Wu Tong,Dong Li

(School of Business Administration,Shenyang Pharmaceutical University,Shenyang 110016,China)

Abstract Objective To analyze the development trend of clopidogrel bisulfate so as to provide suggestions for the research and development (R&D) of China’s pharmaceutical enterprises.Methods By studying the development process of thiophenic pyridine drugs,we found that clopidogrel bisulfate belongs to the second generation product.Then,the patent status of generic drugs of thiophene in the United States and China was analyzed to identify the key points and trends of its R&D.Results and Conclusion This paper analyzes the patent and important technology of clopidogrel to predict its development trend,and put forward countermeasures for Chinese pharmaceutical enterprises.

Keywords:clopidogrel bisulfate;patent;development trend

The chemical name of clopidogrel bisulfate is(+)-(S)-alpha-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-c] pyridine-5 (4H)-methyl acetate bisulfate,and its trade name is plavix.Developed by Sanofi-Aventis,the new and highly effective anti-platelet aggregation drug can selectively block the binding of adenosine diphosphate (ADP) to platelet receptors.Clopidogrel is a second generation of adenosine diphosphate receptor antagonist,which is an inactive drug precursor[1].In 1998,clopidogrel was on the market for the first time in the USA,and then it was listed in Europe,Canada,Australia,Singapore and other countries and regions successively.Since clopidogrel was sold on the market,its sales volume has soared and it becomes the second best-selling drug in the world.In 2001,this drug entered Chinese market[2].

1 Development of thiophene pyridine drugs

By researching a large number of literature,we found that thiophene pyridine drugs on the market have experienced three changes at present,forming three generations of drug products respectively.The first generation is ticlopidine,which is an ADP receptor inhibitor.The second generation of ADP receptor inhibitor is clopidogrel,and the third generation of ADP receptor inhibitor is prasugrel[3].

Ticlopidine,as a first-generation drug,is an anti-platelet aggregation drug,which has shown a better clinical effect than aspirin.In 1973,the French Sanofi company first applied for the relevant patent(FR2215948A1).The protection scope of the patent includes general compound and specific compound.Moreover,the form of general compound and specific compound of ticlopidine was first documented in patent literature.Subsequently,the company applied for patents in other countries successively,carrying out patent layout to improve the protection of the basic patent.

As a second-generation drug,the chemical structure of clopidogrel is similar to that of ticlopidine,with only one more carboxymethyl in the side chain.Although the change is little,the efficacy of clopidogrel is much higher than that of ticlopidine[4].The compound patent of clopidogrel was first applied by Sanofi in France in 1982,and its patent number is FR2530247A1.Its protection scope covers general compound of clopidogrel and specific compound of racemization,and the forms of two clopidogrel compounds mentioned above were documented in patent literature.Then,Sanofi continued to apply for subsequent patents.The patent (FR2623810A2) was applied in 1987 to protect clopidogrel and its salt.This patent was applied for administrative protection in China because the patent law of China at that time could not directly protect the compound patent.Therefore,Sanofi applied for administrative protection for this patent in China and obtained approval.The period of administrative protection of this patented technology in China expired on February 17,2007[5].

As a third-generation drug,prasugrel is a precursor drug.Compared with clopidogrel,the active metabolites of prasugrel are produced faster with higher concentration,and clinical studies have shown that it has better effect than clopidogrel.However,clinical data also show its side effects and the risk of medication because it can increase the risk of bleeding[6].Prasugrel was jointly developed by Lilly and Daiichi Sankyo,its patent in China was applied by Daiichi Sankyo and expired on September 8,2012.Several other patent applications related to prasugrel hydrochloride,maleate and conventional preparations have been authorized.These applications will expire on July 2,2021.As a third-generation drug,prasugrel overcomes the deficiencies of metabolism in the body of clopidogrel clinically.However,due to its high risk of bleeding,FDA has repeatedly reviewed approval of prasugrel.In 2009,prasugrel attained approvals from EMA and FDA.Although it is finally approved for the market,its clinical promotion is greatly limited.

2 Patent status of American generic drug companies

Many pharmaceutical companies are optimistic about plavix because it has achieved considerable market sales after listing.These companies developed and innovated based on the patent information of Sanofi,and they gradually applied for their own patents while making generic drugs.In addition,these generic drug companies have also applied for international patent around the development of this drug.Currently,they have formed a good patent network,which can protect the technology development and products of their generic drugs.The patent application status of foreign generic drug enterprises is shown in Table 1.

Table 1 Manufacturer’s patent information of clopidogrel bisulfate generic drug [7]

3 Patent status of generic drug research and development (R&D) in China

The study of thiophene pyridine derivatives in China is later than abroad,some literature show that relevant research applications in China might start in 2000.Therefore,the research of Chinese applicants is decades later than foreign countries.The information of clopidogrel was retrieved and analyzed from the patent database of China.The specific time of the retrieval is January 20,2020.The retrieval comes from the database of National Intellectual Property Administration,and the subject of the retrieval is clopidogrel hydrogen sulfate.According to the information obtained from the retrieval,the top 10 patent applicants in China are listed in Table 2.

Table 2 Top 10 Chinese enterprises and institutions with the number of clopidogrel applications

Many pharmaceutical enterprises have applied and developed generic drugs for clopidogrel bisulfate in China.From 2000 to 2020,the top 10 enterprises with the number of applications in China are distributed in 10 technical fields and they are shown in Table 3.Among them,A61K31,A61P7 and A61K9 rank in the top 3 with the largest number of applications.It means that the R&D is relatively mature in these technical fields.In addition,Fig.1 shows the R&D distribution among the top 10 enterprises.

Fig.1 Distribution of patent application technology fields of top 10 enterprises

Table 3 distribution of patent application technology of clopidogrel in 10 fields

4 The prediction about the trend of technology improvement and development

From the analysis of patent literature,we can see that with the development of the first generation of thienopyridine drugs,the first related patent application appeared in the world,which is the French Sanofi’s patent in 1973.At the same time,the first general compound and specific compound of ticlopidine were recorded in the literature.In addition,international applications for related patents also increased significantly from 1976 to 1978.Then,until the advent of the second generation drug,the first patent application for clopidogrel was filed in France in 1982,which caused the outbreak of the second round of applications.It is found from the international patent information that the improvement of thiophene pyridine drugs from the first generation to the second generation has accumulated a large number of R&D technologies in this field.From the numerous patent application information,the key points that should be focused on in the follow-up R&D can be found easily.

When the first patent application for prasugrel,a third-generation drug,came out,it took eight years.A lot of related patent applications were made by other enterprises.Therefore,many enterprises need a long technological catch-up period for the development and improvement of the third-generation drugs since the structure of the active metabolites of prasugrel is greatly different from that of the previous two generations of drugs.Besides,its biotransformation process still needs further clinical research.The characteristics of prasugrel play a role in inhibiting platelet aggregation.After entering into the body,prasugrel needs to be hydrolyzed,and then it can be further metabolized and converted into active metabolites to achieve the effect of inhibiting platelet aggregation.Obviously,it is difficult to find a new breakthrough point to improve the structure of prasugrel in a short time.

Therefore,for the subsequent R&D of thiophene pyridine drugs,information can be obtained from the patent literature.One direction is to conduct research on the basis of the second-generation drug clopidogrel from the perspective of structural improvement.The reason is that the R&D technology of the secondgeneration drug is relatively mature and the direction is quite clear.The other direction is to continue the research on the basis of the third generation of drugs.However,the R&D of prasugrel is new,and there are still many technical gaps,which need a lot of investment for continuous improvement and development.

According to their own economic strength,R&D capability and technical reserves,China’s pharmaceutical enterprises can develop new compound if they start with the second generation drugs.It is because the development of clopidogrel has been very mature in the world and these enterprises have many technical means that can be referenced.Therefore,their R&D success rate will be higher.However,if enterprises consider the protection of technological innovation achievements through patent application in the process of R&D,it is prone to have low authorization rate.Due to many patent authorizations and applications in the early stage,it will affect the novelty or creative examination of subsequent patent applications.After all,there are many existing patent technologies.

Some researchers believe that the current improvement of substituent at 6 positions on the thiophene pyridine ring is the possible technological breakthrough,because no breakthrough innovation has been seen in this study.Therefore,it may have certain research prospects for enterprises and researchers.In addition,it is found from the information that there is no relevant application for the improvement of the substituents at the 3 and 4 positions on the thiophene pyridine ring,which is in a state of stagnation due to some technical obstacles.Perhaps such improved experiments will increase the risk of R&D,but it can lead to new results of antithrombotic drugs.

Starting from the third generation of drugs,China’s pharmaceutical enterprises will have the opportunity to make new achievements in preparation methods,crystal forms,compositions,etc.by improving and innovating the peripheral patents.Then new patents can be applied to restrict the basic patents of the original pharmaceutical enterprises and increase competitiveness for the later products.In this way,we can avoid restrictions from the original patents,and expand a broader technical field for China’s drug R&D in this field.

5 Countermeasures and suggestions for the development of generic drugs in China

By analyzing the relevant patents of clopidogrel bisulfate,we find that among the patent applications in this field,Sanofi Company,the original R&D applicant,has obvious strategic characteristics for protecting its related patents,which covers long periods with type consistency.From the perspective of long-term practice,these patent protection strategies are perfect and effective.Therefore,they are worthy of learning for China’s pharmaceutical enterprises.Besides,they also have certain reference value for the R&D of generic drugs in China.

5.1 Information guidance and supporting role of patent documents

The most direct technical guidance and basis for new drug development and project approval come from patent documents.The retrieval and analysis of patent information can bring more than 95% of technical information and ideas to R&D personnel,saving time for R&D units and enterprises.Generally,it can effectively shorten the time of 3 to 5 years and save a large amount of funds,which is extremely important for pharmaceutical industry.

5.2 Carrying out peripheral patent layout with the help of Bolar exception

Chinese pharmaceutical enterprises and researchers should study the practice of Bolar exception to formulate the strategy of generic patent.Meanwhile,they should expand the scope of R&D,and actively carry out the layout of peripheral patents beyond the core patents of original research drug manufacturers.As a result,generic drugs can still implement the strategy of patent protection.

5.3 Patent challenge strategy

For the challenge of patent invalidity,the U.S.government encourages the generic applicant to fight against the patentee.It stipulates that the first applicant to submit an ANDA application to the FDA will get a 180 day market monopoly period as the incentive of the first generic to challenge the patent if the patent challenge is successful.

In China,the generic applicant can make use of the data protection system to be the first generic applicant.Combined with the stability of the original research drug patent,China’s generic applicants can carry out sufficient information retrieval and analysis to invalidate the patents of the original drug manufacturers.They can also avoid infringement of related patents through technology evasion and alternative technology,thus obtaining a data protection period of 1.5 years.