By Kevin E. Noonan –

The measurement of the hydrogen ion concentration in an aqueous solution is represented (on a logarithmic scale) as the pH, wherein water under ambient conditions (a temperature of 25°C) has a neutral pH of 7 and the solution becomes more acidic as the pH value trends towards 1 and more basic as it trends towards 14.  Characterizing such solutions as elements of patent claims has a long judicial history (being critical in the seminal case on the doctrine of equivalents, Warner-Jenkinson Co., Inc. v. Hilton David Chemical Co.) and the property was recently a part of the Federal Circuit’s decision in Actelion Pharmaceuticals Ltd. v. Mylan Pharmaceuticals Inc.

The matter arose in ANDA litigation over Mylan’s attempt to obtain approval for its generic version of Actelion’s hypertension drug Veletri^Ò, having as its active ingredient epoprostenol.  As set forth in the opinion, “[e]poprostenol is a vasodilator and antiplatelet agent that can be used to treat cardiovascular disease” but “is unstable in water and will react with water molecules to form a different compound that lacks epoprostenol’s desirable pharmacological properties.”  This reaction is catalyzed by the presence of acid in solutions of epoprostenol and, due to their catalytic function can even in trace amounts facilitate epoprostenol’s breakdown.  According to the opinion, pH can be influenced by including a base that neutralizes the acid or by decreasing the temperature that reduces acid production in aqueous solutions.

Actelion overcame the existence of prior art formulations of epoprostenol (Flolan^Ò) by distinguishing over three features for increasing the pH: storing epoprostenol as a lyophilized powder that was reconstituted for use; performing such reconstitution in a diluent having a more basic pH than conventional intravenous fluids; and storing the reconstituted epoprostenol formulation by refrigeration.  As disclosed in the ‘802 patent, Actelion’s formulation was reconstituted in commercially available intravenous fluids and kept at room temperature (which had a pH greater than 11 which was greater than the pH of Flolan^Ò).

Actelion’s resulting pharmaceutical composition was patented in U.S. Patent Nos. 8,318,802 and 8,598,227, with claim 1 of the ‘802 patent being representative:

1.  A lyophilized pharmaceutical composition comprising:
    (a) a unit dose of 0.5 mg or 1.5 mg of epoprostenol or a salt thereof;
    (b) arginine; and
    (c) sodium hydroxide,
    wherein said lyophilized pharmaceutical composition is (i) formed from a bulk solution having a pH of 13 or higher and (ii) capable of being reconstituted for intravenous administration with an intravenous fluid.

The beneficial properties of the claimed pharmaceutical compositions (such as greatly reduced degradation rates) were supported by experimental evidence comparing the stability thereof at various basic pH values (pH 10.5, 11, 12 and ultimately pH 13 as claimed).

The District Court’s claim construction regarding the pH limitation was challenged by Mylan in an earlier embodiment of this case and the Federal Circuit vacated that construction; see Actelion Pharmaceuticals Ltd. v. Mylan Pharmaceuticals Inc., 85 F.4th 1167, 1173 (Fed. Cir. 2023).  On remand, the District Court construed the claim term “a pH of 13 or higher” to mean “a pH of 12.98 or higher,” which was unchallenged on appeal.

Mylan argued that its epoprostenol formulation did not infringe the asserted claims of these patents, on the grounds that its bulk solution had a pH “well below” the pH 12.98 recited in the claim as construed by the District Court.  Actelion asserted infringement on the basis that Mylan’s bulk solution would have a pH greater than 13 when refrigerated (the conditions under which Mylan’s bulk solution was manufactured).  Actelion also argued that Mylan infringed under the doctrine of equivalents, because “Mylan’s manufacturing process performs the same function (improved manufacturing stability) to achieve the same result (composition stability) in the same way (reducing hydrogen ion concentration) as the claimed invention.”

The District Court rejected both Actelion arguments and found neither literal infringement, based on its construction that the term “a pH of 13 or higher” specified a pH measured at a temperature standard in the field, nor infringement under the doctrine of equivalents.  The Court held that the skilled worker would consider that the pH 13 claim limitation was determined under standard conditions of 25±2°C, which was supported by implicit disclosure in the specification (“many of the specification’s reported experimental results would ‘not make sense’ if the measurements were not taken at 25±2°C”).  The District Court also considered its application of the construed claims to be supported by extrinsic evidence, including how pH was determined under the United States Pharmacopeia (USP).  Regarding infringement under the doctrine of equivalents, the Court found application of the doctrine to be precluded by the “disclosure-dedication” rule, whereby “Actelion’s specification discloses, but does not claim, pH ranges for bulk solutions including values under 13, e.g., pH 12–13 and 12.5–13.”  The doctrine was also barred by prosecution history estoppel, because during prosecution Actelion amended the claims to recite a pH of 13 or above to overcome an obviousness rejection and thus had surrendered lower pH conditions for the bulk epoprostenol solutions.  Finally, the District Court considered Actelion’s evaluation of the “function” prong of the “function-way-result” test for equivalents was performed “at an impermissibly high level of generality.”

Accordingly, the District Court entered final judgment of non-infringement and this appeal followed.

The Federal Circuit affirmed, in an opinion by Judge Taranto joined by Judges Reyna and Stoll.  Importantly for the Federal Circuit, the term pH was not expressly defined nor were the conditions for measurement directly stated.  (The former perceived deficiency might have been addressed with regard to the statement in Lindemann that “a patent need not teach, and preferably omits, what is well known in the art” (which pH certainly is); Lindemann Maschinenfabrik v. American Hoist and Derrick, 730 F.2d 1452, 1457 (Fed. Cir. 1984)).  The panel rejected Actelion’s arguments that the District Court committed reversible error in construing the meaning of the claim term “a pH of 13 or higher” but held that that meaning was not resolved under its plain meaning because no conditions were specified in the claims.  Turning to other intrinsic evidence, the opinion asserts that this disclosure favors the District Court’s construction over the construction asserted by Actelion on appeal, albeit only implicitly (e.g., to be consistent with the District Court’s construction rather than expressly defining it).  This is particularly true of comparative pH determinations which the opinion characterizes as “straightforward” and “without [having] any suggestion of accommodating the complications of measuring pH at different temperatures.”  The panel also rejected Actelion’s arguments regarding the Examiner’s “reasons for allowance” (which the Court considers to be consistent with pH being determined at standard temperature), and also considered the “purpose of the invention” disclosed in the specification to be similarly consistent with the District Court’s construction.

The opinion states that although such intrinsic evidence is usually enough to support the District Court’s construction, here extrinsic evidence was also considered to the same effect.  Specifically, the opinion states that “extrinsic evidence . . . may sometimes be informative,” citing Seabed Geosolutions (US) Inc. v. Magseis FF LLC, 8 F.4th 1285, 1287 (Fed. Cir. 2021), and Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1584–85 (Fed. Cir. 1996), and that “evidence that relevant artisans use a claim term in an established and consistent way, including evidence of a “[w]ell known industry standard[] can be persuasive of the term’s meaning,” citing Wellman, Inc. v. Eastman Chemical Co., 642 F.3d 1355, 1367 (Fed. Cir. 2011), and Canatex Completion Solutions, Inc. v. Wellmatics, LLC, 159 F.4th 39, 45 (Fed. Cir. 2025).  The opinion states that the District Court “properly relied” on such extrinsic evidence (particularly with regard to the USP) and committed no clear error, rejecting Actelion’s arguments to the contrary as failing to “leave [the panel] with a definite and firm conviction that the district court made a mistake.”

Similarly, the panel found no error in the District Court’s rejection of Actelion’s assertion of Mylan’s purported infringement under the doctrine of equivalents with regard to either prosecution history estoppel (Actelion made a narrowing amendment of its claims to overcome rejection by an examiner, citing Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., 535 U.S. 722, 727 (2002)) or the disclosure-dedication doctrine (Johnson & Johnston Associates Inc. v. R.E. Service Co., 285 F.3d 1046, 1054 (Fed. Cir. 2002) (en banc)).  The Federal Circuit expressly rejected Actelion’s attempt to rely on the “tangential relationship” exception to application of prosecution history estoppel under the circumstances of how that estoppel arose in this case (including there having been several instances of amending the claims to overcome rejection surrounding the pH limitation).  This amounted to a “discernible objective reason for the narrowing amendment” that raised the estoppel under Ajinomoto Co., Inc. v. International Trade Commission, 932 F.3d 1342, 1354 (Fed. Cir. 2019), sufficient for the Court to affirm the District Court’s rejection of Actelion’s doctrine of equivalents assertions.  And with regard to the District Court’s application of the disclosure-dedication rule, the Court held that the disclosures in the common specification of the asserted patents were “sufficiently specific to identify the ranges of pH 12.5 to 13, 12 to 13, and greater than 12,” which were nevertheless not included in the asserted claims.  On this basis, the Federal Circuit affirmed the District Court’s denial of Actelion’s assertions that Mylan infringed under the doctrine of equivalents.

Actelion Pharmaceuticals Ltd. v. Mylan Pharmaceuticals Inc. (Fed. Cir. 2026)
Panel: Circuit Judges Reyna, Taranto, and Stoll
Opinion by Circuit Judge Taranto