Case Name: Novartis Pharms. Corp. v. Mylan Pharms. Inc., Civ. No. 19-cv-201, 2024 WL 384929 (N.D.W.V. Jan. 31, 2024) (Kleeh, J.) 

Drug Product and Patent(s)-in-Suit: Entresto® (sacubitril/valsartan); U.S. Patents Nos. 8,877,938 (“the ’938 patent”) and 9,388,134 (“the ’134 patent”)

Nature of the Case and Issue(s) Presented: The parties stipulated that if Mylan infringed claim 1 of the ’938 patent, then it also infringed the ’134 patent. The ’938 patent recited substantially pure trisodium sacubitril-valsartan hemipentahydrate in crystalline form. Mylan argued that it did not infringe because the API in its ANDA product was not substantially pure, which the court construed to mean an “at least 90% chemical purity,” and because its API was not a hemipentahydrate.

Why Novartis Prevailed: Mylan first argued that it did not infringe because the API in its ANDA product was not “substantially pure.” The maker of Mylan’s API admitted, though, that it produced substantially pure API. Further, the specification in Mylan’s ANDA stated that its API must not have more than 2.95% impurities. Mylan argued that its API dissociates into separate sacubitril and valsartan products, but the court found this not to be the case based on Mylan’s statement to FDA that it “performed studies on both the drug substance and drug product to ascertain that Sacubitril/Valsartan . . . is stable during drug product manufacture and stability . . . with no conversion to other polymorphic forms.” The court found that Mylan’s ANDA product was substantially pure.

Mylan next argued that its API was not a hemipentahydrate. The record evidence was undisputed that an asymmetric unit of Form II API consists of three formula units, such that each asymmetric unit consists of 3x water molecules. In the asymmetric unit of Form II, there are ten positions for water molecules. The court found that Mylan correctly modeled the water molecule OW7 as disordered over two positions, but found that Mylan incorrectly modeled three of the remining water molecules in the asymmetric unit of Form II—OW1, OW3, and OW8—as present at 100% occupancy. For this reason, Mylan was incorrect to model 9 total water molecules per asymmetric unit, that when divided by three formula units per asymmetric unit, equals 3 water molecules per formula unit (i.e., trihydrate). The court found, however, that Mylan’s “trihydrate model of Form II [was] chemically impossible.” Instead, the court concluded that Novartis’s controlled humidity TGA, DVS, and Hi-Res TGA testing all demonstrated that OW1, OW3, and OW8 are present at 50% occupancy, which results in 2.5 bound waters (i.e., hemipentahydrate). For this reason, the court found that Mylan infringed the patents-in-suit.