As a double-edged sword, crystal patent can be used by original research enterprises to extend the protection period of drugs and form patent obstacles to generic drugs; Non-original research enterprises can also apply for patent protection by developing different crystal forms and break through patent barriers [2].
There are many methods to characterize the crystal form of drugs. According to the guiding principles of China Pharmacopoeia (2020 edition, 90 15), the only absolute identification method is single crystal X-ray diffraction (SCXRD). The crystal structure determined by single crystal X-ray diffraction can help enterprises occupy an advantageous position in new drug declaration, quality control, patent protection and property analysis.
There is no potential crisis of "real-name registration system"
The content and layout of pharmaceutical crystal patents directly affect the life cycle of drugs and corporate profits. The crystal patent dispute between apatinib mesylate and atorvastatin calcium is of reference and warning significance to the patent writing, application and layout of pharmaceutical R&D institutions.
Apatinib (Aitan) is a new drug 1. 1 developed by jiangsu hengrui Pharmaceutical Co., Ltd., as the first innovative anti-tumor drug of Hengrui, it is expected to become a heavy variety with more than 2 billion yuan in the future. In 20 16, a company in Shanghai sued Hengrui Pharma for infringement on the grounds that the crystal form of the active ingredient of Aitan fell within the protection scope of its patent ZL201510398190.1.Later, Hengrui Pharma requested to declare the patent invalid and finally won the case. The key point of dispute between the two parties is whether the "methanesulfonate monohydrate" claimed in the patent can enjoy the priority of the previous application 201410323412.9. After trial, the Patent Reexamination Board considers that the water content of "methanesulfonic acid monohydrate" is about 3.52%, which is quite different from the relevant water content recorded in the priority document, and does not have a unique corresponding relationship, so it does not belong to the technical content available in the previous document. Moreover, hydrate crystals with the same powder X-ray diffraction peak do not necessarily have the same water content and belong to the same hydrate, so they are considered not to belong to the same subject and cannot enjoy the priority of the earlier application [3]. Here, the crystal structure determined by single crystal X-ray diffraction plays a decisive role in determining whether it is the same hydrate.
Another example is atorvastatin calcium (Lipitor), which is a heavy lipid-lowering drug of Pfizer (the world's first drug with sales exceeding 10 billion US dollars). Its subsidiary atorvastatin calcium crystal form I patent was involved in a dispute with Jialin Pharmaceutical. This patent claims crystalline atorvastatin hydrate type I containing 65,438+0-8 moles of water, preferably 3 moles of water. However, the preparation methods and related characterization parameters of these eight crystals are not given, and it is impossible to prove that these eight crystal forms are equivalent, so the patent does not meet the requirements of "full disclosure" and is invalid [3]. Here, the crystal structure determined by single crystal X-ray diffraction method can also play a decisive role in the amount of crystal water.
From these two examples, we can see that the patent of pharmaceutical crystal needs careful writing and careful layout to avoid risks, and the crystal structure obtained by single crystal X-ray diffraction can provide a lot of decisive information, so that the crystal patent can be better protected.