Patent Battle Over Entresto: Three Chinese Pharma Giants Challenge Novartis

On July 2, the website of the China National Intellectual Property Administration (CNIPA) published three patent invalidation decisions, revealing that Salubris, CSPC Ouyi Pharmaceutical Co., Ltd., and Nanjing Chia Tai Tianqing had independently challenged the core patent of Novartis's blockbuster drug Entresto (sacubitril/valsartan sodium), titled "Pharmaceutical combination product of angiotensin receptor antagonist and NEP inhibitor." The Reexamination and Invalidation Department of the CNIPA ultimately issued a uniform decision of "partial invalidation of the patent."

Based on the action dates of the three companies, Salubris, CSPC Ouyi Pharmaceutical Co., Ltd., and Nanjing Chia Tai Tianqing filed their patent invalidation applications on November 1, 2018, June 6, 2019, and November 14, 2019, respectively. The earliest patent invalidation application, filed by Salubris, dates back 2.5 years.

While the recent joint challenge against Entresto's core patent by three domestic giants has drawn significant attention, an earlier patent challenge against Entresto in China was actually initiated by a lawyer named Dai Jinliang. The patent he challenged is "Pharmaceutical compositions comprising valsartan and a NEP inhibitor," which also sparked a major stir in January 2018.

In addition to the patent challenges directly initiated by companies and individuals, other enterprises in China have also submitted marketing applications for generic sacubitril/valsartan after completing bioequivalence (BE) studies by circumventing the crystal form patent, namely Nanjing Yixinhe.

Entresto is a crystalline salt complex formed by sacubitril and valsartan in a 1:1 molar ratio, representing the first angiotensin receptor-neprilysin inhibitor (ARNI) class drug. The co-crystal contains 2.5 molecules of water of crystallization, and Novartis’s patent claims for the originator drug cover complexes with 0 to 3 waters of crystallization. The crystal form protection patent expires in 2026.

Entresto Structural Formula

However, the claims regarding crystal form patents are relatively complex, involving comparisons of various crystallographic parameters. Nanjing Yixhin has developed sacubitril/valsartan sodium trihydrate, whose co-crystal structure contains three molecules of water of crystallization, and has completed the filing and registration for the active pharmaceutical ingredient (API). This indicates that Nanjing Yixhin aims to circumvent the crystal form patent protection of the originator drug by utilizing the trihydrate complex, thereby achieving an early market launch for the generic drug.

Whether it is the joint patent challenge by the three Chinese pharmaceutical companies or Nanjing Yixinhe’s strategy to design around the crystal form patent, the objective is to break the market exclusivity of the originator drug. However, all three companies only secured a ruling of “partial patent invalidation” in this instance. Moreover, based on the invalidation decision documents, Novartis has retained the patent for the hemi-pentahydrate form. This indicates that the prospect of the three companies securing early market entry by invalidating Entresto’s crystal form patent is slim. Whether Nanjing Yixinhe can successfully launch its product by adopting a non-infringing trihydrate crystal form remains a key development to watch.

The reason Entresto has received such favorable treatment is that this drug represents a major breakthrough in the heart failure field over the past 20 years; since its market launch in 2015, its global sales have already reached $2.5 billion.

Entresto has also been approved in China for the treatment of heart failure and has been included in the 2020 National Reimbursement Drug List. On June 3, Entresto received approval in China for a new indication for the treatment of primary hypertension. China is the first country to approve Entresto for the hypertension indication. This marks the first new drug breakthrough in China’s hypertension treatment landscape in over a decade and is expected to shift the hypertension management paradigm from solely lowering blood pressure to comprehensive cardiovascular event risk management throughout the entire disease course.

We will continue to closely follow the subsequent developments of the Entresto patent battle in China.