)(A) and 35 U.S.C. § 141(a). DISCUSSION We review the Board’s legal determinations de novo, In re Elsner, 381 F.3d 1125, 1127 (Fed. Cir. 2004), and the Board’s factual findings for substantial evidence, In re Gartside, 203 F.3d 1305, 1316 (Fed. Cir. 2000). A finding is supported by substantial evidence if a reasonable mind might accept the evidence as adequate to support the find- ing. Consol. Edison Co. v. NLRB, 305 U.S. 197, 229 (1938). Couvaras raises several issues on appeal. First, Cou- varas contends that the Board erred in affirming that a skilled artisan would have had a motivation to combine the art asserted by the Examiner. Second, Couvaras contends that the claimed mechanism of action was unexpected, and that the Board erred in discounting its patentable weight by deeming it simply inherent in the claimed method. Third, Couvaras contends that the Board erred in weighing objective indicia of nonobviousness. We address these Case: 22-1489 Document: 45 Page: 5 Filed: 06/14/2023

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arguments in turn. 1 I Couvaras contends that the Board erred in affirming that a skilled artisan would have had a motivation to com- bine the prior art as asserted by the Examiner. Couvaras also asserts that the Board failed to address whether or not a skilled artisan would have had a reasonable expectation of success. As explained by the Examiner and affirmed by the Board, “[i]t is prima facie obvious to combine two composi- tions 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.” Decision at *3 (quoting In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980)). Couvaras does not challenge that the two types of active agents recited in the claims, GABA-a agonists and ARBs, were known. See, e.g., Appellant’s Br. at 9 (“The use of ARBs has been known for more than 30 years.”); id. at 4 (“GABA has been known for more than 65 years”); see also Oral Arg. at 13:27–13:40, https://oralargu- ments.cafc.uscourts.gov/default.aspx?fl=22-1489_0503202 3.mp3 (referring to GABA-a agonists and ARBs as “super well-known compounds”). Nor does Couvaras challenge that GABA-a agonists and ARBs were known to be useful for the same purpose—alleviating hypertension. See, e.g., Appellant’s Br. at 8 (conceding the “undisputed, basic prop- osition that GABA agonists are effective in treating hyper- tension in both animals and humans” and that “[t]here is no dispute that such uses of GABA have been known for 65

1 Couvaras also asserted that the Board violated the Administrative Procedure Act by relying on an obviousness rationale that was disavowed by the Examiner. Couvaras has since withdrawn this issue on appeal; thus, we need not address it here. See Appellant’s Reply Br. at 4 n.2. Case: 22-1489 Document: 45 Page: 6 Filed: 06/14/2023

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years”); id. at 8–9 (conceding the “undisputed, basic propo- sition that oral administration of ARBs are known to treat hypertension” and that “[t]here is no dispute that ARBs have been known and used for such purposes for more than 30 years”). The Board was correct that this fact alone can serve as a motivation to combine because “the idea of com- bining [these compounds] flows logically from their having been individually taught in the prior art.” Kerkhoven, 626 F.2d at 850. Couvaras suggests that this reasoning is too generic to support finding a motivation to combine in the clinical con- text under Cardiac Pacemakers v. St. Jude Medical, 381 F.3d 1371 (Fed. Cir. 2004). We do not agree. In Cardiac Pacemakers, it was undisputed that, before the work of the inventor, there was no device capable of treating the condi- tions of interest. Here, however, the opposite is true. It is undisputed that, before the work of Couvaras, the antihy- pertensive agents recited in the claims existed and were known to treat hypertension. Couvaras further concedes that the prior art teaches the combination of ARBs with other antihypertensive agents to improve treatment. Appellant’s Br. at 16. In par- ticular, the Board took note of the Examiner’s reliance on the prior art Kjeldsen 2 reference, which teaches not only the use of ARBs “in combination with other classes of anti- hypertensive agents to lower blood pressure,” but also that various guidelines “acknowledge the need for multiple- drug therapy in many patients to adequately lower blood pressure.” Decision at *3; J.A. at 1473. The motivation to combine was thus not a general motivation to cure

2 S.E. Kjeldsen et al., Targeting the renin-angioten- sin system for the reduction of cardiovascular outcomes in hypertension: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, 10 EXPERT OP. EMERGING DRUGS, 729 (2005); J.A. at 1472–89. Case: 22-1489 Document: 45 Page: 7 Filed: 06/14/2023

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hypertension, but, rather, the motivation to create a par- ticular cure by co-administering ARBs with another class of known antihypertensive agents as instructed by Kjeld- sen. Couvaras further asserts that, even if there had been a motivation to co-administer two hypertension treatments, such a motivation would fail to identify a “finite number of identified, predictable solutions” as required by KSR Inter- national Co. v. Teleflex Inc., 550 U.S. 398, 402 (2007). See Appellant’s Br. at 29 n.12. We do not agree. First, Cou- varas makes this argument in a footnote, and “[a]rguments raised only in footnotes [] are waived.” Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1294 (Fed. Cir. 2012). Sec- ond, while Couvaras argues that there was a “substantial number of hypertension treatment agent classes” that could be considered for such a combination, he does not cite any evidence supporting this assertion. The Board’s con- clusion that there was a motivation to combine, on the other hand, was supported by substantial evidence and properly aligns with the tenets of KSR. Finally, Couvaras asserts that the Board erred in fail- ing to address reasonable expectation of success. Appel- lant’s Br. at 25–29. But Couvaras did not present any arguments against the Examiner’s findings of a reasonable expectation of success when he appealed the Examiner’s Final Rejection to the Board. See J.A. at 1139–76. Absent exceptional circumstances, see In re DBC, 545 F.3d 1373, 1379–80 (Fed. Cir. 2008), we generally do not consider ar- guments that the applicant failed to present to the Board, In re Watts, 354 F.3d 1362, 1367–68 (Fed. Cir. 2004). Here, no such exceptional circumstances exist. It was not an er- ror for the Board to fail to make express findings regarding that prong of the obviousness analysis. II Couvaras next asserts that the Board downgraded the patentable weight of limitations drawn to the Case: 22-1489 Document: 45 Page: 8 Filed: 06/14/2023

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antihypertensive agents’ mechanism of action by deeming them to be merely inherent. According to Couvaras, even if the recited mechanism of action is, effectively, inherent in the claimed administration of a GABA-a agonist and an ARB, that mechanism, specifically the increased release of prostacyclin, was unexpected. Couvaras contends that be- cause the increased prostacyclin release was unexpected, under Honeywell International Inc. v. Mexichem Amanco Holdings S.A., it cannot be dismissed as having no patent- able weight due to inherency. 865 F.3d 1348, 1355 (Fed. Cir. 2017). But Honeywell held that “unexpected proper- ties may cause what may appear to be an obvious composi- tion to be nonobvious,” not that unexpected mechanisms of action must be found to make the known use of known com- pounds nonobvious. Id. (emphasis added). Here, Couvaras attempts to claim a mechanism of ac- tion that naturally flows from the co-administration of two known antihypertensive agents. See Oral Arg. at 03:18– 03:39 (acknowledging that Appellant has not argued “spe- cifically against that,” i.e., that the claimed co-administra- tion will result in the claimed mechanism of action); id. at 03:56–04:06 (answering a question as to whether or not Ap- pellant agrees that the claimed steps are “necessarily” the mechanism by stating “Yeah, this is the mechanism by which it works”). In the prostacyclin mechanism, the two antihypertension agents exert the same ultimate result as the two separate compounds were known to effect: a de- crease in blood pressure. We have previously held that “[n]ewly discovered results of known processes directed to the same purpose are not patentable because such results are inherent.” In re Montgomery, 677 F.3d 1375, 1381 (Fed. Cir. 2012) (citation omitted); see also In re Huai-Hung Kao, 639 F.3d 1057, 1070–71 (Fed. Cir. 2011) (holding that a “food effect” was obvious because the effect was an inherent property of the composition). While mechanisms of action may not always meet the most rigid standards for inher- ency, they are still simply results that naturally flow from Case: 22-1489 Document: 45 Page: 9 Filed: 06/14/2023

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the administration of a given compound or mixture of com- pounds. Reciting the mechanism for known compounds to yield a known result cannot overcome a prima facie case of obviousness, even if the nature of that mechanism is unex- pected. We therefore agree with the Board that the recitation of various mechanistic steps in the pending claims are in- sufficient to overcome the prima facie obviousness of the claimed methods. III Lastly, Couvaras contends that the Board erred in weighing objective indicia of nonobviousness. The Board’s findings regarding objective indicia involve questions of fact that we review for substantial evidence. Gartside, 203 F.3d at 1316. Couvaras contends that the Board found that the “main, beneficial, medical result” of the claimed invention, namely, an increase in prostacyclin, was “unexpected.” See Decision at *7 (holding, at least, that Couvaras had as- serted this to be the case). According to Couvaras, the Board erred by nonetheless giving no weight to the unex- pected results indicium of nonobviousness. But, as dis- cussed above, recitation of a mechanism of action, even an unexpected one, does not necessarily overcome a prima fa- cie case of obviousness. To establish unexpected results, Couvaras would have needed to show that the co-admin- istration of a GABA-a agonist and an ARB provided an un- expected benefit, such as, e.g., better control of hypertension, less toxicity to patients, or the ability to use surprisingly low dosages. We agree with the Board that no such benefits have been shown, and therefore no evidence of unexpected results exist. Couvaras also asserts various other errors in identify- ing and weighing additional indicia of nonobviousness, in- cluding teaching away, failure of others, and the length of Case: 22-1489 Document: 45 Page: 10 Filed: 06/14/2023

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time that elapsed between the initial discovery of GABA-a agonists and ARBs being useful in treating hypertension and Couvaras’s claimed method of co-administering these types of compounds. For example, Couvaras asserts that the prior art, in particular, Liu 3, teaches away from the combined administration recited in the claims. As ex- plained by Couvaras, Liu purportedly includes data that show a lesser reduction in blood pressure following co-ad- ministration of an ACE inhibitor with γ-aminobutyric acid (GABA), a GABA-a agonist, compared to administration of an ACE inhibitor alone after 24 hours. Appellant’s Br. at 49–50 (citing J.A. at 1198, ¶7.f.ii-iii). But that is insuffi- cient to establish a teaching away. As the Board correctly noted, Liu evaluated ACE inhibitors co-administered with GABA in rats, not ARBs co-administered with GABA-a ag- onists in humans, as claimed. Even Couvaras admits that ACE inhibitors and ARBs “operate through different bio- logical mechanisms.” Appellant’s Br. at 48. The Board was therefore correct to find that Liu did not teach away from the claimed method. Similarly, Couvaras asserts that there was a failure of others to increase prostacyclin release, but the evidence that Couvaras cites involves merely “experimenting with angiotensin II levels.” Appellant’s Br. at 52. As the Board correctly noted, however, an investigation into the impact of angiotensin II is not a failure to find a solution for an inability to increase prostacyclin release or a failure of the claimed method. Decision at *8–9. The Board thus properly found that the purported failure to achieve pros- tacyclin increase through pursuing an unrelated goal did not establish the nonobviousness of this claimed method.

3 C.F. Liu et al., Antihypertensive Effects of Lactoba- cillus-Fermented Milk Orally Administered to Spontane- ously Hypertensive Rats, 59 J. AGRIC. FOOD CHEM. 4537 (2011); J.A. at 1490–96. Case: 22-1489 Document: 45 Page: 11 Filed: 06/14/2023

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Couvaras also asserts that the length of time between when the two antihypertensive classes of compounds re- cited in the claims were first discovered and when Cou- varas first thought to combine them also serves as an objective indicium of the claims’ nonobviousness under Leo Pharmaceutical Products, Ltd. v. Rea, 726 F.3d 1346 (Fed. Cir. 2013). We disagree. In Leo Pharmaceutical, we held that the “length of the intervening time between the publi- cation dates of the prior art and the claimed invention can also qualify as an objective indicator of nonobviousness.” Id. at 1359 (emphasis added). However, that followed from a finding that the record established evidence of a long-felt but unsolved need and failure of others. Here, such indicia of nonobviousness do not exist. Ra- ther, as the Board correctly held, there was no long-felt, unmet need, given the admitted availability of antihyper- tensive agents and a lack of evidence that the available an- tihypertensive treatments were somehow insufficient to meet patients’ needs. Decision at *5. As discussed above, there is also insufficient evidence to establish a failure of others. The Board was therefore correct to note that the mere length of time that the prior art knew GABA-a ago- nists and ARBs to be antihypertensive agents “is not per- suasive of the unobviousness of the combination of their teachings, absent evidence that, notwithstanding knowledge of the references, the art tried and failed to solve the problem.” Decision at *4 (quoting In re Wright, 569 F.2d 1124, 1127 (CCPA 1977)). As no such evidence of fail- ure exists here, the Board’s conclusion that objective indi- cia did not overcome the prima facie case of obviousness was supported by substantial evidence. CONCLUSION We have considered Couvaras’s remaining arguments and do not find them persuasive. For the foregoing rea- sons, we affirm the Board’s final written decision. AFFIRMED