Patent landscape of Chinese Classical Formulas

Ruipeng Shi University of Macau Institute of Chinese Medical Sciences Hua Luo University of Macau Institute of Chinese Medical Sciences Yi Zhao University of Macau Institute of Chinese Medical Science Yuyang Tang University of Macau Institute of Chinese Medical Sciences Zhangfeng Zhong University of Macau Institute of Chinese Medical Sciences Shengpeng Wang University of Macau Institute of Chinese Medical Sciences Yuanjia Hu (  yuanjiahu@umac.mo ) University of Macau https://orcid.org/0000-0001-5244-8577

global supplier that provides accurate and high-quality patent documents, was used to create a dataset of CCF-related patents published before June 31, 2021. To capture the latest patent information, processing and expired patents were also included in our analysis. Publication numbers, publication years, inventors, titles, abstracts, and International Patent Classi cations (IPCs) were considered. We rst standardized the basic data by removing duplicate records caused by abbreviations or misspelling. Accordingly to the rules of preferred reporting items for systematic reviews and meta-analyses (PRISMA) [9].
The whole procedure included the following steps: 1) Patents with duplicate application numbers were manually excluded. 2) According to the current status of patent technologies in development, we categorized patent technologies into seven categories to show the technological advances of CCFs more clearly. When multiple technology types were present, we only maintained the most creative and protective types.
CCF-related technologies were classi ed into seven categories, which included analytical methods, new indications, novel dosage forms, preparation methods, modi ed formulations, quality control methods, and equipment. 3) Patent names with subtle differences were harmonized. 4) Inventors were divided into three categories: universities/hospitals, enterprises, and individuals. 5) Finally, we used hotspot maps, line graphs, cumulative histograms, and matrices to comprehensively describe the evolution process and research status of CCF technologies according to data classi cation and technology labels.

Results
Data cleaning and overview Patent families were de ned as patents of the same invention submitted in different regions. In this study, we included patent les from China. In the CNIPA and Derwent Innovation databases, 335 patent les were identi ed, of which two patents were irrelevant (nonpharmaceutical: Yang Zhi Gan Lu drink) and thus were excluded. In addition, 46 duplicate application numbers were excluded to avoid multiple inclusions of the same patent.
Ultimately, 287 patents with patent publication numbers were included in the analysis (Figure 1 and Table S1). We listed the 10 CCFs with the highest number of patents, of which the largest number was 13. CCFs with more than 10 patents were Banxiaxiexin decoction, Lingguizhugan decoction, Mahuang decoction, Qingfei decoction, and Yangwei decoction (Table 1), which did not contain ingredients from animals. The primary effects of these traditional formulas were focused on clearing heat and detoxi cation and seldom employed animal medicine.

Regions of inventors
The addresses of inventors were predominantly located in economically developed coastal regions, such as the Yangtze River Delta (26%), the Pearl River Delta (11%), and Beijing-Tianjin-Hebei (10%), as well as in the western region of China, Chengdu (6%). Tsumura & Co Ltd., a pharmaceutical company in Japan, was the only overseas inventors ( Figure 2). Tsumura & Co Ltd., which is one of the most successful companies globally in the development of traditional formulas, considers China as a viable market for traditional prescriptions.

Patent inventors
Among the top 10 CCF inventors, six were from companies, three were from universities/hospitals, and only one was an individual ( Table 2). The company with the most CCF patents was Suzhou Zhiweitang Bio-Tech Co, which applied for 34 different patents for protection between 2009 and 2011, including novel dosage forms and preparation methods of CCFs, such as Houpumahuang decoction, Baihedihuang decoction, and Gancaofuzi decoction. The Hebei University of Chinese Medicine was the academic institution with the most applications, which were largely for rapid thin-layer identi cation analytical methods; these were in granted status. Academic institutions, which are the backbones of CCF growth, had a deeper pool of patented technology than did businesses.

IPC code characteristics
The IPC codes of patents indicate the eld of technology to which the invention relates. In this study, we counted the word frequencies of seven-digit IPC codes to identify the main directions covered by CCF patents. First, a total of 191 patents were marked with the code A61K036, which described pharmaceutical preparations containing unde ned structures derived from algae, mosses, fungi, or plants or their derivatives, such as traditional herbs. Second, 93 patents were marked with the code G01N030, which described the use of adsorption, absorption, other similar phenomena, or ion exchange, for example, chromatography, which separates materials into components to test or analyze each material. Third, 89 patents were labeled A61K009, which described pharmaceutical preparations characterized by a particular physical shape. Fourth, 81 patents were marked with the code A61P001, which described drugs for the treatment of diseases of the digestive tract or digestive system. More than half (67%) of CCF patents were focused on formulation research aimed at developing pharmaceutical formulations of acceptable bioavailability.

Technological characteristics
To more clearly and purposefully depict changes in the development of CCF technologies, the number of patented technology classi cations in the seven categories was expressed in a line graph (

Granted patents of CCFs
The number of patents currently available for different CCFs is listed in Table 3. At present, there are 162 granted patents, among which the longest granted patent is CN100515452, which was submitted in 2005 for 4361 days of protection. The three CCFs with the largest number of granted patents are Lingguizhugan decoction (n = 9), Zexie decoction (n = 8), and Dajianzhong decoction (n = 7). Of the Lingguizhushu decoction patents, four were for preparation methods, two for quality control methods, two for analytical methods, and one for equipment (Table 3). Granted included 69 analytical methods (42.59%), 39 preparation methods (24.07%), 25 new indications (15.43%), 20 novel dosage forms (12.35%), 6 quality control methods (3.70%), 2 modi ed formulations (1.23%), and 1 equipment (0.62%; Figure 5). Analytical methods have the potential for commercial application and are currently the dominant type of technology for which patents are led.  Enlightenment. The average implementation rate of Japanese patented technologies is 52%, which is much higher than the world average [17][18][19]. By evaluating Tsumura & Co Ltd.'s patent development trajectory and granted patents, we provide inspiration and references for CCF's R&D.
Traditional formulas development enterprise: Tsumura & Co Ltd. List of core patents from citations, Multi-Component Medicine Evaluation Method (WO2005121777A1), it is possible to provide a method for evaluating the quality, safety, e ciency, and the like of the multi-component medicine to be evaluated, by a single numeric value using the Mahalanobis distance. Panax ginseng C.A.Mey. Cultivation Method (WO2012046601A1), disclosed is an e cient cultivation method of Panax ginseng C.A.Mey. which prevents damage from continuous cropping particular to Panax ginseng C.A.Mey., and is capable of reducing the work involved in cultivation.Microbial Cell Culture Medium, And Microbial Cell Culture Method (WO2008038625A1), disclosed is a microbial cell culture medium which can certainly proliferate a target bacterial cell contained in a sample having an antibacterial activity. Also disclosed is a method for culture of a microbial cell. Speci cally disclosed is a microbial cell culture medium for proliferating a target bacterial cell contained in a sample having an antibacterial activity. Also speci cally disclosed is a microbial cell culture method for proliferating a target bacterial cell contained in a sample having an antibacterial activity, in a microbial cell culture medium.

Policy effects
After a patent application is completed, the waiting time until disclosure is the most time-consuming period before a patent is granted [20]. On average, each patent required at least 800 days to be disclosed before The policy release coinciding with the rapid increase in the number of patents and short time of patent publication indicates a positive impact of policies on the development of CCFs [21]. However, it is worth noting that although the number of patent applications increased rapidly in 2011 and 2019, the number of applications dropped sharply in the year following these growth points and returned to normal growth levels in the following year. The main inventors in the rst phase were businesses, and applications were predominantly for new dosage forms that were simple to develop. Because the policy clari ed the norms and directives, selection of dosage forms with reference to ancient sources Moreover, although applicants were mostly corporations in the second uctuation, the number of patents for new dosage forms fell dramatically, and the focus of patents shifted to analytical methods. This shift in application direction demonstrated that the majority of CCF developers were not self-employed and relied on governmental guidelines for their R&D.
Companies are the primary drivers of the rapid growth and decline in the number of patent applications, which indicates that companies are the most sensitive to policy and that such sensitivity, although bene cial, may necessitate timely introductions of other CCF-related policies to ensure the continued development of technologies. In general, Chinese CCF developers are highly concerned about the policies introduced and are moving towards deeper technical depth.

Commercialization
Although China government encourages the development of CCFs by introducing policies, the level of capital recognition is an important component [22]. We evaluated and predicted the commercialization of CCF development by the trend of change in inventor type and revealed that during the rst 6 years of CCF patent applications, inventors were mainly individuals and universities/hospitals, whereas the rst company-type inventors (Beijing Jinfanghua Pharmaceutical Technology Co Ltd, CN101264276/CN101229306/CN101284051, Dayuan/Guyin/Jichuan decoctions) began appearing from 2008 until 2021, with companies ling patents each year. Company-type inventors dominated the uctuations in application numbers twice. The main goal of companies is pro tability, and the share of companies among all inventors has increased in recent years, which indicates that capital is starting to pay attention to the development of CCFs and recognizing the market for CCF.
The mainstream technology of patents ranges from the development of new dosage forms to the development of analytical methods. The reasons for this change may stem from two o cial actions. In 2011, the director of the State Administration of Traditional Chinese Medicine of China visited Hong Kong to attend an international conference on classical prescriptions and clinical indications. In 2019, a public call was made for comments on the CCFPP and its material reference information. During the early period, most patents were owned by individuals; however, the dominance of individual patents was gradually replaced by companies and universities/hospitals during the later stage. In recent years, universities and research centers have played increasingly more important roles in CCF development compared with companies. These changes re ect the trend of commercialization of CCF-related inventions (Figure 3).
Inventors' priority country or region (i.e., where the inventors protect their patents) could be determined from our data. In general, patent inventors applied for patent rights only in countries or regions where there was a potential market for the product [21]. Furthermore, not only Chinese enterprises led patents in China; for example, Tsumura & Co Ltd. of Japan led patents in China, which demonstrates the continued internationalization and appeal of the Chinese market [23,24]. Overall, capital entry is a positive sign for developers and governments [25], while companies offer dynamism to the development of CCF technology [26]. However, there may also be a boilerplate patent bubble that will eventually not adopted/invalidated these patents.

Recommendation on CCF R&D
To demonstrate the historical route of CCF R&D, we discuss some milestone patents: 1) Marking the beginning of CCF intellectual property, the rst CCF patent CN1232268 was invented by 3) The longest granted time was for the patent CN100515452, which was led by Huang Daju in 2005 and disclosed in 2009. It was marketed as an oral preparation of the Wuweizi decoction, which was developed using modern technology, and has the longest validity and largest commercial value of all granted patents. 4) The patent with the highest citation rate is a patent that is primarily cited by subsequent patents; it represents the most basic and innovative technology with high inventiveness and is what others in the eld try to imitate. CN102895432 was led by Wang Dengzhi in 2011 and is a new dosage form of 'happy pills' for the prevention or treatment of Alzheimer's disease. It was most frequently cited (29 times in total) for inventions of Alzheimer's disease treatments and the preparation of granules. In general, compared with patents of overseas units, patents of Chinese inventors were invalidated because of a lack of commercial value [10,11], which has continued to be a common problem for current patent applications.
We have provided an overview of the development of CCF patents in the previous sections and overview contributes to CCF development.
Each CCF has attracted different levels of attention, and among the 100 CCFs, 39 CCFs had no granted patents, and 82 CCFs had ≤ 4 granted patents. With the entry of corporate capital, CCF is an area to be recognized and will soon enter the 'fast track' period [25]. In addition, CCFs may require the introduction of further relevant policies to ensure a high level of attention [27]. Despite nancial and legislative backing, the majority of CCFs are now method patents with low invention complexity and weak barging power and constitutes only a few key patents. The development of CCFs will need to overcome this issue in the future as it expands internationally [28].
Insights from Tsumura Case.
The R&D of Tsumura & Co Ltd., a leading global developer of traditional prescriptions, analysis of their technological status and development, aid in the further development of CCFs. In 1976, the Japanese government included Kampo medicines in the medical insurance scheme, which gave impetus to the secondary development of traditional prescriptions in Japan, and in the same way as the CCF, policy was the rst driving force behind the development of the industry. In 1983, the JKMA was established, contributing to the cooperation and supervision of the Japanese traditional medicine industry and supporting the development of high quality traditional medicines in Japan. During Tsumura & Co Ltd.'s period of rapid development (1976)(1977)(1978)(1979)(1980)(1981)(1982)(1983)(1984)(1985)(1986)(1987), 129 preparations of Kampo medicines were applied for manufacture and sell them were obtained.At the same time, with patents being led for combinations and new compounds, but most of these patents are ungranted, and now granted patent on production methods and equipment and analysis methods.
In addition, compared to CCF's patents and Tsumura & Co Ltd.'s patents, Tsumura & Co Ltd. often use modern medical terms in the patent text to describe the diseases treated, and the diseases involved are mainly focused on diabetes complications, kidney diseases, cancer and tumour. And the patents are all medicine pairs, so making the patents more adaptable and protective, Tsumura & Co Ltd.'s patents type covers the upstream of the production of the product and is applied for in collaboration with several companies, including cultivation methods, production equipment, production methods and evaluation methods.There are two main points of similarity between the CCF and Tsumura & Co Ltd., They have the same degree of internationalisation, and analysis methods are the same hotspot in recent years. The development and establishment of related cultivation methods, production methods and evaluation methods for CCF can help to improve the integrity of the industry, increase the voice of CCF developers in the industry and further enhance the competitiveness of developers.
Predicting possible future problems from the past experience of Tsumura & Co Ltd. 1) Focus on drug safety to avoid drug abuse. In 1995 the prolonged use of Xiaochaihu decoction by Japanese hepatitis patients caused organic pneumonia [29][30][31], causing the Japanese public to reduce faith about Kampo medicines. 2) Reduce the inconsistencies in raw material crude drugs. Tsumura & Co Ltd. sources 80% of its production materials from China and 15% from Japan, in addition to a Good Agricultural and Collection Practice (GAMP) with a traceability system, a complete transport and storage system [10]. 3) Focus on R&D investment. In 2019, R&D Expenses Margin reached 5.0%, the highest percentage of R&D investment by any Chinese and Japanese Herb medicine company, and the high percentage of R&D investment has helped it to shift its R&D direction and maintain its operations after the Xiaochaihu decoction incident. 4)Scienti c analysis of traditional formulas using new technologies. Tsumura & Co Ltd. has been concentrating its resources on the establishment of scienti c evidence for its Kampo formulations in its research activities, it will be necessary for these formulations to be understood through the framework of Western medicine [10].
There remain several research limitations to our analysis. Although patents are key innovation indicators, this patent-based analyses do not re ect all CCF R&D efforts. But based on a large number of CCF reviews, we believe that patent analysis is necessary supplement to prior work. Furthermore, while the number of CCF patents is steadily increasing and the pace of R&D is quickening, are there any inventions that are both innovative and marketable? If so, how many are there? Also, as a successful representative of the rehabilitation of conventional formulations, what is the patent situation in Japan, and what is their patent landscape? We believe it is important to keep an eye on these issues since it will help us stay focused on the development of traditional therapies.

Conclusions
Policy has a signi cant in uence on CCF R&D, and the popular trend is spreading annually. With companies as primary applicants, CCFs are beginning to be recognized to have considerable market potential, and the number of patent applications is increasing each year, which indicates that the rapid growth of CCF development will continue in the future. However, the lack of high-quality patents may pose future development di culties, which will be an important issue to resolve.  The number of patent applications by different types of assignees. Different colors re ect different sorts of assignees.