Behind ADC, PD- (L) 1. Behind the best-selling medicine of CAR-T, who is the "patent"?

In the first half of the year, the global biomedical patent rankings were released. The list of enterprises/medical institutions mainly came from 13 countries, organizations or regions. Randomly in the world.

*** patent mainly involves technical fields such as biotechnology drugs, genetic engineering drugs, vaccines, diagnostic reagents, micro -ecological preparations, blood products, etc.

In the large health industry, especially the medical field, "patent" directly determines the profit limit of a product. After the patent protection period, there will be a large number of generic drugs to compete with it, and the price of generic drugs will often be less than 1/20 of the original drug. Therefore, the "patented cliff" became the sword of Damocles hanging on each innovative pharmaceutical company.

Each of each best -selling medicine in history is almost unable to open the "patent dispute"; because the patent owner has the right to "divide a share" to the latecomers.

However, in the near future, the fastest and most comprehensive US medical patent system has suffered from the "bitterness of the patent system". Perhaps it is the best time for China's innovative drugs to "establish a system and in -depth innovation".

1

PD- (L) 1, Car-T, ADC

The patent dispute behind the best -selling tumor drug

In the field of great health, sometimes the number of key patents is more important than the patent. Products using key patents are divided into part of the income every year to patent owners.

Therefore, PD- (L) 1 (tumor), CAR-T (tumor), ADC and other most profitable areas in the world are currently emerging. Who is the "rich man" who holds the key patent and collects the "toll"?

PD- (L) 1, Car-T field:

BMS "Single -up" Merhado/Roche/Astrakan/Geely

At present, PD- (L) 1 and CAR-T are the world's most "gold-absorbing" pharmaceutical fields, and BMS has a meticulous patent layout, and weaves a difficult to escape from the "latecomers".

In the past 5 years, BMS has successively brought Merhadon K medicine, Roche T medicine, Astrikon I, and Geely Yescarta to court, and ended most of the prosecution or the biggest winner of the tumor track.

PD- (L) 1: BMS patent network almost "trapped" all new overseas listed products

At present, there are 13 PD-(L) 1 immune checkpoints in the world approved, 9 PD-1, 4 PD-L1.

China has listed all 13 models;

The United States has been listed in 4 models, namely Merhada Keytruda, BMS OPDIVO, Roche Tecentriq, and Astrakon IMFINZI.

The BMS has brought all the products of Merck, Roche, and Astraco, which are listed in the United States.

In 2017, BMS won Murisha, the latter paid $ 625 million in cash and promised to pay patent fees to BMS and Ono Pharmaceutical (6.5%in the first six years, and 2.5%in the next three years).

In the first half of 2022, K medicine re-topped the PD-(L) 1 market again with a sales of US $ 10.061 billion, and the weak gap of US $ 38 million was lower than Xiu Meile, becoming the most powerful competitor in the world's new "Medicine King". Essence

In 2020, BMS won the lawsuit, the latter reached a settlement agreement for its PD-L1 antibody Tecentriq (T drug) and BMS (including paying 324 million US dollars in cash and unveiled patent fees).

In the first half of 2022, T drug sales were 1.758 billion Swiss franc (about 1.85 billion US dollars).

In 2022, BMS sued the Astraon PD-L1 antibody IMFINZI (i medicine) to violate its eight patent rights and is currently being reviewed.

In the first half of 2022, the sales of i medicine were US $ 1.294 billion.

In the field of PD- (L) 1, the firepower of BMS comes from a international patent applied by Japanese scientists Ben Yoshi and Ono Pharmaceutical in 2001. It is stipulated that as long as the specificity is combined with human PD-(L) 1 protein, it violates it. Patent rights; and this basically "sweep" all new PD- (L) drugs, so almost "one one to one".

In 2005, MedareX cooperated with Ono Pharmaceutical to develop PD- (L) 1 drug;

In 2011, BMS acquired Medarex.

In the first half of 2022, O drug sales were US $ 3.986 billion; but perhaps the PD-(L) 1 patent fee received by BMS reached billions of dollars.

CAR-T: BMS patent covers two mainstream design of the second generation CAR-T

In the field of CAR-T, BMS has ownership of US7446190 and US8399645B2 after the acquisition of Juno.

In 2018, the new base acquired Juno for $ 9 billion;

In 2019, Beltay Schimibao acquired Xinji.

Although the scope of patent layout is not as extensive as its PD- (L) 1, the two major designs as the most mainstream of CAR-T second-generation technology have also affected most of the current (second-generation technology) CAR-T products.

In 2015, Novartis had reached a settlement with BMS/Juno before its listing of F-I-C CAR-T therapy Kymriah (CTL-019), paying 12 million US dollars and subsequent patent usage fees. In 2017, BMS/Juno filed a lawsuit against Geely/Kite, saying that it violated its US7446190 technology patent. For example, BMS win, Geely/Kite will pay cash compensation and its product 27.6 % sales to BMS/Juno before the patent expires in 2024.

In 2021, the court sentenced Geely/Kite to victory;

In June 2022, the BMS filed a lawsuit with the Supreme Court of the United States and asked for re -trial; it was not yet renewed.

What exactly is BMS's two design patents (US7446190, US8399645B2) in CAR-T second-generation technology?

(US7446190) is the CD28 co -stimulating signal field patent to commemorate the CD28 applied by the Sloon Katelin Cancer Center. The T cell is activated and requires a co -stimulus signal. Stimulate molecular receptors;

(US8399645B2) is a patent applied by San Juda Children's Research Hospital. The patent involves the use of anti-CD19 single-chain antibodies and polynucleotides that include 4-1BB and CD3ζ. It means that as long as CAR products are targeted at CD19 targets, and at the same time, 4-1BB and CD3ζ have violated the patent, and 6 of the 8 CAR-T therapy in the world are currently based on CD19 targets.

As of March 2022, CAR-T products are approved worldwide

In the first half of 2022, Geely/Kite targeted CD19 CAR-T therapy Yescarta sales of US $ 506 million, which is the king of global CAR-T sales. If the BMS has won the case again, it must be a considerable income.

In summary, having key technical patents not only give pharmaceutical companies the opportunity to create "medicine king", but also collect patent use fees "lying".

ADC field:

SEAGEN VS's first and third, a blood case triggered by a "connection" patent

On August 12, an ADC track patent lawsuit, which lasted two years, involved the most popular ADC drug ENHERTU recently. The third trial finally settled. Different interpretation. "

As a more mature and wide market segmentation area in Domatoma, in just two years, ADC has become the hottest track in the world after PD- (L) 1. Among them, the enhertu jointly developed by the first and third Republic Astrikan was predicted by Nature for about three years.

As a representative of the third -generation ADC technology, the defendant ENHERTU of this patent lawsuit has shown the potential of "magic medicine" from the beginning, and has won 6 indications for three years, covering breast cancer, gastric cancer, and non -small cell lung cancer three. Big cancer species.

In October 2020, Seagen filed an infringement lawsuit on ENHERTU's owner (once the first and third losses were lost, it would compensate Seagen 41.82 million US dollars and pay the patent fee for Seagen each year until the patent expired in 2024). The current results of the final trial were Seagen's losses.

In April 2022, the first three trials lost the case;

In July 2022, the first three trials lost the case;

In August 2022, the first three trials won the case.

The grievances of Seagen and the first and third Communities dates back to a authorized cooperation 14 years ago.

In 2008, the first and third co -authorized introduced the Seagen ADC technology platform. A few years later, due to the failure to succeed in commercial products, the two parties announced the end of the cooperation. Since then, the first three Communist Party continued to develop ADC drugs alone.

In 2019, heavy products such as enhertu were launched in the first and third. Seagen believes that its product "connection" is derived from the improvement of previous authorized technology, violating its patent (US10808039B) and sued it to court.

In August 2022, the court ruled the defendant to win the prosecution first and third. SEAGEN's stock price fell 5%on the day, and may also affect its potential $ 40 billion merger and acquisition transaction with Merida.

In the field of ADC, Seagen is a technical leading enterprise with more than 100 patent cities, and patent types cover comprehensive compounds, sequences, pharmaceutical purposes, and compositions. CD33, etc., mainly in the field of tumor treatment. In addition, more than 30%of the approved 14 ADC marketing drugs were developed in cooperation with Seagen.

As of 2022, the global approved ADC products in the first half of the year

However, due to monoclonal anti -resistance, Due -specific drugs have more detailed and rigorous requirements for patent applications because of the complexity of their own structure. Taking ADC drugs as an example, its patent layout involves three parts: antibodies, connectors and small molecular toxins. Therefore, a thousand miles of losing the slightest miles, a small restriction clause may become a key factor in the success or failure of patent litigation. 2

American VS China, the patent system is very different?

A country's protection of intellectual property rights to a large extent will affect the innovation and development of the industry. As the country with the most complete laws and regulations in the world, its system evolution has also led a global trend.

There are three main ways to apply for patents in the United States:

1. Apply to the United States directly to the United States (you need to prepare a confidential review at the Chinese Patent Office in advance, and you can apply to the United States directly after passing the confidential review);

2. Apply for a patent to the United States through the Paris Convention (only 12 months of priority);

3. Apply for patents to the United States through the PCT "Patent Cooperation Treaty" (priority can reach 30 months).

Among them, the PCT "Patent Cooperation Treaty" is not only the first choice for Chinese innovative pharmaceutical companies including Hengrui Pharmaceutical and Baiji Shenzhou, but also the main way for foreign -funded enterprises to apply for patents in China.

Applicants can apply to almost all countries around the world through the PCT route, that is, to submit an application to the target State Intellectual Property Office within 30 months from the application date of the country.

US patent application process

The Chinese patent application process is roughly the same as the United States, but the relevant legal system has only begun to join the WTO in 2001.

China Patent Application Process

The system is the first to improve, becoming an important promoter of American pharmaceutical innovation

In 1951, the United States promulgated the "Prescription Pharmaceutical Act", stipulating that the benefits of the development of a pharmaceutical company to develop an innovative drug far exceeded the generic drug; the bill greatly promoted the research and development innovation of US pharmaceutical companies.

In 1980, the US "Bydu Act" was promulgated, and its significance was that it stipulated that individuals and enterprise units could also enjoy national funding of scientific research patent rights, which means that scientific research projects of universities and other non -profit institutions also enjoy patent protection and can conduct commercial transactions; Stimulated the transformation of basic pharmaceutical research industries.

Different from other industries, innovative drugs from the formation of concepts, to data support, preclinical trials, clinical trials, commercialization, and other stages that almost need to apply for patent protection, and the focus of intellectual property rights is different. Therefore, the "experimental data protection, extension of patent period, and patent dispute after listing" has become the three major pain points for innovative pharmaceutical companies.

In 1984, the United States took the lead in passing the Hatch-WAXMAN Act, which first designed a drug link system.

In 1992, through the "GENERIC DRUG Act", the pharmaceutical registration and patent were established closely. For the first time, the drug patent link system was improved. Essence

The implementation of this series of regulations has achieved remarkable results. In 2000, the number of innovative drugs in the United States accounted for 45.9%of the world. For the first time, it surpassed Europe to become the world's largest source of innovative medicines and maintained to this day.

The system is 25 years behind, and the long slope of China Medicine has long snow

The Chinese drug patent link system is 25 years later than the United States.

In September 2017, China CDE issued a public solicitation for the "Catalog of China" (Chinese version of the Orange Book);

In October 2017, the General Office of the Central Committee of the Communist Party of China and the General Office of the State Council jointly issued the "Opinions on Deepening the Reform of the Review and Approval System to Encourage the Innovation of Drug Medical Device Innovation" for the first time.

Sino -US patent link system comparison

In July 2021, the Chinese drug patent link system that has been explored for many years has finally been in line with international standards, and China has also opened a accelerator for medical innovation. As of now, the top five of the medical patents in the Chinese market are Hengrui on the list.

Patent application ranking in China

Once the development of one brother Hengrui, it is still the most patented Chinese pharmaceutical company. In the first half of 2022, he ranked 13th in the global pharmaceutical patent list with 231 patents. The current research and development of a brother Baiji Shenzhou ranks 66th with 60 patents.

3

"Double Blade Sword" for patent protection -the American system welcomes the "inflection point"

For China, the "double -edged sword" of the patent system is reflected in:

On the one hand, the relevant system is perfect, causing relatively backward medical innovation.

On the other hand, the imitation drug market is active and the return of the original research drug market price. For example, from 2019, the country's volume procurement has been carried out in the seventh round of drugs, involving major categories such as chemicals, biopharmaceuticals, and insulin; the third round of medical consumables involves cardiovascular stent, orthopedic joints, orthopedic spine, and about to be about to be about to be about to be about to The expanded dental implants, etc.; the average price reduction exceeds 50%, and the maximum price is nearly 99%.

For the United States, a comprehensive patent protection system makes the new drugs during its patent period forming a "small monopoly" on their own indications. Like a double -edged sword, it catalyze the development of American innovative drugs, and on the other hand, it has also become an important factor for American pharmaceutical companies to increase the price of drug prices.

Until recently, the balloon has finally detonated. This patent protection system that is imitated by the world is criticized as "outdated system" by American lawyers and scientists. In the past five years, 34 million US people have lost their family and friends. Critics believe that the US drug patent system has won more "gold absorption" time for innovative pharmaceutical companies, and it seems to be unreasonable for patients.

Since 2012, US drug prices have risen by about 68%; comparison here is that the US Patent and Trademark Office found that 78%of the patents applied for from 2005-2015 have come from old medicine.

For example, there are more than 245 patents established by Albervi's "patented wall" for the Medicine King Xiu Meile, and 89%are applied after the drug is approved. According to the statistics of its extended monopoly period, it will make American patients spend at least 144 more 144 One hundred million U.S. dollars.

On the 12th of this month, the U.S. House of Representatives passed a new bill with 220 votes in favor and 207 votes opposed to reduce medical insurance prices in the form of legislation. The bill also includes many severe measures involved in compulsory pharmaceutical companies, such as a fine of $ 1 million per day.

From a patent point of view, the road to overseas of Chinese innovative pharmaceutical companies has been approved by the regulatory bureau to go public. After listing, it will also face the impact of the "flood beast" that will face overseas patents.

Taking PD- (L) 1 as an example, the relevant patents applied for BMS/Ono Pharmaceutical in China have not involved relevant patent proceedings in the Chinese market because of their meticulousity to the six major amino acid sequences. Once China PD- (L) 1 is approved overseas, it will also face relevant patent lawsuits.

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