[exclusive] Analysis on the patent layout strategy of orlistat in China

In recent years, overweight and obesity (hereinafter referred to as "obesity") have become a common public health problem in the world According to the survey results published in 2017 by the World Health Organization (who) global burden of disease 2015 obesity collaborative group, in 2015, 603.7 million adults (588.2 million-619.8 million) and 107.7 million children (98.7 million-118.4 million) worldwide suffered from different degrees of obesity, accounting for 12.0% and 5.0% of the adult population and children population respectively In addition, the study also found that the number of obese people in more than 70 countries, including China, has more than doubled in the past 35 years Specifically in China, according to the 2014 national physique monitoring bulletin issued by the General Administration of sport and the Ministry of education on 25, 2015, in 2014, the overweight rate of adults and the elderly in China was 32.7% and 41.6%, respectively, 0.6 and 1.8 percentage points higher than that in 2010; the obesity rate of adults and the elderly was 10.5% and 13.9%, respectively, 0.6% and 0.9 percentage points higher than that in 2010 Although the increase of detection rate has slowed down, overweight and obesity are still prominent problems affecting the constitution of adults and the elderly in China In addition, the incidence of obesity in children and adolescents is becoming more and more serious As obesity is not only a risk factor of chronic diseases such as type 2 diabetes and cardiovascular disease, but also closely related to a variety of cancers, the increasing prevalence of obesity is a serious threat to public health, which brings a serious economic burden to the public health system of developed and developing countries Obesity is caused by excessive or abnormal fat accumulation caused by the intake of calories is greater than the consumption of calories Therefore, diet control and physical activity in lifestyle intervention start from two aspects of reducing the intake of calories and increasing the consumption of calories respectively to achieve the purpose of weight loss Although both Europe, America and China have written lifestyle intervention as the basic weight control means into relevant guidelines or consensus, due to the body's adaptability to weight loss and the poor long-term compliance of individual lifestyle, individual lifestyle intervention can only moderately reduce body weight, and it is easy to rebound, and drug combined lifestyle intervention plays an important role in the treatment of obesity The role of Orlistat is the only weight-loss drug approved by the State Drug Administration, and the only peripheral weight-loss drug on the market worldwide The drug can inhibit the absorption of 30% fat in the diet after oral administration, so as to reduce the energy intake and achieve the goal of weight loss More than 100 clinical trials involving more than 30000 subjects at home and abroad have verified the effectiveness and safety of orlistat for various types of obesity Orlistat can not only moderately reduce the weight of obese people, but also significantly reduce waist circumference, visceral fat, blood pressure, blood lipid metabolism, blood glucose control and type 2 diabetes The systemic absorption level of orlistat is very low after oral administration, so it has better safety and tolerance characteristics The main adverse reactions of orlistat are digestive tract adverse reactions represented by oily spots These adverse reactions are caused by the efficacy of orlistat, and many of them are mild to moderate and can disappear by themselves In November 2000, orlistat 120mg capsule obtained the import product license (Roche pharmaceutical, trade name: seneco) issued by China's original Drug Administration (SDA), and was approved to be transferred to OTC drugs in 2005 Orlistat's basic compound patent us4598089 did not enter China, and the administrative protection of sanico in China on October 20, 1999 also expired on April 20, 2007 Therefore, after Chongqing Zhien Pharmaceutical Co., Ltd took the lead in realizing the localization of orlistat capsule in 2010, many brands of orlistat products emerged in the domestic market With the increasingly fierce competition in the domestic market of orlista, manufacturers are also actively promoting the patent layout of orlista This paper analyzes the patent information of orlistat in China, and further discusses the patent layout of domestic enterprises 1 Roche pharmaceutical patent layout analysis Roche is the original research company of orlistat, and naturally the first company to apply for orlistat related patents in China Although orlistat's earliest basic compound patent us4598089 has not entered China, Roche has applied for several patents on orlistat preparation, medical use and preparation method in China (Table 1), and all of them have been authorized Table 1: overview of orlistat related patents applied by Roche company it is worth noting that the above patents applied and authorized by Roche company do not constitute substantive protection for its exclusive right in China For example, the American patent of zl98800369.4, a Chinese patent, is included in the FDA's orange book The validity of the patent is as of January 23, 2018 However, prior to that, orlistat generic drugs, represented by Chongqing Zhien, had already been listed in the domestic market, indicating that domestic enterprises have well evaded the patent In addition, Roche Applied for a number of composition products (including zl99809507.9, zl99809508.7, zl00812679.8, zl00812680.1, zl02811498.1 and zl03809368.5) and other compound composition and pharmaceutical use patents with "orlistat is easy to cause adverse reactions in digestive tract" as technical problems However, the patent related to orlistat applied by Roche pharmaceutical has a potential and powerful destructive effect on the creativity and / or novelty of the patent similar to the subject of invention applied later because of its early publication and wide coverage For example, in the examination decision No 110841 made by the Patent Reexamination Board of the State Intellectual Property Office on June 14, 2016, zl94109091.4 in the table was used as the reference document to maintain the rejection decision previously made by the State Intellectual Property Office on patent application No 201110146932.3 of Lunan Pharmaceutical (requiring to protect the "composition containing orlistat and miglitol") Another patent (application No.: 201110195582 X) applied by Lunan Pharmaceutical Co., Ltd for protection of "composition containing orlistat and acarbose" was rejected by the State Intellectual Property Office because it was not creative compared with zl94109091.4 The rejection decision has come into force 2 Patent layout analysis of Chongqing Zhien Pharmaceutical Co., Ltd Chongqing Zhien Pharmaceutical Co., Ltd (hereinafter referred to as "Zhien pharmaceutical") is the first enterprise to introduce domestic orlistat in the Chinese market It adopts the full synthesis process to prepare orlistat API and emphasizes the advantages of "less impurities and high safety" Therefore, the patent zl200710130146.8 protecting orlistat's full synthesis process and key intermediate is the patent zl200710130146.8 of Zhien pharmaceutical in orlistat The most important chess piece in his patent layout Table 2: orlistat, an over-the-counter version of GlaxoSmithKline's Chinese invention patent applied by Zhien pharmaceutical, has been approved by the European Union EMA In addition to 60mg low-specification capsules, there are 27mg chewing tablets However, the marketing status of the latter is not clear On December 30, 2014, Zhien pharmaceutical applied for a patent for the invention "containing orlistat chewable tablet composition", and was authorized on July 16, 2017 (Patent No.: ZL) Zhien Pharmaceutical Co., Ltd is the only manufacturer of orlistat chewable tablets holding the patent of orlistat chewable tablets, and also the only domestic enterprise holding the effective clinical approval of orlistat chewable tablets (corresponding to the clinical application acceptance number; cxhl1300973; clinical approval date: January 14, 2016) A large number of in vitro and animal studies have confirmed that orlistat has a potential antitumor effect However, the development of orlistat as an antitumor drug has been greatly limited due to its insoluble in water and low oral bioavailability In 2017, Zhien Pharmaceutical Co., Ltd applied for three composition invention patents with "improving the hydrophobicity of orlistat" as one of the technical problems to be solved, namely: cn201710316607.4 (liposome patent), cn201710316854.4 (inclusion compound patent) and cn201710316871.8 (nanospheres patent) All of the three patents provide data of in vitro anti-tumor test, which makes the Zhien pharmaceutical industry in the forefront of ollistat anti-tumor application patent applications On July 19, 2017, Zhien pharmaceutical also applied for the invention patent cn201710590270.6 of "pharmaceutical composition containing orlistat and voglibose" However, voglibose, migliol and acarbose belong to α - glucosidase inhibitor type antidiabetic drugs In view of the previous experience of cn201110146932.3 and cn201110195582 X being rejected, as well as the two patent works For the destructive effect of the prior art on the creativity of the patent pending, the authorization prospect of cn201710590270.6 of Zhien pharmaceutical is not optimistic 3 Patent layout analysis of Zhejiang Haizheng Pharmaceutical Co., Ltd after Zhien pharmaceutical, Zhejiang Haizheng Pharmaceutical Co., Ltd (hereinafter referred to as "Haizheng pharmaceutical") launched the domestic brand "yiningman" (tablet, 60mg and 120mg) in 2011 Unlike Zhien pharmaceutical, the orlistat API used by Haizheng pharmaceutical was prepared by fermentation and semi synthesis In April 2015, Bishengyuan Holding Co., Ltd (hereinafter referred to as "Bishengyuan control") repackaged "yiningman" and launched it into the market with the new brand "Laili" Haizheng pharmaceutical has only applied for one invention patent related to orlistat, namely zl200910169508.3, which has been authorized to protect a "purification method of orlistat" 4 Patent layout analysis of Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd (hereinafter referred to as "Huadong pharmaceutical") although Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd (hereinafter referred to as "Huadong pharmaceutical") and Haizheng Pharmaceutical Co., Ltd obtained the production approval of orlistat APIs and preparations in the same year, their time of listing is later than the latter, and the trademark is "kayuping" At present, there are relatively few reports about the company, and the patent applied by the company is shown in Table 3 Table 3: the comparison results of the comprehensive data before and after the application of orlistat China patent of Huadong pharmaceutical show that Huadong pharmaceutical applied for the related invention patent of orlistat the earliest time, suggesting that the company may start the related research of orlistat at the earliest time Among the orlistat related invention patents that Huadong pharmaceutical has authorized, in addition to zl201210020953.5 protecting the composition product, other patents all protect the technology related to the preparation process of orlistat It is particularly noteworthy that zl201310302148.6 protects the strain (Streptomyces toxicosis st-5423) for the preparation of lipostatin, an intermediate of orlistat, while zl201310173041.6 protects the method for the production of lipostatin by controlling the production of toxostatin, which not only suggests that Huadong pharmaceutical can use the fermentation semi synthesis method to prepare orlistat, but also makes the company the only one with advantages Orlistat manufacturing enterprise with the invention patent of statins producing bacteria 5 Lunan pharmaceutical / new era pharmaceutical As a subsidiary of Lunan Pharmaceutical Group Co., Ltd (hereinafter referred to as "Lunan pharmaceutical"), Shandong new era Pharmaceutical Co., Ltd (hereinafter referred to as "new era pharmaceutical") holds the production approval documents of orlistat API (fermentation semi synthesis process), tablet (120mg) and capsule (60mg, 120mg) According to the product catalog on Lunan pharmaceutical website, only There are capsules with the trade name of "shuerjia", which went on the market in 2015 Statistics show that Lunan pharmaceutical and new era pharmaceutical apply for and hold OLLIS