The case arose in an inter partes review (IPR) proceeding by challenger Amneal over Almirall's U.S. Patent No. 9,517,219.  The patent is directed to methods for treating acne or rosacea with formulations of dapsone as the active ingredient, the formulations comprising acrylamide/ sodium acryloyldimethyl taurate copolymer ("A/SA") as a thickening agent and diethylene glycol monoethyl ether ("DGME") as a solvent.  DGME is useful for increasing concentrations of dapsone that remain soluble in the formulation and A/SA is useful for minimizing the intensity of yellowing of the composition with time, as well as reducing dapsone particle size and thereby minimizing grittiness in the final formulation.

Claims 1 and 6 of the '219 patent were considered representative by the Court:

1.  A method for treating a dermatological condition selected from the group consisting of acne vulgaris and rosacea comprising administering to a subject having the dermatological condition selected from the group consisting of acne vulgaris and rosacea a topical pharmaceutical composition comprising:
    about 7.5% w/w dapsone;
    about 30% w/w to about 40% w/w diethylene glycol monoethyl ether;
    about 2% w/w to about 6% w/w of a polymeric viscosity builder comprising acrylamide/sodium acryloyldimethyl taurate copolymer;
    and
    water;
    wherein the topical pharmaceutical composition does not comprise adapalene [emphasis in opinion].

6.    A method for treating a dermatological condition selected from the group consisting of acne vulgaris and rosacea comprising administering to a subject having the dermatological condition selected from the group consisting of acne vulgaris and rosacea a topical pharmaceutical composition comprising:
    about 7.5% w/w dapsone;
    about 30% w/w diethylene glycol monoethyl ether;
    about 4% w/w of a polymeric viscosity builder comprising acrylamide/sodium acryloyldimethyl taurate copolymer; and
    water;
    wherein the topical pharmaceutical composition does not comprise adapalene [emphasis in opinion].

Amneal's IPR petition asserted International Pub. No. WO 2009/061298 ("Garrett") and International Pub. No. WO 2010/072958 ("Nadau-Fourcade") to render the '219 claims obvious, or in the alternative the combination of the Garrett reference and Bonacucina et al., 2009, "Characterization and Stability of Emulsion Gels Based on Acrylamide/Sodium Acryloyldimethyl Taurate Copolymer," AAPS PHARMSCITECH 10: 368–75.  As set forth in the opinion, Garrett taught topical dapsone for treating acne and rosacea, in "microparticulate form, dissolved form, or both."  Garrett's disclosure included the commercial product Aczone®, which lacked adapalene.  While disclosing thickening agents, Garrett did not disclose A/SA specifically, but did disclose the parameters of useful thickening agents and their advantageous concentrations, specifically "between about 0.2% to about 4% by weight of the composition," and a preferred embodiment that included DGME.  The opinion notes that these formulations and their concentrations were capable of component optimization, stating that "[t]he relative percentages for each of the reagents used . . . may vary depending upon the desired strength of the target formulation, gel viscosity, and the desired ratio of microparticulate to dissolved dapsone.  Unless otherwise designated, all reagents listed . . . are commonly known by one of ordinary skill in the art and are commercially available from pharmaceutical or cosmetic excipient suppliers."  The Nadau-Fourcade reference discloses A/SA (Sepineo®) for use as thickening agents for dermatological formulations for treating acne or rosacea.  In the alternative obviousness assertion, the Bonacucina reference discloses a "concentrated dispersion of acrylamide/sodium acryloyldimethyl taurate copolymer in isohexadecane."  In the Board's opinion, either of these provided sufficient disclosure in combination with the Garrett reference to render Almirall's claims obvious.

The Board's decision that either of these combinations of references rendered the claims of the '219 patent obvious depended on whether the skilled artisan would have been motivated to substitute the thickening agent disclosed in either the Nadau-Fourcade or Bonacucina references in the formulations disclosed in the Garrett reference and have had a reasonable expectation of success in achieving the claimed invention.  The Board found that either combination taught every limitation in the claimed invention, that the skilled artisan would have been motivated to combine them and have had a reasonable expectation of success, supported by expert testimony supporting these conclusions.  In particular, these experts testified that the thickening agent disclosed in Garrett, Carbopol®, "was known to have drawbacks, for example, requiring neutralization to achieve maximum viscosity and producing grittiness and possible agglomeration."  In addition, the overlapping ranges of the different thickening agents and their properties in common provided the reasonable expectation of success in the Board's opinion.  Finally, Garrett also taught the negative limitation to avoid adapalene, stating "it is not Garrett's mere silence as to the presence of adapalene, but its disclosure of complete dapsone formulations to treat acne in its absence that suggests that adapalene is not included in Garrett's formulations."  The Board found Almirall's claims to be obvious, and this appeal followed.

The Federal Circuit affirmed, in an opinion by Judge Lourie, joined by Judges Chen and Cunningham.  Almirall argued that the Board's reliance on overlapping ranges of thickening agents between their claims and the art in finding obviousness was an erroneous presumption and that the Board's determinations were not supported by substantial evidence.  Amneal successfully argued on appeal that disclosure of "ranges for structurally and functionally similar compounds can establish a prima facie case of obviousness," citing Valeant Pharms Int'l Inc. v. Mylan Pharms Inc., 955 F.3d 25 (Fed. Cir. 2020), and Anacor Pharms., Inc. v. Iancu, 889 F.3d 1372 (Fed. Cir. 2018).  The Federal Circuit agreed, stating that "[a]prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art" and citing In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (citing In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997), as well as E.I. du Pont de Nemours & Co. v. Synvina C.V., 904 F.3d 996, 1006 (Fed. Cir. 2018), and Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004), in support of this principle.  Overlapping ranges are informative for an obviousness determination, according to the opinion, because "in the absence of evidence indicating that there is something special or critical about the claimed range, an overlap suffices to show that the claimed range was disclosed in—and therefore obvious in light of—the prior art," as held in du Pont v. Synvina.  The Court held that the Board had relied on substantial evidence, including factual findings and expert testimony, regarding the similarities of the thickening agents disclosed in the art and the effective ranges thereof in raising the presumption of obviousness that Almirall did not overcome, including by ineffective assertions of unexpected results and failure of others.  The opinion further states that the issue of overlapping ranges was not determinative because this case simply "substitute[es] one known gelling agent for another."

Turning to Almirall's (lack of) substantial evidence assertion, the Federal Circuit first addressed the Board's finding that avoiding adapalene was "effectively [taught]" by the Garrett reference.  "[A] reference need not state a feature's absence in order to disclose a negative limitation," according to the Court, citing AC Techs., S.A. v. Amazon.com, Inc., 912 F.3d 1358, 1367 (Fed. Cir. 2019).  Here, the panel held that the skilled artisan would have recognized that the Garrett reference disclosed a "complete formulation" that "exclud[ed] the possibility of an additional active ingredient" which was sufficient to support the Board's conclusion, citing Novartis Pharms. Corp. v. Accord Healthcare, Inc., 21 F.4th 1362, 1373 (Fed. Cir. 2022).  Then taking the combination of references in turn, the Federal Circuit held that the Board had substantial evidence in each combination for a motivation to combine and a reasonable expectation of success.  The former evidence was based on expert testimony that the thickening agent taught in Garrett (Carbopol®) could be substituted with Sepineo® taught in the Nadau-Fourcade reference because they are closely related and were used in the same concentration range.  The Court considered the record to disclose A/SA as a thickening agent wherein substitution thereof for the agent disclosed in Garrett to have been a "predictable design choice[]" for the skilled worker, consistent with the Supreme Court's teaching in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007) (famously stating "[w]hen there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp").  The Court also rejected Almirall's arguments regarding a lack of reasonable expectation of success in this combination, saying that what is required is an expectation not certainty of such success, citing OSI Pharms., LLC v. Apotex Inc., 939 F.3d 1375, 1385 (Fed. Cir. 2019), and finding that the Board's determination of reasonable expectation was supported by substantial evidence.

Regarding the second combination (Garrett and Bonacucina), the Court similarly found that the Board's finding for a motivation to combine was supported by substantial evidence including expert testimony, on the grounds that dapsone combined with carbomer thickening agents like Carbopol® would be understood to be "gritty" and need neutralization, both disadvantages being successfully addressed by Sepineo®.  And the Court held the Board had substantial evidence for finding the skilled worker would have had a reasonable expectation of success that the substitution would be effective.

Almirall, LLC v. Amneal Pharmaceuticals LLC (Fed. Cir. 2022)
Panel: Circuit Judges Lourie, Chen, and Cunningham
Opinion by Circuit Judge Lourie