IP Law Daily, PATENT—D.D.C.: FDA’s approval of generic Entresto upheld following Novartis’s challenge, (Oct 16, 2024)

By Saurabh Kashyap, B.A., LL.B., LL.M.

The FDA’s decisions on labeling carveouts, active ingredient sameness, and safety assessments were reasoned, lawful, and consistent with regulatory standards.

Ruling on multiple summary judgment motions in a lawsuit filed by Novartis challenging the Food and Drug Administration’s approval of a generic version of its heart failure medication Entresto, the federal district court in the District of Columbia granted the defendants’ cross-motions for summary judgment and denied the plaintiff's motion. The court ruled that the FDA lawfully approved MSN Pharmaceuticals Inc.'s abbreviated new drug application (ANDA) with appropriate labeling carveouts, despite Novartis’s allegations of patent infringement. The court found that the generic product met the statutory requirements for labeling and active ingredient sameness under the Federal Food, Drug, and Cosmetic Act. It also held that the FDA acted within its discretion by excluding patented indications and dosage instructions from MSN’s label without undermining the safety or effectiveness of the generic drug for remaining uses (Novartis Pharmaceuticals Corp. v. Becerra, No. 24-cv-02234 (D.D.C. Oct. 13, 2024)).

Background. The plaintiff, Novartis Pharmaceuticals Corporation, is a leading pharmaceutical company specializing in innovative therapies and the developer of Entresto, a widely used heart failure medication. Entresto is a fixed-dose combination of sacubitril and valsartan marketed for the treatment of chronic heart failure.

The federal defendants include Xavier Becerra, the Secretary of Health and Human Services, and the Commissioner of the Food and Drug Administration. The Department of Health and Human Services and the FDA oversee the approval and regulation of drug applications, ensuring both generic and brand-name drugs meet safety and labeling standards. Intervenor-defendant MSN Pharmaceuticals Inc. is a pharmaceutical company focused on developing and distributing generic drugs, including the generic version of Entresto.

The contested drug, Entresto, is covered by several Orange Book-listed patents central to Novartis’s infringement claims. These patents include U.S. Patent 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). The '226 patent covers treatment methods for chronic heart failure patients with preserved ejection fraction. The '143 patent focuses on the drug's clinical use for specific patient subgroups. The '192 patent further expands the drug's indication to a broader population of heart failure patients. Finally, the '667 patent protects the dosing regimen outlined in the Entresto label. Novartis argued that the generic drug infringed on these patents by replicating protected uses and formulations.

MSN Pharmaceuticals filed an ANDA in 2019, seeking FDA approval to market a generic version of Entresto. To avoid infringing Novartis’s patents, MSN submitted a Section viii statement under 21 U.S.C. § 355(j)(2)(A)(viii), proposing to omit patented indications and dosing instructions from its generic product’s label. In response, Novartis filed two citizen petitions urging the FDA to reject MSN’s ANDA, arguing that the generic’s label did not meet the regulatory sameness standards and that its active ingredients were not identical to those in Entresto. The FDA denied both petitions, emphasizing that the generic product satisfied the required statutory criteria. In July 2024, the FDA approved MSN’s ANDA. Then Novartis filed this lawsuit, claiming the agency's approval violated the APA and the Federal Food, Drug, and Cosmetic Act. Novartis sought to set aside the approval and filed a motion for a preliminary injunction. While the court initially stayed the approval, it ultimately denied Novartis's request for preliminary relief, leading to the present summary judgment proceedings.

Skinny label carveout. The court found that MSN's label properly utilized a "skinny-label" carveout, allowing a generic drug manufacturer to omit patented uses without violating FDA regulations. The court relied on Bristol-Myers Squibb Co. v. Shalala, 91 F.3d 1493 (D.C. Cir. 1996), which established the validity of such carveouts to facilitate the timely introduction of generic drugs. The court dismissed Novartis’s argument that the Bristol-Myers Squibb precedent had been weakened by the Supreme Court’s recent ruling in Loper Bright Enterprises v. Raimondo, 144 S. Ct. 2244 (2024). Instead, it held that the FDA acted within its statutory authority by approving the generic label, which excluded only those uses still under patent protection. The court further noted that the FDA correctly compared the generic label to the most current version of the Entresto label, ensuring that the approval met regulatory standards.

Dosing regimen carveout. Addressing the dosing regimen carveout, the court upheld the FDA’s decision to approve MSN’s generic without including the specific dosing instructions protected by the ’667 patent. The FDA relied on the TITRATION study, which compared two dosing regimens for Entresto, finding that a slower escalation might reduce the risk of side effects for certain patients. However, the court emphasized that the FDA concluded the study's findings were not definitive and that the absence of the specific dosing regimen would not render the generic drug unsafe. The agency's decision to omit the dosing instructions was consistent with its regulations under 21 C.F.R. § 314.127(a)(7), which allow for labeling modifications as long as the drug remains safe and effective for all non-protected uses.

Ingredient sameness. In evaluating the active ingredient sameness requirement, the court deferred to the FDA's scientific determination that MSN's generic product contained the same active ingredients as Entresto. Both drugs feature sacubitril sodium and valsartan disodium, which are chemically identical in their anionic forms. The court rejected Novartis's argument that differences in solid-state form—whether the ingredients appeared as co-crystal or individual salt—undermined the sameness requirement. It cited Cytori Therapeutics, Inc. v. FDA, 715 F.3d 922 (D.C. Cir. 2013), emphasizing the high level of deference courts must afford to the FDA’s scientific expertise.

Nomenclature. The court also addressed Novartis's claim that the FDA's use of scientific nomenclature in describing the active ingredients reflected a change in agency policy. Novartis argued that the shift from referring to the compounds as “sacubitril” and “valsartan” to the more specific terms “sacubitril sodium” and “valsartan disodium” indicated inconsistency. However, the court found the distinction was not material, as both versions referred to the same chemical compounds. The court noted that under longstanding FDA guidance, differences in solid-state forms do not affect the active ingredient sameness requirement, and the agency's approach was consistent with its prior rulings.

Conclusion. The court ultimately concluded that the FDA acted within its discretion in approving MSN's ANDA and found no evidence that the agency's decision was arbitrary or capricious. It upheld the FDA's generic drug approval, affirming that MSN's labeling carveouts and active ingredient formulations complied with statutory and regulatory requirements. Thus, the court denied Novartis’s motion for summary judgment, granted the cross-motions filed by the federal defendants and MSN, and dismissed Novartis’s infringement claims.

The Case is No. 24-cv-02234.

Judge: Friedrich, D.

Attorneys: Marlan Golden (Hogan Lovells US LLP) for Novartis Pharmaceuticals Corp. Gabriel Schonfeld, U.S. Department of Justice, for the United States. Chad A. Landmon (Polsinelli PC) for MSN Pharmaceuticals Inc.

Companies: Novartis Pharmaceuticals Corp.; MSN Pharmaceuticals Inc.

MainStory: TopStory Patent DistrictofColumbiaNews GCNNews