Bayer's Blockbuster Drug Xarelto Loses Key Formulation Patent in China

On July 18, the China National Intellectual Property Administration issued a decision on the request for invalidation, declaring the patent “Method for Preparing Solid Pharmaceutical Compositions for Oral Administration,” with application/patent number “200480035106.X” held by Bayer Intellectual Property GmbH, as “wholly invalid.”

The technology described in the patent involves special surface treatment of rivaroxaban during the wet granulation stage, which improves absorption properties and significantly enhances the bioavailability of the resulting formulation. Sodium lauryl sulfate is used as the wetting agent, and hydroxypropyl methylcellulose serves as the hydrophilic binder.

It has been pointed out that the invalidation of a formulation patent is not unusual, as it merely involves a conventional wet granulation process.

It is not yet time to draw a conclusion. Pursuant to Article 46, Paragraph 2 of the Patent Law, Bayer may file a lawsuit with the Beijing Intellectual Property Court within three months.

The patent expired in 2020.

According to the Decision on Examination, the China National Intellectual Property Administration (CNIPA) accepted the request for invalidation on March 20, 2019, and forwarded the Request for Invalidation and the evidence to the patentee, while simultaneously constituting a collegial panel to examine the case. Ultimately, the CNIPA declared the patent invalid.

In fact, the compound patent for rivaroxaban is also set to expire in 2020, and currently, only the original research product is available on the market. Public information shows that rivaroxaban was jointly developed by pharmaceutical giants Bayer and Johnson & Johnson. It is a blood thinner with the brand name Xarelto.

The drug was approved for marketing in Canada and the European Union in October 2008, officially entered China in June 2009, and received FDA approval for marketing in the United States in July 2011. After its introduction into China, Xarelto was used solely for the prevention of thrombosis in patients undergoing hip or knee replacement surgery.

In May 2015, two new indications for rivaroxaban tablets were approved by the China Food and Drug Administration (CFDA): treatment and prevention of deep vein thrombosis (DVT) and prevention of pulmonary embolism (PE); and stroke prevention in patients with atrial fibrillation. Rivaroxaban is listed as a Class B drug in the 2017 National Reimbursement Drug List, with reimbursement restricted to patients with non-valvular atrial fibrillation who have inadequate control with warfarin therapy or are at high risk of bleeding, as well as patients undergoing lower-extremity joint replacement surgery.

According to Bayer’s financial reports, rivaroxaban has become a star product for Bayer in the global market in recent years. In 2018, global sales of rivaroxaban reached €3.631 billion, representing a 10.1% increase compared to 2017.

Bayer has repeatedly emphasized the importance of the Chinese market. In its first-quarter 2019 financial report, Bayer reported sales of €776 million in the Chinese market, a year-on-year increase of 24%. Among these, sales of Bayer’s best-selling product rivaroxaban (Xarelto) doubled in China during the first quarter, reaching €75 million (approximately RMB 560 million).

Stefan Oelrich, President of Bayer Prescription Drugs Worldwide, stated in a conference call that he was highly satisfied with the company’s performance in the Chinese market and expressed hope that its sales in China would exceed €3 billion in 2022.

Ironically, shortly after Stefan Oelrich finished speaking, the formulation patent for rivaroxaban was declared invalid.

Chinese Generic Drug Companies Welcome New Opportunities

From the perspective of industry insiders, a request for invalidation of patent rights is a legitimate market practice. By convention, once a patented drug is declared invalid or its patent expires, the market becomes dominated by generic drugs.

In January last year, the Patent Reexamination Board of the China National Intellectual Property Administration issued a notice on the results of patent examination: the invention titled “Pharmaceutical Compositions Containing Valsartan and an NEP Inhibitor,” owned by Novartis AG (hereinafter referred to as “Novartis”), was “declared entirely invalid.” This caused a sensation at the time.

The aforementioned pharmaceutical composition is Entresto (generic name: sacubitril/valsartan sodium tablets), indicated for the treatment of heart failure. At the time, sales projections estimated that the drug would achieve revenue as high as $10 billion.

Although the invalidation of the patent created opportunities for domestic generic drug manufacturers, this did not mean that producing a generic version of “Entresto” was an easy task. At that time, the patent barriers surrounding “Entresto” still existed.

According to 21st Century Business Herald, citing lawyers, the two patents CN101098689B and CN102702119B still protect the core compound of Entresto, with an expiration date in 2026. If these two patents remain valid, it is estimated that generic versions of Entresto will have to wait another 8 years.

In November of the same year, Shanghai Suntas Haimen Pharmaceutical submitted an application for market approval of a generic version of sacubitril/valsartan sodium tablets, marking the first such domestic application for this generic drug. Although the patent protection for Entresto in China is weakening, the specific launch date for this class of generic drugs remains uncertain due to the remaining two patents.

The situation regarding the formulation patent for rivaroxaban, however, is different. Apart from the absence of any disclosed additional patent protection, its patent was also set to expire in 2020. This means that the invalidation of rivaroxaban’s formulation patent merely advanced the market launch date of generic drugs by six months.

In fact, as the patent for rivaroxaban nears expiration, the domestic generic drug competition has already begun. According to the Yaozhi Drug Registration and Acceptance Database, there are as many as 63 acceptance numbers for generic rivaroxaban applications. Among the 42 acceptance numbers filed under the old Class 6 category, 40 have been approved for clinical trials. There are 21 acceptance numbers filed under the new Class 4 generic drug category, involving 15 companies, including Huahai, Chia Tai Tianqing, CSPC Ouyi, and Yangzijiang.

On May 23, Huahai Pharmaceutical announced that it had received notification from the U.S. Food and Drug Administration (FDA) that its Abbreviated New Drug Application (ANDA) for rivaroxaban tablets had been granted tentative approval. (Tentative approval indicates that the FDA has completed all review requirements for the generic drug, but approval is withheld due to unexpired patent or exclusivity rights.)

Huahai Pharmaceutical disclosed that in 2018, the sales revenue of this drug in the U.S. market was approximately $5.158 billion, while the sales revenue in the domestic hospital market was approximately RMB 1.527 billion. To date, Huahai Pharmaceutical has invested approximately RMB 14.7005 million in research and development expenses for the rivaroxaban tablet project.

Source: Jian Shi Ju Author: Yu Yi