Reprinted from Snowball
Chronic lymphocytic leukemia (CLL) is a disease in which a large number of mature phenotypic, insufficient B lymphocytes accumulate in the periphery, bone marrow, lymph nodes, spleen, liver and other tissues for a long time. CLL is the adult leukemia with the highest incidence in developed countries in Europe and America (accounting for 1/3 of all leukemias), and it is relatively rare in Asian countries. CLL is more common in elderly patients, and its incidence gradually increases with age. The age of onset is mostly 67-72 years old, and there are more men than women. The course of CLL varies in length, and the clinical course and prognosis are highly heterogeneous. Although the incidence rate in my country is lower than that in developed countries such as Europe and the United States, the incidence of CLL is increasing year by year due to the large population base in my country and the ageing society.
In the past few decades, the treatment of CLL was mainly based on alkylating agents, but long-term use of alkylating agents can cause continuous pancytopenia, abnormal myelodysplasia, secondary tumors and other side effects. Although the combination therapy of alkylating agents and purine analogs, such as fludarabine combined with cyclophosphamide, can improve the overall effective rate and PFS rate of CLL patients in clinical practice, these chemotherapy regimens cannot bring survival benefits to patients. beneficial.
In recent years, as humans continue to understand the key molecules and pathways of the pathogenesis of CLL, a large number of highly effective, low-toxic, and convenient drugs have emerged. Among them, Ibrutinib (Ibrutinib, ImbruvicaTM) and Venetoclax (VenclextaTM), which have been successively approved by the US FDA, are two targeted drugs that can be used to treat CLL (see Table 1 for details). The advent of Ibrutinib and Venetoclax provides a new treatment plan for the treatment of CLL. At the same time, these two drugs have high hopes and are expected to become blockbuster varieties in the future.
Table 1 Information on Ibrutinib and Venetoclax approved for the treatment of CLL in Europe, America and other countries
In view of the clinical needs that my country cannot meet at present, it is expected that many domestic companies will pay attention to Ibrutinib and Venetoclax and begin to put on the imitation schedule. To provide domestic enterprises with project support for the above two products, Renault is now sharing with readers and friends the core patent status and registration information of Ibrutinib and Venetoclax in China. If there are any shortcomings, I hope that all readers and friends will provide valuable comments.
Patent analysis:
1. Ibrutinib
So far, the original research company has applied for a number of core patents related to ibrutinib in China. Among them, 5 have been authorized (see Table 2 for details).
Table 2 Application status of core patents related to ibrutinib in China (data deadline: 2011-11-01)
According to the data listed in Table 2, the application number of CN101610676B is 200680056438.5. Except for the parent application 200680056438.5, which has been authorized, the other three divisional applications have been authorized. The authorization announcement numbers are: CN102887900B, CN101805341B and CN102746305B. In addition, the authorized announcement number of another patent granted is: CN101674834B. in,
Compound patent: CN101805341B provides protection for specific compounds. Among them, article 10 of the claims claims ibrutinib or a pharmaceutically acceptable salt thereof. The patent expires in China on December 28, 2026.
Use for the treatment of chronic lymphocytic leukemia: Article 11 of the claims of CN101610676B claims the use of ibrutinib or a pharmaceutically acceptable salt thereof in the preparation of inhibitors for inhibiting Bruton's tyrosine kinase, wherein The inhibitor is used to treat cancer. In addition, claim 5 of CN102887900B clearly states that Ibrutinib can be used to treat chronic lymphocytic leukemia, and the patent expires on December 28, 2026 in China.
Preparation method: CN102746305B claims a method for preparing compounds including ibrutinib. The patent expires in China on December 28, 2026.
Crystal form and preparation: Although CN104736178A has not yet been authorized in China, the patent may be very likely to be authorized. The development of this product should follow up the legal status of the patent in China from time to time. The patent document reports that Ibrutinib has polymorphic form, and what the patent claims is Ibrutinib crystal form A and related oral preparations. If the patent is granted, the expiration date of the patent in China will be June 3, 2033.
In summary, the expiration date of Ibrutinib's compound patent, preparation method patent and use patent for the treatment of CLL in China is December 31, 2026. Although the crystal form patent CN104736178A has not yet been authorized, in view of the possibility of the crystal form patent being authorized, the development of this product should also consider the possible risks of the patent.
2. Venetoclax
So far, the original research company has applied for a number of core patents related to Venetoclax in China, and a total of 5 have been authorized (see Table 3 for details).
Table 3 Venetoclax's core patents applied for in China (data deadline: 2011-11-01)
Compound/use patent: CN102448959B (application number: 201080023068.1) requires protection of compounds of general formula including Venetoclax. The patent also claims that compounds of general formula including Venetoclax are used to treat tumors including lymphocytes and leukocytes. The expiration date of this patent in China is May 26, 2030.
It is worth mentioning that CN103328474A reports that Venetoclax can exist in various forms such as anhydrate, hydrate, dichloromethane solvate, ethyl acetate solvate, acetonitrile solvate and acetone solvate. CN103328474A claims protection The above-mentioned Venetoclax exists in various crystal forms. In view of the fact that the US FDA approved the active ingredients of VenclextaTM to be an anhydrate, rather than a hydrate or solvate, special attention should be paid to whether the crystal form of Venetoclax approved by the US FDA for marketing is consistent with the crystal form of the anhydrous reported by CN103328474A, and You should always pay attention to the legal status of the patent in China to avoid the possibility of infringement. If the application is authorized, its expiration date in China will be November 22, 2031.
In summary, Venetoclax's compound patent and use patent expire in China on May 26, 2030. Although the crystal form patent CN103328474A has not been authorized yet, the possible risks of this patent should be considered when developing this product.
registration message:
1. Ibrutinib
It is reported that the original research company has submitted the import registration of ibrutinib capsules to my country's CFDA and has obtained clinical approval. Currently, the original research company is carrying out clinical trials in China, with trial registration numbers: CTR20130303, CTR20132169, CTR20132531, CTR20132625, CTR20140436 and CTR20140718. In addition, many domestic companies have filed applications for registration of this product with my country's CFDA in category 3.1. Among them, the raw materials and preparations developed by 5 companies have been reviewed. as follows:
Table 4 Domestic registration information of Ibrutinib
As mentioned above, although many domestic companies have filed applications for registration of this product to my country’s CFDA, due to the limitation of the original research patent, the earliest time for localization of this product must be made after the expiration of the compound patent and the use patent. It is expected to be listed, that is, after May 26, 2030.
2. Venetoclax
It is reported that ABBVIE has submitted the import registration of this product to my country's CFDA on December 11, 2015 (acceptance numbers are JXHL1500295, JXHL1500296 and JXHL1500297), and it has now obtained clinical approval. It is estimated that ABBVIE is currently starting clinical trials in China. So far, domestic companies have not yet submitted registration applications for this product to my country's CFDA, but it does not rule out that domestic companies have started to develop this product. The registration time is just a matter of time.
In short, although the original research company separately filed an import registration application for this product with my country’s CFDA for Ibrutinib and Venetoclax, and Ibrutinib is currently undergoing clinical trials in China, it is expected that Ibrutinib will be launched in China. It is earlier than Venetoclax. Because both Ibrutinib and Venetoclax enjoy multiple patent protections in China, it is optimistic that the earliest localization of Ibrutinib and Venetoclax in China should also be after December 2026 and May 2030, respectively.
