Authors: Chen Wenping, Ma Hui, Intellectual Property group, King & Wood Mallesons
The revised Chinese Patent Law became effective on June 1. With fierce debates on how Article 76 should be implemented and construed, “linkage” litigation introduced by Article 76 on drug patents will gradually enter the public eye. As an administrative agency, the China National Intellectual Property Administration (“CNIPA”) can accept administrative ruling requests from parties to confirm whether the disputed technical solutions of a drug fall within the scope of patent protection. In combination with the CNIPA’s ongoing review function of patent invalidity requests, drug patent disputes will usher in a new era. Against such background, the decisions on drug patents in the ten most significant cases of the CNIPA in 2020 have more practical and effective guiding significance for the medicinal industry and can enable the public to further understand the CNIPA’s standards and approaches in evaluating the validity of drug patents.
Among the ten cases in 2020, three of them involve drug patents, respectively patents on compound, formulation and use. The relevant drugs all have been on the market for some years. All three cases are concluded with the validity of the patent fully or partially upheld. For the compound patent, the rules for determining inventiveness demonstrated in decision are consistent with the CNIPA’s decision on velpatasivir case (one of the 10 most significant cases in 2018). The panel further stressed in all three cases that the prior art should be evaluated as an integral whole. For the preparation patent and the use patent cases, decisions have demonstrated the idea of conducting examination based on comprehensive consideration of the background of the invention and the prior art market situation of related products, which is more grounded and reflects the legislative purpose of the patent law to promote scientific and technological progress and innovation.
The inventiveness of compound patents: focusing on the structure, efficacy and the relationship between the two.
Rivaroxaban tablets are an oral anticoagulant, jointly developed by Company B and Company J. It was first approved in Canada for marketing on September 15, 2008. Rivaroxaban tablets were marketed in China on March 31, 2009 under the trade name Xarelto®.
Right after being approved for marketing in 2009, rivaroxaban tablets were included in the medical insurance for postoperative treatment for lower limb arthroplasty. In the subsequent updates of the medical insurance catalogue, the indications covered have been expanded gradually.
The disputed patent ZL00818966.8 is a compound patent of rivaroxaban, and the patent rights expired on December 11, 2020. Since 2019, invalidity requests have been successively filed. The petitioner in this case is Company N, which is the first domestic manufacturer obtaining generic marketing approval. The generic rivaroxaban tablet manufactured by the petitioner (Anrixin®) was approved for marketing in 2019. In the invalidity request, the petitioner raised invalidation grounds of lacking sufficient disclosure, lacking support and lacking inventiveness. Upon examination, the CNIPA issued Decision No. 45997, maintaining the validity of the patent on the basis of the amended text submitted by the patentee.
The reasoning and evaluation of inventiveness in this decision embodied the policy guidance in recent years that inventiveness of compound patents should be evaluated by construing the invention against the development context of the industry, and by interpreting the contribution made by the invention in the eye of those skilled in the art. That is, evaluation should start from the search for the closest prior art, which is the starting point of the compound invention, and analyze the structural differences between the claimed compound and the closest prior art, thereby determining the technical problems actually solved by the patent based on the use and/or efficacy obtained by said structural change. After that, the prior art should be viewed as an integral part to see if there is technical suggestion for those skilled in the art to apply the distinguishing technical features to solve the technical problem actually solved.
The structures of rivaroxaban compound of claim 1 and compound A of the prior art is as follows:
Compound A (the closest prior art)
The closest prior art reference describes in a general manner that the compounds recited therein have Xa inhibitory activity, but does not disclose the specific activity data of compound A. Based on the IC50 experimental data of the inhibitory activity of rivaroxaban, the collegial panel determined that the technical problem actually solved by the present patent is to provide a compound with good Xa inhibitory activity. It is worth noting that when evaluating whether the prior art gives suggestion for group substitution, the decision discussed in detail the starting point of the invention, and determined that the closest prior art reference discloses benzamidine compound, i.e., the group at the left side of the molecular formula, . The overall disclosure of the reference documents shows that benzamidine is the core part of the invention. Therefore, those skilled in the art need clear technical suggestion when making changes to it.
That is, for compound inventions, when determining whether the prior art has suggestion to improve the closest compound, one should not only consider whether there is technical suggestions for group substitution in the prior art but also consider the overall structure of the closest compound, evaluating the similarities or differences between its skeleton moiety and those of other reference documents. In this case, given that the closest prior art and other exhibits all “disclose benzamidine compound as a Xa inhibitor”, the collegial panel pointed out that “based on the overall teaching of the above exhibits, those skilled in the art, when facing the benzamidine compound of exhibit 3, would recognize that benzamidine or formamidine are necessary structures to achieve the Xa inhibitory activity, and therefore, would more be motivated to conduct research on other groups while maintaining said structure”.
The Guidelines for Patent Examination provide that when judging whether the prior art gives a technical suggestion, one should consider the prior art as a whole in determining whether there is a suggestion of using specific technical means to solve the technical problem actually solved by the present invention. In the field of medicinal chemistry, this requirement has more meaning, i.e., on Structure-Activity Relation. After a drug compound enters the human body as an effective ingredient, it will participate in complex biological processes, such as dissolution, absorption, metabolism, etc. The change of the substituents in the compound will also affect its binding site and binding strength within the target tissue or with various enzymes in vivo, which is a manifestation of the structure-activity relationship of the compound. Therefore, compound modification without considering the structure-activity relationship is meaningless. As in this case, under the circumstance that none of the exhibits focuses on the configuration of the carbon atoms on the oxazolidine ring, the presence or absence of alkyl substitution on the amide nitrogen, and the possible effect of p-chlorophenyl and multiple equivalent options disclosed in the prior art on the activity of Xa factor, those skilled in the art would not obtain the technical suggestion for modifying the skeleton of the closest prior art, either.
The reasoning for compound inventiveness, in this case, is in line with the evaluation criteria in one of the ten prominent cases of the Patent Reexamination and Invalidation Department in 2018 on Company G’s velpatasivir patent (No. ZL201280004097.2). This case is directed to the compound structure of velpatasvir, which is the main active ingredient of Company G’s anti-hepatitis C drug Epclusa®. In this case, the Reexamination and Invalidity Examination Department also emphasized that for inventions in the medicinal field, it is necessary to examine the structure and the efficacy, as well as their relationship on a sliding scale. In principle, a novel compound that is not structurally close to known compounds and has a certain use or effect, are deemed to possess inventiveness; whether two compounds are structurally similar should be judged based on their technical fields; and structurally close compounds usually have the same or very close core parts. Therefore, the structure/efficacy will be a key point in compound patent prosecution.
The inventiveness of formulation patents —— acknowledging the inventiveness involved in moving from possibility to certainty
For a long time, the invalidity rate of preparation patents in the field of medicinal chemistry is higher than that of compound patents. The reasons are on multiple aspects. First, the formulation technology is usually described in various textbooks in the field of Pharmaceutics, so it is easy to combine these disclosures to obtain the technical features defined in the claims; second, the industry is often of the opinion that such “secondary inventions” such as formulation inventions or crystalline form inventions are made on the basis of compound inventions, and subjectively believes that these secondary inventions is not so high in inventiveness level as compared with active ingredients patents. Also, some scholars believe that secondary patents are designs for patent ever-greening, and thus should be questioned in terms of their reasonableness. However, the truth is, formulation technology is the key for stable preparation of active ingredients into drugs and is at least as important as the development of active ingredients. Statistics show that currently, nearly 40% of drugs in development have been abandoned due to difficult drug delivery. In China, complex preparations are heavily dependent on imports. The competition in formulations may become a new breakthrough for innovative drugs in the future.
The patent, in this case, is entitled “CYCLODEXTRIN OR CYCLODEXTRIN DERIVATIVE INCLUSIONS OF BUTYLPHTHALIDE AND PREPARATION METHOD AND USE THEREOF” (Patent No.: ZL02123000.5). The patentees are Company Z and Company E. The petitioner is a natural person. The patent involves the innovative drug butylphthalide, which is a Type I new drug independently developed in China. The therapeutic effect of butylphthalide injection has now been widely recognized in the medical profession. However, butylphthalide itself is lipophilic, so when developing butylphthalide into injection, the problem of its insolubility in water must be solved first.
Claim 1 of the present patent is as follows:
A cyclodextrin derivative inclusion of butylphthalide, characterized in that it comprises butylphthalide and cyclodextrin derivative, the molecular molar ratio of butylphthalide to cyclodextrin derivative being 1:1-10; the dextrin derivative being hydroxypropyl-β-cyclodextrin.
In the invalidity decision, the panel found that the technical problems disclosed in the description and the technical effects demonstrated in the present patent are both on improved water solubility. The closest prior art discloses butylphthalide capsules, which is different from the inclusion of butylphthalide and cyclodextrin. The petitioner believes that based on the teachings of cyclodextrins for inclusion of other drugs in the prior art, those skilled in the art have the motivation to use cyclodextrin as an inclusion agent to achieve the purpose of increasing solubility. In response to this, after analyzing a large number of teachings in the prior art, the collegial panel believes that “the emergence of good adjuvants in the pharmaceutical field only provides the possibility of preparing good preparations”, and “the emergence of potential solubilizers is to open a door for drug development, but if the inventive work of scientific researchers to transform the vague ‘possibility’ to ‘certainty’ on other drugs that are not similar in structure is directly denied merely because said solubilizers could be applied to dozens of drugs, this is obviously not conducive to the promotion and protection of inventions and creations.” It is worth noting that the collegial panel conducted a detailed analysis on the solubilization effect of the cyclodextrin in the prior art on different drugs, and concluded that the technical suggestion must be clear and specific. In fact, the prior art even provided β-cyclodextrin inclusion of volatile ligusticum slnense oil (exhibit 8), and the petitioner claims that the phthalide ingredients accounts for about 90% of the volatile ligusticum slnense oil, “exhibit 8 does not disclose the changes in the solubility of phthalide before and after inclusion, and as stated in the foregoing exhibit 4, it is difficult to predict the degree of solubilization effect of a certain cyclodextrin molecule on a drug, so in absence of any patterned technical information being explicitly disclosed, those skilled in the art, based on exhibit 8, still cannot expect that inclusion of butylphthalide with hydroxypropyl-β-cyclodextrin can achieve such excellent technical effect as described in the present patent, which provided possibility of preparing butylphthalide into injections and other dosage forms for in vivo injection”. The above shows that the panel believes that technical suggestions need not only to be specific, but also should be patterned technical information to enable those skilled in the art to expect similar technical effects.
In this decision, the panel also showed an evaluation rule of considering the prior-art as an integral whole. That is, the panel on the one hand look at why the prior-art preparation is in capsules, and on the other hand investigated the solubilization effect of cyclodextrin on different drugs in the prior art, with a view to understanding the invention in the context of the prior art.
A new application of an old drug —— Avoiding hindsight due to ignorance of the diversity and uncertainty of pathogenesis
Infant hemangioma is a type of benign tumor in infants or children, and there was no effective treatment method before the filing date of the present patent. Propranolol (propranololum) was originally a traditional β-blocker drug for the treatment of cardiovascular diseases. In 2008, the inventors of the present patent unexpectedly discovered that propranolol can be used to treat infantile hemangioma. The discovery of said new use is widely acknowledged by the industry as opening a new chapter for the treatment of infantile hemangioma (Chinese expert consensus on oral propranolol for the treatment of infantile hemangioma; Shanghai J Stomatol, 2016, 25(3): 257-260).
The patent-in-suit is titled “USE OF A BETA BLOCKER FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF HEMANGIOMAS” (Patent No.: ZL200880111892.5) owned by B University. The invalidity request is raised by Company Y.
Claim 1 reads:
Use of a beta blocker for the manufacture of a medicament for the treatment of capillary infantile hemangiomas, wherein said beta-blocker is propranolol or a pharmaceutical salt thereof.
The patentee made amendment to the claims during the oral hearing, limiting the indications to “capillary infantile hemangiomas”. This indication is narrower than either “hemangiomas” at the time of issuance or the “capillary hemangiomas or capillary infantile hemangiomas” as amended during the response period for the invalidity request. The patentee further submitted that the capillary infantile hemangiomas of claim 1 equal strawberry hemangiomas. The petitioner has different opinions on this and submitted several pieces of evidence showing the similarities in not only the names but also the mechanisms.
Because the interpretation of the indication is closely related to the evaluation of the teaching of the prior art, the collegial panel, before commenting on inventiveness, determined whether the capillary infantile hemangiomas are strawberry hemangiomas claimed by the patentee. Upon study of the content of the prior art such as classifications, causes of disease, etc., the collegial panel confirmed the patentee’s interpretation of the claim scope.
After confirming the protection scope of the claims, the decision determined that, based on the teaching of the prior art regarding the use of the compound for the treatment of vascular malformations, those skilled in the art would not have thought of using them for the treatment of another disease with a different pathogenic mechanism. The collegial panel also determined that the emergence of a technical solution for a pharmaceutical invention with a clear and definite curative effect requires careful observation and conception, or a great amount of trial and error; but once the technical solution is proposed, it could be easy to reconstruct a path that conforms to the linear logical relationship if one follows the clues of the known pharmacology and pathology-related mechanisms to arrive at the technical solution; if such a reconstruction ignores the complex physiological environment in vivo, or neglects the diversity and uncertainty of the pathogenic mechanism, then it is obviously a “hindsight” and will harm the legitimate interests of the patentee.
The essence of useful inventions is based on the discovery of a new property of a known compound. The discovery and verification of the new property requires a lot of research and experimentation. The decision comprehensively considered the complex physiological environment in vivo as well as the diversity and uncertainty of the pathogenic mechanism, and on such basis confirming the inventiveness of the use invention.
Furthermore, the determination of the protection scope of the claim in this case, in fact, further clarifies the prior art status in the technical field of the present invention and prepares for the subsequent determination of whether there is suggestion. After the implementation of the new patent law, the CNIPA has a new function of ruling on when whether the disputed technical solution falls within the protection scope of the patent rights, this case is even more significant and is typical in the interpretation of the protection scope of the patent rights.