Novartis' Blockbuster Heart Failure Drug Entresto Faces Renewed Challenges to Core Chinese Patents

Author: Y.J.M

Entresto is an angiotensin II receptor blocker developed by Novartis. In the Chinese market, Entresto (brand name: Nuo Xin Tuo; Chinese generic name: Sacubitril/Valsartan Sodium Tablets; alias: LCZ696 tablets) was approved on July 26, 2017, for adult patients with chronic heart failure with reduced ejection fraction, to reduce the risk of cardiovascular death and heart failure hospitalization. In 2018, global sales of Entresto reached $1.028 billion, representing a 103% increase compared to 2017, thereby entering the ranks of blockbuster drugs.

Entresto is a co-crystal complex of the sodium salts of sacubitril and valsartan (The isolated active substance is a co-crystal complex of the sodium salts of two individual active components, sacubitril and valsartan, in hydrated form). It should be noted that the Center for Drug Evaluation (CDE) of the National Medical Products Administration reviewed this complex as a new chemical entity (as shown in the figure below).

[Source: CDE Technical Review Report]

By the end of August, more than 20 pharmaceutical companies in China had submitted applications for registration or clinical trials for this product. As sales of Entresto continue to surge, it is reasonable to believe that an increasing number of companies will target this product for research and development. To clear patent infringement obstacles and accelerate market entry, launching patent challenges against the originator drug will be their optimal choice.

According to the Yaozhi Patent Connect database, to protect Entresto, Novartis primarily holds three granted Chinese patents and one under examination: CN101098689B (Application No. 200680001733.0), CN102702119B (Application No. 201210191052.2, a divisional application of 200680001733.0), CN102091330B (Application No. 201110029600.7), and CN103251587A (Application No. 201310154064.2). These patents respectively protect solid complexes and crystals (with 2.5 water molecules), solid complexes and crystals (with 0–3 water molecules), pharmaceutical compositions, and pharmaceutical formulations.

The patents involved in this case are CN101098689B and CN102702119B, which serve as core patents for Entresto, protecting solid complexes and crystals. According to information from the Reexamination and Invalidation Adjudication Department of the Patent Office of the China National Intellectual Property Administration (CNIPA), multiple domestic companies have separately filed requests for invalidation declarations against these two patents with the Patent Reexamination Board, and most of these cases have already undergone oral proceedings. The relevant information is summarized as follows:

The status of two other Chinese patents, CN102091330B and CN103251587A, is also not optimistic. CN102091330B was declared entirely invalid by the Patent Reexamination Board of the China National Intellectual Property Administration on December 27, 2017, due to insufficient disclosure and lack of inventiveness (note that this patent is currently still in a valid state, primarily because Novartis disagreed with the invalidation decision and filed an administrative lawsuit with the Beijing Intellectual Property Court). Meanwhile, CN103251587A has undergone multiple rounds of substantive examination and reexamination procedures but has not yet been granted, and its prospects for approval are not promising.

Overall, the several patents filed by Novartis for Entresto have all faced challenges to varying degrees. We will continue to track and report on the final outcomes of these related patents.