Entresto patent upheld in US, invalidated in Korea…Approval the next hurdle

US court finds Orange Book listing of Entresto combination patent lawful

Korean counterpart invalidated the listing in 2024...Generics prevail in complex patent case this year

Major patent barriers cleared, but no Entresto generics yet...Formulation, approval remain hurdles

The patent dispute surrounding Novartis’ heart failure treatment Entresto (sacubitril/valsartan) is drawing renewed attention in the US after a federal court ruled that Novartis lawfully listed an early combination patent for the drug in the Orange Book.

This contrasts with the outcome in Korea. A Korean patent stemming from the same original invention as the US patent whose Orange Book listing was upheld was invalidated in a decision finalized in 2024. Generic drugmakers also secured a final victory this year in litigation over subsequent patents related to the complex used in Entresto.

While the major patent barriers have effectively been cleared in Korea, no generic has yet reached the market. The key barrier to generic entry now has shifted from patents to formulation technology and regulatory approval.

US court upholds Orange Book listing of Entresto combination patent

The US District Court for the Southern District of New York recently granted Novartis’ motion to dismiss a lawsuit filed by the Iron Workers Local 580 Insurance Fund.

The issue was whether Novartis lawfully listed U.S. Patent No. 8101659 in the Orange Book for Entresto. The patent covers a pharmaceutical composition containing valsartan and sacubitril in an approximately 1:1 ratio. It was set to expire on Jan. 15, 2025, but pediatric exclusivity extended the protection through July 15 of that year.

The insurance fund argued that because Entresto contains the two active ingredients in a combined complex, it was improper to list a patent that did not directly claim the complex itself in the Orange Book. The lawsuit alleged that without the patent, generics could have launched on Jan. 16, 2025, but pediatric exclusivity delayed their entry until July, forcing the fund to continue paying the higher cost of branded original Entresto in the interim.

The court rejected the argument. It found that because the patent covers the combination of valsartan and sacubitril, the core active ingredients of Entresto, the fact that the two ingredients exist as a complex in the marketed product alone does not make the patent unrelated to Entresto.

The US Court of Appeals for the Federal Circuit had previously upheld the validity of the patent in 2025. The court made clear at the time that the patent protects the “combination” of sacubitril and valsartan, rather than the sacubitril-valsartan “complex” itself.

Related patent invalidated in Korea...Initial patent barrier removed

In Korea, however, the corresponding patent based on the same original invention was ultimately found invalid. Novartis had obtained a Korean patent for a “pharmaceutical composition comprising valsartan and an NEP inhibitor.” Although its claims are not identical to those of the US ’659 patent, it similarly covers the combination of valsartan and a sacubitril-class NEP inhibitor.

Hanmi Pharmaceutical and other Korean generic drugmakers challenged the validity of the patent. In November 2023, the Patent Court ruled in favor of the generic companies, finding that the patent specification did not contain sufficient experimental data or specific descriptions demonstrating the therapeutic effects of using the two ingredients together for conditions including heart failure.

The Supreme Court declined to hear Novartis’ appeal in April 2024, finalizing the invalidation of the patent. While the corresponding early combination patent in the US was recognized as valid protection for Entresto, the patent itself was invalidated in Korea.

Entresto is not simply a mixture of sacubitril and valsartan. The two active ingredients, along with sodium and water molecules, form a supramolecular complex with a defined structure. While the initial patent broadly protected the combined use of sacubitril and valsartan, subsequent patents specifically protected the complex and crystalline forms used in the marketed product.

Korean generic drugmakers also challenged these complex-related patents. One dispute centered on whether the 2.5-hydrate supramolecular complex used in Entresto and a different hydrate form developed by a generic company fell within the scope of the same patent.

In January this year, the Supreme Court ultimately ruled that the generic company’s product did not fall within the scope of Novartis’ patent. The original complex contains valsartan, sacubitril, sodium, and water molecules at a ratio of 1:1:3:2.5, while the generic product has a ratio of 1:1:3:3, which the court found resulted in different crystal structures and properties.

Generic drugmakers also prevailed in an invalidation action involving another complex patent. The Supreme Court found that the patent did not sufficiently describe manufacturing methods to enable the various complexes claimed in the patent to actually be produced, and dismissed Novartis’ appeal in January this year.

Patent battles won, but no generics yet on market

Despite these victories, no Entresto generic has yet reached the Korean market. This is because invalidating or designing around a patent is a separate matter from developing a product equivalent to Entresto and obtaining regulatory approval.

In Entresto, its two active ingredients form a specific structure. Even if a generic drugmaker develops a different crystalline form or formulation to avoid the patents, it must still achieve drug absorption and dissolution characteristics comparable to those of the originator and demonstrate bioequivalence.

In other words, winning the patent disputes does not translate directly into a market launch.

The situation also differs from that in the US. In the US, MSN launched its Entresto generic on July 22, 2025, shortly after pediatric exclusivity for the ’659 patent expired. Ten more generics entered the market two days later. According to the court ruling, 18 companies had sought approval for Entresto generics, 13 of which ultimately received final approval.

In Korea, by contrast, generic companies have cleared the major patent barriers, but no product has yet received approval. Therefore, the focus of Korea’s Entresto generic race has shifted from whether companies can “overcome the patents” to whether they can “design around them while actually developing an equivalent product capable of securing regulatory approval.”