Wei Xiaoning| wrote an article

Wang Chen| edit

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_Baigene Shenzhou announced that it has filed patent infringement lawsuits against Sandoz and MSN in New Jersey. This is a response to the two pharmaceutical companies submitting a generic zebutinib marketing application (also known as the Abbreviated New Drug Application (ANDA) to the FDA and challenging the zebutinib patent. _

From the perspective of the Chinese pharmaceutical industry, in the U.S. market, we have long been a generic drug producer, and we often appear as a defendant challenging patent invalidity in ADNA litigation. For example, in 2022, in the ANDA lawsuit between the United States and Novartis over the multiple sclerosis drug fingolimod, Dong Sunshine from China was the defendant's generic pharmaceutical company, and then won the case, challenging the success of the original patent.

In China's patent linking system (the State Food and Drug Administration and the State Intellectual Property Office have issued the "Implementation Measures for the Early Resolution Mechanism of Drug Patent Disputes (Trial)" in 2021), there are countless cases in which Chinese generic pharmaceutical companies are defendants. For example, Hausen, Kelun, Wanbang, Sino-US Huadong, and Zhengda Tianqing jointly applied for the invalidation of the Boehringer Ingelheim empagliflozin compound patent and were accused, and Hausen teamed up with Shiyao Ouyi applied for the invalidation of the sunitinib core compound patent and defendant, etc.

第一次，This is because Chinese pharmaceutical companies, as original pharmaceutical companies, took the initiative to initiate a lawsuit against generic pharmaceutical companies, announcing that they would counterattack the patent challenge of generic pharmaceutical companies, and it occurred in the U.S. market.

It seems that such a precedent can only be set by zebutinib. At present, there are four original innovative drugs in China that have been successfully launched in the United States. In addition to the legendary/Johnson & Johnson & CAR-T City-T Sidd; Car-T Sidd; Car-T Sidd; Co., which will be successfully launched in 2022, two will only be approved in 2023.

Baiji's BTK inhibitor zebutinib, as China's first innovative drug to successfully sail to the United States, was approved for marketing in the United States as early as 2019. Since then, its indications have continued to expand and sales have increased steadily. It has been announced recently. It has reached a milestone of US$1 billion in annual sales, with US$1.3 billion sold globally in 2023.

Gu Yang, a lawyer at Hankun Law Firm, pointed out that since the promulgation of the Hatch Waxman Act in 1984, ANDA litigation has been very common in the American pharmaceutical industry and is a system that is beneficial to both generic pharmaceutical companies and original pharmaceutical companies.

In the eyes of industry insiders, Baekje Shenzhou, which has global genes, has a very mature patent layout, and the achievements of zebutinib no longer need to be proved by the actions of generic pharmaceutical companies. ** Patents being challenged are just a "champagne issue" for Baiji:I have already done my best to prepare, and I have the ability to bear the burden regardless of winning or losing. **

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Sandoz and MSN are both well-known generic pharmaceutical companies in the United States. According to Baiji's announcement, the two pharmaceutical companies had previously submitted an ANDA application with the FDA, seeking FDA approval for the marketing of generic zebutinib drugs. They also submitted a paragraph IV patent statement in the ANDA application, challenging some zebutinib Orange Book patents that are invalid/unenforceable/non-infringing, and Baiji announced that they would file a patent infringement lawsuit.

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The so-called ANDA is a drug registration application path corresponding to the NDA's New Drug Application. It can be understood as being exclusive to generic drugs. Generally, it does not require the submission of complete preclinical and clinical data, but it needs to be proved that it is bioequivalent to the original drug, and the process is simpler than the original drug application.

Orange Book refers to the FDA's original drug patent status register, which is used to review and approve corresponding generic drugs.

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Specific to the case of Baiji vs. Sandoz and MSN this time, according to Baiji's announcement, ** the two pharmaceutical companies have not challenged the core material component patents of zebutinib, and generic drugs will not be available until at least 2034. The core patents of zebutinib expire before they can be marketed. In other words, what generic pharmaceutical companies intend to circumvent is another non-core patent of zebutinib (the patent period may be longer than the core patent)**. The types of patents that can be registered in the Orange Book include compound (active ingredient) patents (i.e., core material component patents), formulation/composition patents, and method/use patents.

而接下来的流程，根据专利律师们的经验，短则数月，长则可能达到七八年。一旦原研药企选择起诉，该仿制药就进入30个月的遏制期无法上市。以30个月为期，仿制药胜诉、败诉、和解都有可能； If the patent lawsuit is still not decided after 30 months, the FDA can also approve ANDA to be the first to go public.，但若最终原研药企胜诉，仿制药企仍要承担产品上市后侵权赔偿的责任。

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For generic pharmaceutical companies, it can improve the certainty of research and development before drugs are marketed, and speed up the process of drug marketing within a 30-month period, thus saving them from the entanglement of a long patent protection war to a certain extent;

For original pharmaceutical companies, challenges by generic pharmaceutical companies to their patents trigger prosecution/non-prosecution procedures, which reduces the cost of prosecuting generic pharmaceutical companies.

It should be noted that the ANDA system is only used for small molecule chemical drugs. The review of biosimilars has a more complicated process. Generally, patent wars will start after the drug is launched.

They are all patent disputes about zebutinib. The Baiji v. Sandoz and MSN case is still fundamentally different in nature from the Abbwe v. Baiji Shenzhou case in June 2023. This time, the generic drug wants to challenge the invalidity of some of the patents of zebutinib before going on the market, which is a game between the generic drug and the original drug; and the last time, AbbVie immediately sued zebutinib, which had been on the market for several years, for infringement after a new application of ibutinib was approved, which was a confrontation between the original drug and the original drug.

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Baiji's "Champagne Problem"

It is never a good thing that the patents of original pharmaceutical companies are challenged, which means that their drugs risk being eroded by generic drugs in advance. However, from the outside world, this time Baiji lawsuit against generic pharmaceutical companies in the United States cannot help but have some sense of pride-innovative drugs from China have finally been "copied" by American pharmaceutical companies, and we are going to sue them this time.

However, apart from this significance, some people in the pharmaceutical patent industry believe that this matter is common and common in the mainstream pharmaceutical industry in the United States. Just like financing, expansion, recruitment and other actions, drug patent layout is a normal business action. Winning or losing will definitely affect the company, but it will not cause a major issue of life and death for a while.

美国有专利延长和分化制度，律师为原研药企不停撰写专利、为仿制药企找到原研药的专利漏洞，已是非常成熟的做法，“这是他们的工作，他们就靠这个吃饭的” 。Actually,“为原研药企写专利”在业内几乎已被公认为“不如为仿制药企找漏洞”赚钱，“一单能有几千万美金”。

The two sides are constantly interacting and playing games between writing patents and looking for loopholes. The ANDA system is to speed up the process of reaching a conclusion in the patent battle to a certain extent, so that generic drugs can be launched earlier.

Industry insiders mentioned that for Baekje, zebutinib has been copied, indicating that the drug's market prospects are still optimistic, and sales results may exceed "US$1 billion a year" in the U.S. pharmaceutical industry.

After zebutinib chose to initiate head-to-head trials with abbvi ibrinib in 2017 and was launched in the United States in 2019, its indications expanded and it has grown into the most powerful BTK inhibitor in the world, both clinical and sales levels have surpassed ibrinib;

而百济神州，也在泽布替尼的成绩之上成长为一家全球性的biopharma。中国人王晓冬与外籍的欧雷强联手，一个是美国科学院院士，一个是业界经验丰富的全球顶级CRO创始人，二者共同为百济神州打造了“中国二级市场融资机遇+全球化布局”的成长路径。在美国业界看来， The "Chinese local color" of Baiji is no longer obvious. It is no different from other medium-sized biotech in the mainstream pharmaceutical industry in the United States.

For Chinese pharmaceutical companies, their innovative R & D strength has been recognized, and it has long been a global consensus before zebutinib was copied.:In the past two years, China has become the largest "exporter" of licenses out of innovative drug pipelines. ADC, GLP-1, double antibodies, CAR-T... have a reputation for high quality and high prices. When pharma purchased pipelines, China has become an unavoidable market, and its status as a global R & D center is beyond doubt.

更何况，百济有非常强大的专利和法务团队。北京君都上海律师事务所生命科学与健康医疗法律部律师张文波评价，百济宣布要起诉仿制药企之举，在舆论上有利于掌握主动地位，其表述、流程做法都体现了其专利团队的专业性。另一位专利律师指出， "Zebutinib's Orange Book lists many patents, which shows that the early patent establishment and protection work is still good."

Judging from public information, Zhang Wenbo believes that Baiji's patents for several marketed drugs, including zebutinib, have a wide variety of names and relatively clear patent layout ideas; they are malleable, which reflects that Baiji will continue to improve its patent layout. To meet the challenges of future generics.

It is also reported that Baiji currently has hundreds of legal teams. Scott Samuels, the former general counsel, was a partner in an American law firm. He served for about 5 years and will leave in mid-2022. The new general law Chan Lee is a Chinese citizen who has worked in well-known American pharma such as Pfizer and Sanofi, and has rich experience in handling patent litigation.

This battle for non-core patents is a harmless "champagne issue" at the party for advanced biphharma. From the outside world, it may indeed be a toast moment to celebrate a new milestone in Chinese medicine.

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What will happen?

If Baiji's announcement is accurate and Sandoz and MSN have not challenged zebutinib's core patent, then Sandoz and MSN's generic zebutinib products should not be on the market until the core patent expires in 2034. After that, whether Sandoz and MSN's generics of zebutinib can be marketed immediately or whether they will have to wait until other non-core patents of zebutinib expire will depend on the final result of the case.

According to industry judgment, Sandoz and MSN are very well-known generic pharmaceutical companies in the United States. In particular, Sandoz has extremely rich experience in patent challenges. Therefore, this challenge to zebutinib's patent theoretically has a certain possibility of success. **"Before generic drug producers put their products on the market, they are actually very clear about the patent layout of the original drug. The decision to give it a shot is a decision after conducting a full 'risk-cost-benefit' analysis." An American lawyer commented. **

Generic pharmaceutical companies have a very strong motivation to challenge the original drug patents and shake the foundation of the original drug monopoly."The purpose of dismembering the original drug patents is to imitate it and get their own drugs on the market as soon as possible, even if it is delayed for so many years." Zhang Wenbo said that some large generic pharmaceutical companies may even gather the strength of a team of two to three hundred people to specifically attack the patent of a drug.

Zhang Wenbo introduced that drug patent litigation cases in the United States are very complex. Even after the 30-month containment period has passed, the litigation may still last for as long as seven or eight years."It is very common to fight directly until the patent expires." The reasons for patent invalidity correspond to many laws and regulations, complex evidence, and certain subjectivity. **"Both parties use a magnifying glass to review the patent, especially the originator of generic drugs."** It is common for decisions of courts at different levels to reverse."Drug patent litigation often reaches the Supreme Court."

Zhang Wenbo reminded that the U.S. patent law system is unique and closely related to the judicial system, patent system, drug protection system, and drug application system, forming a "judicial ring" for drugs. The system is complex and "different from the systems of most other countries." China's patent law was gradually established in the 1980s, and the patent system learned from Europe is different from the American system. For example, the Chinese system does not have much room for patent differentiation and extension.

Therefore, although China will also have a patent linking system starting in 2021, innovative pharmaceutical companies still need to pay special attention to the differences between the patent systems of China and the United States when they go abroad, make patent layout in advance, proceed steadily and continuously improve it, and treat it as a systematic process for the company."This way, you won't be too panicked when others challenge you."

"If Chinese pharmaceutical companies want to effectively protect their original drugs in the United States or any market, they must own or control a strong patent portfolio in the country or region where the relevant market is located." 那位美国律师预测，随着中国药企创新性的提升、或license in的IP逐渐开花结果，中国药企在美国专利维权的情况会逐渐增多。但愿到时都能是如百济此案一般的“香槟问题”。

_References: _

_ [1] Ding Jinxi, Han Beibei. A comparative study of Sino-US drug patent linkage systems [J]. China Pharmaceutical Industry Journal, 2008: 39(12) _

_ [2] ≤, 30 months, only the weather is sunny! When the drug patent linkage system is implemented, why don't generic pharmaceutical companies pay the bill? _

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