Veletri® (epoprostenol)
Case Name: Actelion Pharms. Ltd. v. Mylan Pharms. Inc., 2024-1641, 175 F.4th 1336, 2026 WL 1314700 (Fed. Cir. May 13, 2026) (Circuit Judges Reyna, Taranto, and Stoll presiding; Opinion by Taranto) (Appeal from N.D.W.V., Bailey, J.)
Drug Product and Patent(s)-in-Suit: Veletri® (epoprostenol); U.S. Patent Nos. 8,318,802 (“the ’802 patent”) and 8,598,227 (“the ’227 patent”)
Nature of the Case and Issue(s) Presented: Actelion owns the patents-in-suit, which claim pharmaceutical compositions including epoprostenol, the active ingredient in Actelion’s hypertension drug Veletri. Epoprostenol is a vasodilator and antiplatelet agent that can be used to treat cardiovascular disease. But its efficacy is diminished in water as it reacts with water molecules to form a different compound that lacks epoprostenol’s desirable pharmacological properties. This undesirable reaction occurs in acidic conditions as the presence of hydrogen ions catalyzes the breakdown of epoprostenol.
Prior formulations of epoprostenol, such as Flolan®, have demonstrated several ways to prevent this acid-catalyzed breakdown. Flolan is stored as a lyophilized (freeze-dried) powder and is reconstituted into an aqueous solution (by mixing with liquid diluent) just before it is administered. Flolan also includes a special diluent for reconstituting the freeze-dried powder that is more basic than typical intravenous fluids. Finally, the reconstituted solution is refrigerated. While these methods are effective, the need for a special diluent and refrigeration are inconvenient and undesirable. Thus, patents-in-suit allow users to reconstitute the epoprostenol formulation with any commercially available intravenous fluid and store it at room temperature by creating a highly basic “bulk solution” that includes epoprostenol, which is then freeze-dried into a powder. After trial and error, the inventors found that bulk solutions with a pH of 13 or higher demonstrated desirable room-temperature stability.
Mylan filed an ANDA with FDA seeking to market generic epoprostenol. Actelion sued Mylan for patent infringement. The district court held that there was no literal infringement, as the pH of Mylan’s bulk solution was outside Actelion’s claimed pH range when measured at standard temperature (25±2°C ). Actelion argued that a POSA would measure the pH of the bulk solution at the refrigerated “operating temperature” rather than at standard temperature to capture Mylan’s drug within their patented pH range. However, the district court ultimately rejected that argument. The district court also rejected Actelion’s infringement theory under the doctrine of equivalents. Actelion appealed, and the Federal Circuit affirmed.
Why Mylan Prevailed: Actelion makes two arguments on appeal. First, it claims the district court erred in construing the phrase “formed from a bulk solution having a pH of 13 or higher” from the ’802 patent to refer to a pH measurement made at the standard temperature rather than the refrigerated “operating temperature.” Second, it claims the district court erred in finding no infringement based on the doctrine of equivalents.
The Federal Circuit relied on both intrinsic and extrinsic evidence to resolve the first issue. The claim language “simply does not specify the conditions for taking the pH measurement.” Actelion never stated outright the conditions of any of the pH measurements reported in its patent examples. Thus, any reports in the specification merely listed different pH measurements with no suggestion of altering the temperature at any point, favoring the Federal Circuit’s construction of the phrase. The Federal Circuit next looked towards extrinsic evidence, referring to the United States Pharmacopeia (USP), which both the parties and their experts agreed is an important set of standards in the pharmaceutical industry. Under the USP, the default understanding is that “unless otherwise specified, pH measurements are made at 25±2°C.” The Federal Circuit also referenced several popular chemistry textbooks to support its construction. Although Actelion attempted to introduce contrary evidence to prove otherwise, the Federal Circuit was unconvinced and found no error in the district court’s conclusion of the phrase at issue.
Lastly, the Federal Circuit found no error in the district court’s application of both prosecution history estoppel and disclosure-dedication bars to prevent Actelion from capturing equivalents. T Actelion amended its claim during prosecution with respect to the pH limitation several times, with the final amendment narrowing claim 1’s pH limitation from “a pH of greater than 12” to “a pH of 13 or higher.” Due to that narrowing, the Federal Circuit concluded that Actelion is estopped from asserting the doctrine of equivalents. Similarly, the disclosure-dedication rule also prevented Actelion from capturing equivalents. Actelion’s patent discloses that “[t]he pH of the bulk solution is preferably adjusted to about 12.5–13.5, most preferably 13.” However, they only claim a pH of 13 or greater in their claims. As a result, these disclosures are dedicated to the public and cannot be claimed by Actelion.
