Research prospects and patent layout analysis of CDK inhibitors

Nowadays, with the continuous improvement of people's awareness of tumor immunotherapy, as well as the listing of new biological drugs or biosimilar drugs, so that some tumor market into the "no chemotherapy era", small molecules anti-tumor drug market has been affected by a certain impact, however, in a short period of time, biological drugs can not significantly affect the market position of small molecule drugs, analysis of the reasons, small molecule anti-tumor drugs compared to biological drugs have the following advantages:(1) through blood circulation distribution, so as to reach the peak blood concentration;(2) oral administration, through the passive diffusion of the intestinal epithelial and active transport combination to mediate further spread of the drug;of course, small molecule anti-tumor drugs compared to biological drugs also have the following disadvantages:(1) small molecule drugs once the patent expires, the competition from generic drugs is more intense;is the existence of the above advantages and disadvantages, so that the market share of the two drugs will not change significantly in the short term, so the development of small molecules anti-tumor drugs, especially high clinical value of bio-target inhibitors is still very attractiveWhen it comes to drug market share, it has to be mentioned here as a weapon to increase market share - patentsHere is an example of a patent layout related to CDK4/6 inhibitorsa certain class of small molecule anti-tumor drugs in the market performance, from the sales of some star drugs, in recent years, drug sales data, the performance is more bright is CDK4/6 inhibitors, market share increased year by year, especially CDK4/6 inhibitors in Palcicbolib, Ribocic and Abemacliblib three brothers, in the drug sales market data strong performance, so that the original research manufacturerpf, Novartis, the company earned pots and baskets in recent yearsTable 1 CDK4/6 inhibitor drug sales (in millions of dollars)from the above table shows that the Ibrance ® (Palbociclib, Pfizer) performance is far higher than kisqali ® (Ribociclib, Novartis) and Verzenio ® (Aerlebelib, Lilly) annual sales, is the most reliable new drug in recent yearsIbrance ® is so popular in the market because it explores the development of breast cancer treatment, as the world's first CDK4/6 selective inhibitor, is China's only breakthrough innovative treatment for advanced breast cancer in 10 years, it can effectively extend the patient's 10 months of progression lifeA report by Pharma, a pharmaceutical market research firm, predicts that Ibrance ® global sales of $9.128 billion by 2024, making it the world's best-selling CDK4/6 inhibitorin addition to the Ibrance ®, Kisqali ® and Verzenio ® post-market sales data are also encouraging, with year-on-year growth, the above three drugs can achieve such surprising results, behind the decades of scientific research on CDK inhibitors (cell cycle protein-dependent kinase inhibitors) actively exploreCDK inhibitors have been the most popular research at home and abroad small molecule anti-tumor drugs, by major pharmaceutical manufacturers and research institutes have high hopes, however, cdK family targets are numerous, how to choose the action target, according to the target design of biologically active chemical structure, and compounds in the clinical stage, still show a type of tumor high selectivity and strong inhibition effect, is the difficulty and challenge facing the field The wide-spectrum and non-selective performance of the first generation of CDK inhibitors has stopped it in clinical trials, and compared with the first generation of CDK inhibitors, the second generation CDK inhibitors focus on improving the specificity of one or several CDKs, in which the successful marketing of CDK4/6 inhibitors is highly anticipated CDK4/6 inhibitor is a new type of selective drug, which induces cell cycle blockin in G1 to prevent tumor progression and is effective in many tumor treatments, including breast cancer The discovery of CDK4/6 inhibitors is a milestone In 2001, three scientists won the Nobel Prize in Physiology and Medicine for their study of key factors in the cell cycle (CDK and Cyclin) Selective CDK4/6 inhibitors approved for marketization are 2nd generation CDK4/6 inhibitors, including Palbociclib, Ribociclib and Abemaciclib Figure 1 Palbociclib Chemical Structure Figure 2 Ribociclib Chemical Structure Figure 3 Abemaciclib chemical structure from the listed drugs, it can be seen that the above three effective drugs, its structure contains radon, radon, radon structure, has a certain common structure Therefore, when enterprises in the project to study CDK inhibitors, not only need to analyze the structure of listed compounds, but also from clinical research experiments, patent database research, comprehensive analysis can effectively combine with the target of the advantage structure, looking for biologically active pilot compounds Looking at patent applications related to CDK inhibitors in recent years, it can be seen that, although the field has been studied for decades, patent applications have not stopped and innovation continues, with patent applications peaking for the second period in 2014-2017 Chart 4 Global trend in CDK inhibitor patent applications (pieces), organized by extraordinary intellectual property rights
an area where patent applications can be filed continuously, both to indicate that one or more studies have opened up a new path, but also to indicate that there are gaps in the emerging technological routes that can be laid out Therefore, timely adoption of high-specific, large-data patent analysis is an effective way to identify technical gaps As we can see from Figure 5, as of 2020.5.22, TOP10 Pharmaceuticals holds a large number of PATENTS related to CDK inhibitors, especially the top 3 companies, Novartis, Cyclacel, AstraZenec, and AstraZeneca hold more than 200 patents Figure 5 The global cdK inhibitor invention patent holding ranking (pieces), by the extraordinary intellectual property rights finishing in this group of male division, how do domestic pharmaceutical companies build their own business circle? Let's look at the practices of Jiangsu Hengrui and Dongsun Pharmaceuticals, screening patents with the number of citations, screening patents with higher citations to illustrate how to break the law An invention of Dongsun Pharmaceuticals is called "The Compounds and Their Uses of CDK Small Molecule Inhibitors" by the Chinese patent CN105294683B, the application date 2015-07-24, the estimated expiration date 2035-07-24, right 1 protects the following one Makus structure: Figure 6 Style (I) compared with the Abemaciclib structure, we can find that the formula (I) contains a similar parent nuclear structure to Abemaciclib lactin, unlike Abemaciclib, the type (I) of the two-bit group of radon has been structurally modified, the modified structure of CDK1, CDK2, CDK4, CDK6 or CDK9 are inhibited It can be seen that for star drugs or drugs with better clinical results, structural modification of specific groups can not only be innovative in technology, but also can be screened out of better-active compounds an invention in Jiangsu Hengrui named "Yuli derivatives, its preparation method and its application in medicine" of the Chinese patent CN104470921B, the application date 2014-04-15, the estimated expiration date 2034-04-15, right 1 protects the following one Makush structure: Chart 7 contrasting with Palbociclib, we can find that the formula (II) contains a mother-core structure similar to palbociclib, unlike Palbocic, the type (II) has a structural modification of the two-bit group of the crucive, but the modification is not large, mainly for Palbociclib's briginic ring structural modification According to the FDA Orange Book disclosed that Palbociclib was first approved the market date of 2015-02-03, and the patent application date 2014-04-15, it can be seen that early discovery, early research, early application for drug research, not only can seize the competition did not notice the blank point, in the patent layout early entry, layout will be relatively difficult In addition, pay close attention to the research and development dynamics of competitors, timely update the discovery and research of important targets for tumor treatment at home and abroad, is also one of the necessary work content in drug research , on the basis of the mother core, the structure of modification is one of the commonly used means of small molecular drugs patent applications, or for domestic pharmaceutical enterprises to provide a point of thinking on the layout of pharmaceutical patents reference: Pfizer, Novartis and other official websites