Entresto® (sacubitril/valsartan)
Case Name: Novartis Pharms. Corp. v. Becerra, Civ. No. 24-cv-2234 (DLF), 2024 WL 4492072 (D.D.C. Oct. 15, 2024) (Friedrich, J.)
Drug Product and Patent(s)-in-Suit: Entresto® (sacubitril/valsartan); U.S. Patents Nos. 9,517,226 (“the ’226 patent”), 9,937,143 (“the ’143 patent”), 11,135,192 (“the ’192 patent”), and 11,058,667 (“the ’667 patent”)
Nature of the Case and Issue(s) Presented: In 2015, FDA approved Entresto to treat chronic heart failure in all adult patients. In 2021, FDA approved a supplement to Entresto’s indication to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. The ’226, ’143, and ’192 patents cover this indication. Entresto’s label explains that introducing Entresto more slowly to patients new to or taking only low doses of ACE inhibitors and ARBs resulted in moderately fewer adverse side effects. The ’667 patent covers the dosing regimen.
MSN submitted an ANDA to make and sell generic sacubitril and valsartan tablets in 2019, which included a Section viii carve out to omit those patented methods, namely, treatment of adult preserved ejection fraction patients and the dosing regimen.
In April 2019, Novartis submitted a citizen petition requesting FDA refrain from approving any Entresto-related ANDA for drugs not comprised of “one complex with coordinated ionic bonds between anionic sacubitril, anionic valsartan, and cationic sodium.” In May 2024, FDA denied the petition as inconsistent with its longstanding position that active ingredient sameness generally depends on the chemical “identity of [a drug’s] individual active ingredients,” rather than the ingredients’ physical form (for example, as a co-crystal). FDA further explained that it viewed Entresto as a fixed-combination of its active ingredients: sacubitril sodium and valsartan disodium. In September 2022, Novartis submitted another citizen petition requesting that FDA refrain from approving ANDAs proposing the labeling carveouts like those of MSN. On July 24, 2024, FDA denied the petition. That same day, FDA approved MSN’s ANDA.
On July 30, 2024, Novartis filed suit to challenge the denial of Novartis’s citizen petitions and the approval of MSN’s ANDA, alleging that FDA’s actions violate the APA, the Hatch Waxman Act, and FDA regulations. The court denied plaintiffs’ motin for summary judgment and granted defendants’ motion for summary judgment.
Why FDA Prevailed: FDA regulations define permitted changes between a generic label as compared to the branded reference label. These include the “omission of an indication or other aspect of labeling protected by patent or accorded exclusivity.” These changes are acceptable so long as they do not render the proposed generic drug product less safe or effective than the branded reference drug for all remaining, non-protected conditions of use. Therefore, FDA’s approval of MSN’s carved out label did not violate statutory same-labeling requirements.
MSN’s carve out also complied with FDA regulations permitting the “omission of an indication or other aspect of labeling protected by patent.” Any omission under the regulations must turn on the “substance of the information that is omitted—not whether that substantive omission is accomplished by adding words or deleting them.” Novartis’s argument to the contrary—that a generic label may only omit patented uses by deleting words rather than adding them—“puts form over substance.” MSN’s carveout narrows the scope of the current Entresto indication by limiting coverage to reduced ejection fraction patients. Additionally, FDA provided a reasoned scientific basis in its response to Novartis’s citizen’s petition for its conclusion that carving out the dosing regimen section in the branded label will not render MSN’s generic drug less “safe or effective.”
Finally, with respect to the issue concerning active ingredient sameness, the court deferred to FDA’s factual determination that Entresto and MSN’s generic contain the same two active ingredients—sacubitril sodium and valsartan disodium. Both labels use the same language to describe the active ingredients. The parties dispute whether MSN’s generic product takes the form of a “co-crystal” or whether it is a physical mixture of “two independent salts.” But this distinction is irrelevant to the sameness inquiry: “a co-crystal composed of two active ingredients is merely a different solid-state form of the ingredients, not a new active ingredient.”
