Recitation of a Previously Unappreciated Mechanism of Action Does Not Overcome Prima Facie Obviousness of Drug Combination

By Chris Holman

In re Couvaras, 2023 WL 3984753 (Fed. Cir. June 14, 2023)

A prima facie obvious combination of prior art chemical compounds can sometimes be deemed nonobvious if the result of the combination is sufficiently surprising, such as when a combination of pharmaceutical active ingredients results in an unexpected synergy. See, e.g., Sanofi-Aventis Deutschland GmbH v. Glenmark Pharms. Inc., USA, 748 F.3d 1354 (Fed. Cir. 2014).  In a recent Federal Circuit decision, In re Couvaras, Judge Lourie (writing for a unanimous panel) explains the important distinction between unexpected results in a pharmaceutical combination product as opposed to the mere recitation of an unexpected mechanism of action.

The case is an appeal of a Patent Trial and Appeal Board decision affirming an Examiner’s rejection of the claims at issue as obvious.  A representative claim recites:

11.  A method of increasing prostacyclin release in systemic blood vessels of a human individual 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 combined into a deliverable form, the ARB being an Angiotensin II, type 1 receptor antagonist;

delivering the composition to the human individual’s circulatory system by co-administering 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 prostacyclin by blockading angiotensin II in the human individual through the action of the dosage of the ARB to reduce GABA-a receptor inhibition due to angiotensin II presence during a period of time, and

activating the uninhibited GABA-a receptors through the action of the GABA-a agonist during the period of time; and

relaxing smooth muscle of the systemic blood vessels as a result of increased prostacyclin release.

Judge Lourie leads off the decision by observing that, while the claims at issue “literally recite methods of increasing prostacyclin release … by co-administering two well-known types of antihypertensive agents[, i]n reality, the claims relate to combatting hypertension with known antihypertensive agents and claiming their previously unappreciated mechanism of action.”

He then affirms the Board’s conclusion that 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 which is to be used for the very same purpose.”  It was undisputed that the two types of active agents recited in the claims, GABA-a agonists and ARBs, were both known to be useful for alleviating hypertension.

The appellant, citing Honeywell International Inc. v. Mexichem Amanco Holdings S.A., 865 F.3d 1348, 1355 (Fed. Cir. 2017), argued that the mechanism of action recited in the claims, i.e., the increased release of prostacyclin, was unexpected, and that the Board had erred in dismissing the limitation as having no patentable weight due to inherency.  But the Federal Circuit rejected this argument, noting that “Honeywell held that ‘unexpected properties may cause what may appear to be an obvious composition to be nonobvious,’ not that unexpected mechanisms of action must be found to make the known use of known compounds nonobvious.” The court agreed with the Board that the recitation of various mechanistic steps in the claims was insufficient to overcome the prima facie obviousness of the claimed methods, observing that:

While mechanisms of action may not always meet the most rigid standards for inherency, they are still simply results that naturally flow from the administration of a given compound or mixture of compounds. 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 unexpected.

. . .

To establish unexpected results, Couvaras would have needed to show 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. We agree with the Board that no such benefits have been shown, and therefore no evidence of unexpected results exist.

25 thoughts on “Recitation of a Previously Unappreciated Mechanism of Action Does Not Overcome Prima Facie Obviousness of Drug Combination

  1. 3

    I suspect the applicant (or the patent practitioner who drafted the claim) was trying to get around any inherency issues by including the word “synergistically” in the claim. I wonder how it would have come out if instead the claims had specific numbers for each of the components, each number being less than half of the normal dose considered efficacious. I see there was one claim in the application, claim 15, that recited specific amount of each API, but the decision does not discuss that claim, presumably because the applicant did not argue that claim separately; and the application does not appear to discuss what would normally be considered an efficacious amount for either of the two components.

    1. 3.1

      I cannot speak to the procedural aspect of what was or was not argued separably, but would not your last comment of, “application does not appear to discuss what would normally be considered an efficacious amount for either of the two components.</i." BE the very type of thing that inherency would cover?

      In other words, you make a point of (possibly) attempting to get around inherency, but then seem to fall to a point that would need not be made to get around inherency.

      1. 3.1.1

        My point is that had the application been drafted differently, had the claims been worded differently, and had the case been argued differently, there might have been a chance. Of course, if pigs had wings, they could fly.

        The spec in this case was only 12 pages long, without any lab data. There’s one paragraph that discusses some ranges for the active ingredients, but nothing beyond that. So there really wasn’t much basis for the applicant to try to claim “synergism” in a way that might have rendered the claim non-obvious. In addition to claim 15, there was claim 12, that tried to claim the method by mentioning a decreased amount of the ARB, but that claim wasn’t separately argued before PTAB and the CAFC didn’t relate to it separately. And I’m not sure it really did the trick, even if it met the requirements of 112.


          Sure, lot’s of what-if’s and could-have-beens (and was not taking issue with your points).

          I was merely making sure that I was hearing the inherency angle correctly.

  2. 2

    “providing a human individual expressing GABA-a receptors in systemic blood vessels due to essential hypertension;”

    Is there a typographical error in this claim clause? What is being provided? Am I reading this wrong?

    1. 2.1

      I have not bothered with context, but the words on their own appear to be providing a “human individual” (as opposed to, say, a non-human individual) that has the conditions of the rest of the clause.

    2. 2.2

      Exactly what is written is being provided. This is part of the patent applicant’s feeble attempt to incorporate mechanistic “limitations” into its obvious claims.

  3. 1

    The right result for the right reasons. Outside of the pharma context, I seem to recall earlier case law addressing the same or nearly identical issue. Any reasonable motivation to combine will suffice to establish a prima facie case of obviousness of a combination claim. The motivation does not have to be the same as the motivation that inspired the alleged inventor. And “financially practical” is not an “unexpected result” that the patent system should recognize, just as a newly discovered “mechanism of action” is not relevant (or claimable on its own terms).

    1. 1.1

      Any reasonable motivation to combine will suffice to establish a prima facie case of obviousness of a combination claim.

      Wrong on its face as motivation is only one of the necessary elements.

      Are you really an attorney?

      (and this is not even getting to the point that the entire phrase is different than the word “motivation” as may arise from a singular look at any one reference).

      1. 1.1.1

        “motivation is only one of the necessary elements.”

        Tell everybody the other necessary elements, you insufferable p r i c k.


          You are the one that wants to assert something that any 1L would immediately see as bogus (motivation alone is enough), AND want to call me an “insufferable p r 1 c k”….

          Anybody other than Malcolm I might ascribe this to some combination of gumption and stu p1d 1ty, but as this is Malcolm, I cannot give any credit to gumption.


            We are all still waiting, Billy. This was very important to you! Tell everyone the “other elements” that are missing.


              You be funny.

              Clearly you have an untenable assertion, and instead of recognizing that clear reality, you want to double down and demand (in the false sense of ‘plurality’) more from me.


              I will give you two words from me and offer that your substantive reply can be as many words as you may feel that is necessary:

              Graham Factors.


          Reasonable expectation of success.

          From MPEP 2143.I.G:

          “G.Some Teaching, Suggestion, or Motivation in the Prior Art That Would Have Led One of Ordinary Skill To Modify the Prior Art Reference or To Combine Prior Art Reference Teachings To Arrive at the Claimed Invention
          To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:

          (1) a finding that there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings;
          (2) a finding that there was reasonable expectation of success; and
          (3) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
          The rationale to support a conclusion that the claim would have been obvious is that “a person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so.” DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006). If any of these findings cannot be made, then this rationale cannot be used to support a conclusion that the claim would have been obvious to one of ordinary skill in the art.

          The courts have made clear that the teaching, suggestion, or motivation test is flexible and an explicit suggestion to combine the prior art is not necessary. The motivation to combine may be implicit and may be found in the knowledge of one of ordinary skill in the art, or, in some cases, from the nature of the problem to be solved. Id. at 1366, 80 USPQ2d at 1649. “[A]n implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the ‘improvement’ is technology-independent and the combination of references results in a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. Because the desire to enhance commercial opportunities by improving a product or process is universal—and even common-sensical—we have held that there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves. In such situations, the proper question is whether the ordinary artisan possesses knowledge and skills rendering him capable of combining the prior art references.” Id. at 1368, 80 USPQ2d at 1651.”

          If the two drugs had not been combined before, and the combination is what results in the unexpected property, it seems like the inherency argument may not be valid.


            Question wasn’t for you. I already said the motivation must be REASONABLE. Just let your pedantic p r I c k buddy dance around like a c l o w n. It’s what he does best. Point and laugh.


              Move the goal posts back Malcolm — you stated that ONLY “motivation to combine” was necessary, and that was clear error.

              The modifier of “reasonable” does not change your error, and my pointing out your error included that modifier as part of my direct quote of your incorrect statement.


                “ The modifier of “reasonable” does not change your error”

                I made no “error”, you ridiculous pedantic imbecile.


                The expectation of success must be reasonable. Do you really not know the difference?

                1. PM – Malcolm’s error was NOT any type of distinction as to the “motivation to combine” in and of itself, but rather in his pronouncement that such a “reasonable motivation to combine ALONE was enough to establish a prima facie case.

                2. … now he may have wanted to say something else, and should have corrected his own error at the first instance that I pointed it out, but instead he decided to double and then triple down on it.

    2. 1.2

      … someone who is always so eager to see patents rejected…

      And claims to not be anti-patent…

      Is the epitome of gas-lighting.

      1. 1.2.1


        That’s so incredibly d u m b you cracked me up a little bit. I didn’t think you were capable of that after all these years. Are you preparing to steal the title from Wiper?

    3. 1.3

      I am a little surprised that this was released as a non-precedential opinion. I do not know that the court has ever addressed the issue of expected results from an unexpected mechanism of action before. I agree that this is the right result for that situation, but a non-precedential decision does not bind any future panels to this outcome.

      1. 1.3.1

        Sorry, I am confusing this with a different case. Now that I click the link, I see that this was released as a precedential decision.

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