Here’s the Chance?! A Core Patent of Novartis’ Entresto in China is Fully Declared Invalid

By Caicai

The festive atmosphere has become increasingly strong as the Chinese New Year is approaching, and there has been good news in the pharmaceutical circle in China: the Patent Reexamination Board of the State Intellectual Property Office of China has recently announced the composition patent examination results of Novartis’ billion-USD blockbuster drug Entresto (sacubitril/valsartan sodium tablets, LCZ696): "Patent fully declared invalid" for the invention Pharmaceutical compositions comprising valsartan and NEP inhibitors of the patentee Novartis on the ground of inventiveness problem. In other words, the patent portfolio of this heart failure "miracle drug" Entresto that has been marketed in China just in 2017 is officially broken through, and the chance for Chinese generic drug enterprises has come.

Past and present of the "most encouraging" heart failure "miracle drug" Entresto over the 20 years

Heart failure’s main manifestation is insufficient blood pumping of heart, and it is a potentially deadly disease of which most patents need life-long treatment. Before Entresto, the most popular therapeutic regimen for heart failure is the "Golden Triangle Regimen", namely, angiotensin converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) + aldosterone receptor antagonist + β-receptor blocker, mainly used to regulate the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS), wherein, the representative drug of ACEI is enalapril, and the representative drug of ARB is valsartan. However, the effects of SNS-RAAS against heart failure are not satisfactory, with high mortality: about 50% patients die 5 years after the diagnosis. There was no remarkable progress in the heart failure field in more than a decade.

Entresto is the world’s first ARB-NEP (neprilysin) inhibitor, with the active ingredient of sacubitril and valsartan sodium, being a sodium salt crystal complex combined by 1:1 molar ratio of the two "old drugs": the ARB valsartan and the NEP inhibitor sacubitril, with the former blocking the angiotensin II receptor blocker in RAAS, and the latter’s metabolite inhibiting NEP, functioning as vasodilation, prevention and reversal of cardiovascular remodeling, and natriuresis, etc. It has significant therapeutic advantages over the existing heart failure drugs.

The drug was approved by the U.S. FDA in July 2015, and approved by the EU in November of the same year; it obtained the top Class I recommendation in the new Guideline for the Management of Heart Failure issued by the American College of Cardiology (ACC), American Heart Association (AHA), Heart Failure Society of America, and European Society of Cardiology (ESC) in 2016, and is called the "most encouraging" heart failure drug in the past 20 years. Entresto was filed the marketing application to the CFDA in February 2016, and was included in the priority review by the CDE in December of the same year by reason of "having significant therapeutic advantages compared to existing treatment means". Entresto (the trade name in Chinese: 诺欣妥) was officially approved for marketing in China by CFDA in July 2017, for adult chronic heart failure patients with reduced ejection fraction, to reduce their risks of cardiovascular death and heart failure hospitalization.

There are about 60 million heart failure patients in the world, with the morbidity in the population aged above 45 of 3-5%. According to a large epidemiological survey in 2003, the prevalence of heart failure in adults in mainland China reached 0.9%, with about 4.50 million heart failure patients, meaning that the market potential is tremendous. According to the financial report of Novartis, the sales revenue of the drug was USD 170 million in 2016, and grew to USD 322 million in the first 3 quarters of 2017; the figures were not as high as expected, but already showed the strong growth momentum. An industry analyst forecast that the annual sales peak of the drug might exceed USD 5 billion, and approach USD 10 billion.

Patent of the compositions declared invalid not powerful enough

There are 3 patents granted to Entresto in China, with the patent No. separately being ZL200680001733.0, ZL201210191052.2, and ZL201110029600.7.

Patent portfolio of Entresto in China

Wherein, ZL200680001733.0 and ZL201210191052.2 are the parent application and divisional application of the same family, and both protect the solid composition and crystal complex, and the ZL201110029600.7 is the patent fully declared invalid this time.

The patentee Novartis filed the application for the patent titled "Pharmaceutical compositions comprising valsartan and NEP inhibitors" on January 16, 2003, with the priority date being January 17, 2002, which was granted on April 8, 2015 (patent No.: ZL201110029600.7). On April 5, 2017, the Lawyer Dai Jinliang from Guangdong Sino-Win Law Firm filed the request for invalidation of the patent to the Patent Reexamination Board on the ground that "the specification of the patent involved is not fully disclosed", "claims are not supported by the specification", "scope of protection of claims is not clear", and "claims are not inventive", not complying with relevant provisions of the Patent Law, and the patent was fully declared invalid thereafter (this reexamination was listed as the fifth case in the "significant cases public hearing" by the State Intellectual Property Office of the P.R.C.).

The Claim 1 of the patent declared invalid this time is as follows:

1. A pharmaceutical composition comprising (i) the AT 1-antagonist valsartan or a pharmaceutically acceptable salt thereof and (ii) an N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester or N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenyImethyl)-4-amino-2R-methyibutanoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compositions patent is declared invalid, however, according to a professional patent lawyer of the industry, Novartis has not completely lost protection of Entresto, because it still possesses the patent (patent No. CN101098689B) that is specially used to protect the valsartan + sacubitril combination; in other words, other enterprises still need to successfully challenge this patent to directly imitate Entresto, otherwise, they can only develop the combination of valsartan + other NEP inhibitors.

The distinctive Chengdu Easton

Once a patent is declared invalid, any enterprise on the market may use the technology originally within the scope of protection thereof for free, and most generic enterprises only need to conduct BE tests. Furthermore, the first generic drug successfully marketed after a patent is invalidated can obtain certain market exclusivity, which is 4 years among the Class 3.1 new drugs in China. There have been Chinese enterprises applying for the clinical trial of the Entresto generic drug since 2015, wherein, the most notable enterprises are Chengdu Easton and Salubris.

List of Entresto Generic Drugs Applied for by Chinese Enterprises

Compared to Entresto, the salt type of sacubitril/valsartan calcium disodium tablets applied for by Chengdu Easton is changed, and the drug is applied for as a Class 2.1 chemical drug, therefore, it is not within the scope of protection of patent of Entresto: the original patent protects the sacubitril/valsartan trisodium hemipentahydrate. And Salubris is likely the first and currently the only Chinese pharmaceutical enterprise that has launched the clinical trial.

However, things have not come to a close, because Novartis may file a lawsuit to a people’s court within three months upon receipt of the notice.