Because No One is Immune to the Law
July 20, 2023 - Intellectual Property, Litigation, Pharma, Biotech, United States

Obviousness in Drug Combinations – Unexpected Results Vs. Unexpected Mechanisms of Action

paperwork and pen

Ascertaining the differences between prior art and claims at issue requires interpreting the claim language and considering both the invention and the prior art references as a whole.[1] The Supreme Court emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art”[2] and discussed circumstances in which a patent might be determined to be obvious. An objective analysis for determining obviousness includes considering: (1) the scope and content of the prior art, (2) the differences between the prior art and the claims at issue, (3) the level of ordinary skill in the field of art, (4) and any objective indicia of non-obviousness.[3] Objective evidence of non-obviousness, or “secondary considerations,” includes evidence of commercial success, long-felt but unsolved needs, failure of others, and unexpected results.[4]

Pharmaceutical composition claims and method of treatment claims may often face obviousness rejections and validity challenges involving arguments that a claim feature (e.g., pharmacokinetic parameters or an effect of a therapeutic combination) is inherent. To establish inherency in an obviousness analysis, “the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art.”[5] In general, the burden to establish inherency in the obviousness context is high.

A prima facie case of obviousness for methods using a combination of known chemical compounds can be overcome if the combination yields unexpected results, such as a synergistic effect.[6] The precedential decision of In re Couvaras[7] contains cautions on the importance of distinguishing between unexpected results obtained with a combination of two known pharmaceuticals as opposed to an unexpected mechanism of action – if a claim merely recites a mechanism of action in a known use of a known compound (or a combination of compounds), the claim limitation is likely inherent and cannot be used to overcome a prima facie case of obviousness, even if the mechanism of action is previously unappreciated or surprising.


Inventor John Couvaras filed a patent application for combatting hypertension, with claims directed to methods of increasing the release of prostacyclin in blood vessels by co-administering two antihypertensive agents: (1) a gamma-aminobutyric acid-a (GABA-a) agonist and (2) an angiotensin II receptor blocker (ARB).[8] During prosecution of the application, Couvaras conceded that GABA-a agonists and ARBs “have been known as essential hypertension treatments for many, many decades.”[9] The examiner not only agreed, but also found that the results of the compounds’ administration (i.e., increasing prostacyclin release, activating uninhibited GABA-a receptors, and smooth muscle relaxation) were not patentable because they naturally flowed from the administration of known antihypertensive agents.[10]

Patent Trial and Appeal Board (“Board”)

Couvaras appealed to the Board, arguing that the mechanism of action recited in the claims, e.g., increasing prostacyclin release, was an unexpected result sufficient to overcome the prima facie case, and thus patentable. Unpersuaded, the Board affirmed the rejection, holding that the claimed result of increasing prostacyclin release was inherent in the obvious administration of the two known antihypertension agents.[11] In particular, the Board found that the increase in prostacyclin release was “simply a recitation of an inherent, but unknown, property of an otherwise obvious formulation” and that “identifying an inherent result of the combination of GABA and ARB compounds does not constitute a patentable invention unless there is also a showing that the newly discovered inherent result also provides an unexpected benefit.”[12]

Federal Circuit

Couvaras appealed to the Federal Circuit, in part arguing that because the increased prostacyclin release was unexpected it cannot be dismissed as having no patentable weight due to inherency, citing Honeywell International Inc. v. Mexichem Amanco Holdings S.A., 865 F.3d 1348, 1355 (Fed. Cir. 2017).[13] In rejecting Couvaras’ argument, the Federal Circuit noted that Honeywell “held that ‘unexpected properties may cause what may appear to be an obvious composition to be nonobvious,’ not that the unexpected mechanisms of action must be found to make the known use of known compounds nonobvious.”[14]

After addressing representative independent claim 11, the Federal Circuit noted that the dependent claims included limitations “drawn to dosing amounts and time-release formulations”[15] and that all of the claims stand or fall based on the analysis provided.[16]

The court further found that Couvaras attempted to claim a mechanism of action that naturally flows from the co-administration of two known antihypertensive agents – “the two antihypertension agents exert the same ultimate result as the two separate compounds were known to effect: a decrease in blood pressure.”[17] In quoting another Federal Circuit case, the court explained that “[n]ewly discovered results of known processes directed to the same purpose are not patentable because such results are inherent.”[18] Thus, even if the mechanisms of action are unexpected, they are still results that naturally flow from the administration of a mixture of compounds, and therefore, are inherent. Unfortunately, Couvaras did not show any benefit of the combination or that the ultimate result from administering the combination is different from that of individually administering the antihypertension agents. In the absence of such an unexpected benefit or result, the mere recitation of a mechanism of action is insufficient to overcome a prima facie case of obviousness.

In re Couvaras is informative in that it emphasizes the importance of secondary considerations (e.g., unexpected results) in overcoming prima facie cases of obviousness, particularly in combination therapy cases where individual pharmaceutical active ingredients have known effects that can be related to the claimed effect.

Practical Tips for Prosecution

When addressing a prima facie case of obviousness, the arguments should be focused on actual unexpected therapeutic results.[19] Practitioners should consider adding claim limitations that recite the therapeutic result, as the Court noted that Couvaras’ success in establishing unexpected results relied on the demonstration that “the co-administration of a GABA-a agonist and an ARB provided an unexpected benefit, such as, e.g., better control of hypertension, less toxicity to patients, or the ability to use surprisingly low dosages.”[20] This would be consistent with case law where the result of a combination of known compounds is sufficiently surprising, such as when the combination results in an unexpected synergy.[21]

Further, practitioners should keep in mind that “when unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art”[22] and a direct or indirect comparison is permissible.[23] Further, in order to establish unexpected results for an invention, the unexpected results must be commensurate in scope with the claims.[24]  

Arguments associated with an unappreciated mechanism of action may be useful if they are tied to an unexpected ultimate effect (which may, but does not need to be, recited in a claim), otherwise the mere recitation of the mechanism of action in the claim may be discounted as inherent. The additional limitation of the mechanism of action may also make it more difficult to prove infringement. As a result, practitioners should consider avoiding mechanism of action limitations in at least the independent claims and instead focus on establishing the benefits of the claimed subject matter.


[1] See MPEP §§ 2111-2116.01.

[2] KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415 (2007).

[3] Graham v. John Deere, 383 U.S. 1, 17-18 (1966).

[4] See MPEP § 2141(II).

[5] PAR Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186, 1195-96 (Fed. Cir. 2014).

[6] Sanofi-Aventis Deutschland GmbH v. Glenmark Pharms. Inc., USA, 748 F.3d 1354 (Fed. Cir. 2014).

[7] In re Couvaras, No. 2022-1489, 2023 WL 3984753 (Fed. Cir. June 14, 2023).

[8] See In re Couvaras, 2023 WL 3984753, at *1.

[9] See id., at *3 (quoting J.A. at 998).

[10] See id. (quoting J.A. at 1011-18).

[11] In re: John L. Couvaras, No. 2022-001037, 2021 WL 6124743, at *3-4 and *7 (P.T.A.B. Dec. 24, 2021) (“Decision”).

[12] See Decision, at *14.

[13] See In re Couvaras, 2023 WL 3984753, at *8 (citing Honeywell International Inc. v. Mexichem Amanco Holdings S.A., 865 F.3d 1348, 1355 (Fed. Cir. 2017).

[14] See id. (citing Honeywell International Inc., 865 F.3d at 1355).

[15] See In re Couvaras, 2023 WL 3984753, at *3 (quoting J.A. at 982-87).

[16] See id.

[17] See id., at *8.

[18] See id. (quoting In re Montgomery, 677 F.3d 1375, 1381 (Fed. Cir. 2012)). See also In re Huai-Hung Kao, 639 F.3d 1057, 1070-71 (Fed. Cir. 2011).

[19] Application of Gershon, 372 F.2d 535, 537 (C.C.P.A. 1967) (explaining that “[e]xpected beneficial results are evidence of obviousness of a claimed invention, just as unexpected beneficial results are evidence of unobviousness thereof”).

[20] See In re Couvaras, 2023 WL 3984753, at *9.

[21] See Sanofi-Aventis Deutschland GmbH, 748 F.3d at 1354.

[22] In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991).

[23] In re Payne, 606 F.2d 303, 316 (C.C.P.A. 1979). See also In re Merchant, 575 F.2d 865, 869 (C.C.P.A. 1978) and In re Blondel, 499 F.2d 1311, 1317 (C.C.P.A. 1974).

[24] In re Clemens, 622 F.2d 1029, 1035 (C.C.P.A. 1980).