Lessons for Biopharma From the Battle of Entresto®

After more than six years of high-stakes litigation in multiple courts and regulatory fights at the Food and Drug Administration (FDA), generic versions of Novartis Pharmaceuticals Corp. (“Novartis”)’s Entresto® have entered the market.

Entresto® (sacubitril/valsartan) is a fixed-dose combination regimen for treating heart failure. It is a blockbuster drug, generating billions of dollars since its approval in 2015 and expanded approvals thereafter. Over six years, Novartis and MSN Pharmaceuticals Inc. (“MSN”) battled in multidistrict patent infringement litigation (“MDL”) before the FDA, the District of Columbia district and appellate courts, and the Federal Circuit.

The litigation surrounding Entresto® is a preeminent example of the challenges of protecting blockbuster drug products and provides strategic lessons on both offensive and defensive patent litigation for biopharmaceutical drugmakers. Novartis used a number of different offensive and defensive strategies to protect Entresto®, but was faced with certain challenges, including the expiration of pediatric exclusivity of one of its asserted patents during the dispute. And while timing in Hatch-Waxman litigation is relatively predictable, other factors, including parallel proceedings, newly issued patents, stays, and appeals, can skew expectations of the timing for resolution. As such, both sides in Hatch-Waxman litigations of blockbuster drugs should prepare for the long haul.

The “complex” battle begins: U.S. Patent No. 8,101,659

Novartis’ Orange Book-listed ’659 patent claims administering a composition of valsartan and sacubitril in combination. The ’659 patent was set to expire on January 15, 2025, but included a period of pediatric exclusivity running through July 15, 2025. In 2019, Novartis sued 18 generic drugmakers for infringement of the ’659 patent. The lawsuits were consolidated into multidistrict litigation (MDL) in the District of Delaware. In re: Entresto (Sacubitril/Valsartan) Patent Litigation, 1:20-md-02930. Over time, most of the 18 generics exited the dispute, leaving MSN as the primary generic competitor.

During claim construction, the parties asked the court to interpret a claim term directed to administration of valsartan and sacubitril “in combination.” Novartis argued for the plain and ordinary meaning. MSN contended that the term limited the claim to administration of valsartan and sacubitril “as two separate components,” seeking a construction that would exclude its Abbreviated New Drug Application (ANDA) product, which — like Entresto® — is a chemical complex of valsartan and sacubitril. The court agreed with Novartis that “in combination” should be given its plain and ordinary meaning.

With “in combination” construed to cover both a physical combination and a complex, MSN stipulated to infringement but asserted that the ’659 patent did not enable and describe such complexes and therefore was invalid. Novartis argued that a valsartan/sacubitril complex was a novel after-arising invention that need not have been enabled or described in the ’659 patent.

The district court agreed with Novartis on enablement but not written description. Central to its decision was that valsartan/sacubitril complexes were unknown in the art as of the 2002 priority date. The court thus determined that such complexes need not have been enabled. This fact, however, supported the opposite decision for written description. The court found that, because complexes were unknown in the art as of the priority date, Novartis could not have possessed and described them. In a July 7, 2023, opinion, the court found that the ’659 patent lacked written description.

Novartis appealed the written description determination to the Federal Circuit. In a January 10, 2025, opinion, the Federal Circuit reversed the district court’s determination on written description and affirmed that the claims were not invalid for obviousness or lack of enablement. The court reasoned that “[b]ecause the ’659 patent does not claim valsartan-sacubitril complexes, those complexes need not have been described.” In re Entresto, Case No. 23-2218 (Fed. Cir. Jan. 10, 2025) (Lourie, Prost, Reyna, JJ.) at 12.

The Federal Circuit’s January 10 opinion triggered a flurry of motion practice, resulting in the issuance of a temporary restraining order (TRO) and an injunction preventing MSN from launching its generic Entresto®. MSN requested that the court stay the injunction, which it denied. MSN’s continued efforts to overcome the stay were also unsuccessful, with the Federal Circuit denying its petition for panel rehearing and en banc rehearing. In late August 2025, MSN filed a petition for a writ of certiorari asking the Supreme Court to resolve the question of whether courts may consider after-arising technology to hold that a patent is invalid under Section 112.

A multifaceted front: FDA citizen petitions and the D.C. courts

Novartis also mounted a separate front to protect Entresto® by filing citizen petitions with FDA. In 2019, Novartis requested that FDA not approve any ANDA for generic Entresto® that did not meet FDA’s active ingredient sameness requirement. Like the MDL litigation, physical combinations versus valsartan/sacubitril complexes was at the center of Novartis’ petition. For an ANDA applicant to rely on a reference-listed drug for approval, the active ingredient must be the same. 21 U.S.C. 355(j)(2)(A)(ii). Novartis argued that for a generic’s active ingredient to be the same as that of Entresto®, it must be a co-crystal complex. FDA disagreed, reasoning that a co-crystal composed of two active ingredients is merely a different solid-state form and not a new active ingredient.

In 2022, Novartis filed a second citizen petition requesting that FDA refrain from approving ANDAs with certain label carve-outs. Namely, MSN sought to carve out treatment of patients with left ventricular ejection fraction and associated dosing regimen instructions. FDA rejected Novartis’ argument that MSN’s carve-out was improper because it did more than merely delete words in the label but instead added words to it, finding that that argument “puts form over substance.”

On July 25, 2024, FDA denied both citizen petitions and tentatively approved MSN’s ANDA. Soon after, Novartis sued in the District of D.C. seeking a declaration that FDA’s denials were unlawful, an order vacating MSN’s ANDA approval, and injunctive relief. Novartis Pharms. Corp. v. Becerra et al., No. 24-CV-02234. Both MSN and the government filed oppositions to Novartis’ request for a TRO or preliminary injunction. The court denied Novartis’ request for a preliminary injunction but granted a 24-hour TRO. Novartis appealed the injunction decision to the Court of Appeals for the D.C. Circuit in August 2024. While the appeal was pending, Novartis, the government, and MSN filed cross motions for summary judgment. The court denied Novartis’ summary judgment motion but granted the government and MSN’s on October 13, 2024. Novartis again appealed.

In September 2025, the D.C. Circuit affirmed the district court. Regarding the 2019 citizen petition, the court reiterated that longstanding FDA regulations and guidance make clear that drugs can have the same active ingredient even if they have different solid-state forms. Regarding the 2022 citizen petition, the court held that carving out an indication by adding words to the label rather than omitting them is not contrary to the regulatory scheme. Novartis Pharms. Corp. v. Kennedy, No 24-5235 (D.C. Cir., Sep. 26, 2025).

The last stand: U.S. Patent No. 11,096,918

While Novartis and MSN battled over the ’659 patent at the Federal Circuit, disputes regarding the Orange Book-listed ’918 patent continued in Delaware. The ’918 patent claims an amorphous solid form comprising sacubitril anions, valsartan anions, and sodium cations, and expires in November 2026. After a December 2024 trial, the court found that Novartis did not prove that MSN infringed the ’918 patent based on an insufficient comparison analysis by Novartis’ expert.

On appeal, Novartis sought and was granted a temporary injunction barring MSN from launching its generic Entresto®. The Federal Circuit, however, lifted the injunction on July 22, 2025. With the injunction lifted and the July 16, 2025, expiration of pediatric exclusivity for the ’659 patent, multiple generic drugmakers launched generic Entresto® at the end of July.

Lessons from the battle of Entresto®

The Entresto® litigations highlight the complex nature of defending blockbuster drugs against generic competition, and there are many strategic lessons in them. The “in combination” construction in the MDL litigation highlights the double-edged sword claim construction may present on infringement versus validity. Biopharmaceutical litigants should pressure test proposed claim constructions on all claims and defenses and consider their impact on parallel proceedings. Likewise, the tension between Section 103 obviousness and Section 112 written description/enablement may set a party up for the “squeeze.” Thoroughly vetting the state of the art may aid in navigating this tension. Like Novartis, biopharmaceutical litigants may also want to consider the strategic benefits and disadvantages of using multiple litigation forums (e.g., FDA, district court, the Patent Trial and Appeal Board, the International Trade Commission, etc.) in parallel. When determining forums in which to litigate, consider historic likelihood of success, time to resolution, and cost.