By Kevin E. Noonan —

One of the casualties of the Leahy-Smith America Invents Act in 2012 was 35 U.S.C. § 145, which had provided recourse to U.S. District Courts for U.S. patent applicants disgruntled with a determination of unpatentability before the U.S. Patent and Trademark Office, but was abrogated under certain circumstances (e.g., IPRs) by the AIA.  This avenue had as one advantage the ability to present new evidence and to have that evidence evaluated by the Court.  While providing an alternative outlet, the outcome was not always to the applicant's benefit; an example of a negative outcome arose recently in ImmunoGen, Inc. v. Hirshfeld, an appeal to the Federal Circuit from a decision against the applicant by the District Court (because after all, recourse to the District Court does not guarantee an outcome different from that before the PTO).

The case arose over ImmunoGen's U.S. Application No. 14/509,809, directed to administration of mirvetuximab (an immunoconjugate between an antibody and an anticancer drug) for treating ovarian and peritoneal cancer cells that overexpress Folate Receptor 1 ("FOLR1").  A disadvantage arising from mirvetuximab administration was a severe ocular side-effect that could compromise sight in patients receiving the treatment.  ImmunoGen determined that if the dose was adjusted to 6mg/kg of the patient's adjusted ideal body weight (as set forth below) these side effects could be avoided.  The claims of the '809 application were directed to these adjusted administration methods; Claim 1 is representative:

1.  A method for treating a human patient having an FOLR1-expressing ovarian cancer or cancer of the peritoneum comprising administering to the patient an immunoconjugate which binds to FOLR1 polypeptide,
    wherein the immunoconjugate comprises an antibody or antigen-binding fragment thereof that comprises the variable light chain (VL) complementarity determining region (CDR)-1, VL CDR-2, VL CDR-3, variable heavy chain (VH) CDR-1, VH CDR-2, and VH CDR-3 of SEQ ID NOs: 6-9, 11, and 12, respectively, and a maytansinoid, and
    wherein the immunoconjugate is administered at a dose of 6 milligrams (mg) per kilogram (kg) of adjusted ideal body weight (AIBW) of the patient.

As disclosed in the specification, the adjusted ideal body weight (or "AIBW") was defined as "a size descriptor that accounts for sex, total body weight, and height."  A related value used to calculate AIBW is "ideal body weight" ("IBW"), which is "a size descriptor that is unrelated to total body weight," as it is "an estimate of weight corrected for sex and height, and optionally frame size."  These measurements are disclosed in Green and Duffull, 2004, British Journal of Clinical Pharmacology 58: 119-33, incorporated by reference in the specification, wherein ImmunoGen disclosed exemplary formulae for each of AIBW and IBW for men and women:

                    AIBW = IBW + 0.4(Actual weight in kg – IBW)
                    IBW (male) = 0.9H – 88
                    IBW (female) = 0.9H – 92

The PTO rejected the claims for obviousness and obviousness-type double patenting and ImmunoGen appealed to the U.S. District Court for the Eastern District of Virginia.  That Court granted summary judgment against ImmunoGen for being "fatally indefinite and fatally obvious" as a matter of law.  This appeal followed.

The Federal Circuit vacated the District Court's grant of summary judgment against ImmunoGen and remanded, in an opinion by Judge Clevenger joined by Judges Newman and Stoll.  Prior to the Court's legal analysis, the opinion notes that "the district court resolved numerous factual disputes against non-movant ImmunoGen," which the opinion characterized as "an error that is fatal to its ultimate ruling."  In the opinion the panel explicates its reasoning as follows.  Both indefiniteness and obviousness are questions of law and thus amenable to summary judgment determinations; how a Court comes to decisions on these questions is governed by regional Circuit law but have in common that questions of fact should be decided in favor of the non-movant (here, ImmunoGen).  In the District Court action, the USPTO asserted (not improperly) for the first time indefiniteness as a ground for denying a patent to ImmunoGen.  The basis for this decision was that the specification described its formula for determining AIBW as "exemplary" which the District Court held as a matter of law made the value capable of being calculated in multiple ways, "leav[ing] a skilled artisan to wonder or to guess whether the formula provided is the only one covered by the '809 Application."  This situation was compounded in the Court's view by the definition of IBW as correcting for "sex and height, and optionally frame size" (emphasis in opinion).  The District Court refused to consider an express example in the specification as well as expert testimony for the question of whether the skilled artisan would be able to understand the scope and meaning of the AIBW parameter.

The Federal Circuit disagreed, finding the specification replete with intrinsic disclosure that would inform the skilled worker on the meaning of the measurement.  These included:

(1) the claims and specification are drawn to a specific dosing regimen for a specific immunoconjugate, which is significant in light of expert testimony that the correction factor used to calculate AIBW is drug-specific; (2) Example 4 describes dosing mirvetuximab in accordance with the claimed method and uses the same AIBW and IBW formulas disclosed in the definitions section; and (3) during the prosecution of the '809 Application, the USPTO never disputed the definiteness, or gave any indication it failed to understand the meaning, of the now-allegedly indefinite term.

The Federal Circuit also credited extrinsic evidence presented by both parties'  experts as well as the Green reference.  According to the panel, "[w]hen we view this evidence in the light most favorable to ImmunoGen—as we must in our review—we conclude that there are still disputed questions of material fact and summary judgment is therefore inappropriate."

Turning to the District Court's grant of summary judgment on obviousness, the Federal Circuit opined that "the district court improperly resolved a number of factual findings against ImmunoGen."  These included the determination that "ocular toxicity was a known negative effect of [immunoconjugates] like [ImmunoGen's]," about which the panel recognized there was conflicting expert testimony.  In addition, on this question ImmunoGen presented contrary evidence, including that "(1) ocular toxicity is not well-understood; (2) immunoconjugates have unique pharmacokinetic characteristics, making it difficult to generalize pharmacological effects; (3) it was not known that mirvetuximab would cause ocular toxicity; and (4) published results for Phase 1 testing of mirvetuximab reported no study drug-related serious adverse events or dose-limiting toxicity."  In addition, the District Court credited statements in published PCT applications, Nos. WO 2011/106528 and WO 2012/135675 that mirvetuximab dosing could be "easily determined" in the face of expert testimony to the contrary.  Finally, the District Court found that changing the dose as disclosed in the '809 specification did not "significantly change the dose for patients who are not significantly overweight or underweight," despite evidence in the '809 application and Phase 1 clinical trials leading to the opposite conclusion.  The District Court's finding that there were no undisputed questions of material fact in view of this evidence was error according to the Federal Circuit, which "repeats across its other factual findings, including those relating to motivation to combine, reasonable expectation of success, and secondary considerations."  Accordingly, the Federal Circuit remanded the case to the District Court "for proceedings consistent with [their] opinion."

ImmunoGen, Inc. v. Hirshfeld (Fed. Cir. 2022)
Panel: Circuit Judges Newman, Clevenger, and Stoll
Opinion by Circuit Judge Clevenger

Hat tip to Kip Werking, Dmitry Karshtedt, and Janice Mueller for noting that the AIA did not completely abrogate § 145.

By Kevin E. Noonan —

The Federal Circuit addressed questions of motivation to combine and reasonable expectation of success in finding obviousness as well as when an obviousness determination by the Patent Trial and Appeal Board is supported by substantial evidence, in Almirall, LLC v. Amneal Pharmaceuticals LLC.

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