Through comparative study with European and American practices, this part puts forward suggestions for improving the current examination standards for compound patents in China, especially the examination standards for inventiveness issue.
- The Issue of Selecting the Invention Starting Point in Determining Inventiveness of a Compound Patent
Selection of invention starting point is a very important focus of dispute in the United States. In Europe, it is an issue that needs to be carefully considered under certain circumstances. In examination practice of invalidation declaration in China, when the “three-step method” is used to determine the inventiveness of a compound, the existing technical solution selected by the invalidation petitioner is often directly adopted.
In the evaluation of inventiveness (non-obviousness), the United States attaches great importance to the invention starting point, that is, the choice of the lead compound. In a large number of US patent invalidation disputes, the focus of deliberation is usually on whether or not those skilled in the art would choose the technical solution pointed out by the invalidation petitioner as the lead compound. The lead compound is usually one of the compounds with the best effect in the same technical field in the prior art. The compound in the prior art with the smallest structural difference from the present invention is not necessarily the lead compound. If the prior art compound selected by the invalidation petitioner cannot be used as the lead compound, then it should be directly determined that the compound of the present invention is non-obvious.
The European Patent Office recognizes that invalidation petitioners are free in selection of the existing technical solution as the closest prior art, but emphasizes that there may be hindsight existed in selection of the closest prior art. When the existing technical solution has defects so obvious that those skilled in the art would not consider making improvements from it at all, such technical solution cannot be used as a proper starting point of the invention. Otherwise, there will be issue of hindsight.
In the practice of inventiveness examination in China, whether or not to examine the reasonableness of the invention starting point has always been controversial. In invalidation examination and administrative litigation procedures, invalidation petitioners usually select the compound with the closest structure to the compound of the present invention as the closest prior art, rather than selecting the compound with better technical effect. However, in examination practice, the technical solution indicated by the invalidation petitioner is usually taken as the closest prior art and the invention starting point, and whether or not the technical solution is suitable as the invention starting point is not examined. Some judgments have even pointed out that the first step in the “three-step method” (i.e., selection of the closest prior art) can be chosen arbitrarily. If there is prior art closer to the present invention than the prior art selected by the petitioner and the present invention possesses inventiveness, then the evaluation based on the “three-step method” starting from the prior art selected by the petitioner should also conclude that the invention possesses inventiveness.
We believe that the essence of the “three-step method” is to remove the influence of subjective factors from inventiveness determination through comparison as objective as possible, and return to the pre-filing state for objective determination. In determination of the closest prior art, the closest prior art is selected with reference to the technical solution of the invention. This method can indeed quickly find the prior art closest to the invention. However, on the other hand, it should also be admitted that since the closest prior art is selected afterwards according to the technical solution of the present invention, allowing the invalidation petitioner to select the closest prior art at will after the filing date, instead of determining the invention starting point that would most likely to be selected on the filing date from the perspective of those skilled in the art, may cause deviation from the general rule of invention and innovation in this field, and underestimate the difficulty of invention creation, which will inevitably be suspected of “hindsight”.
For determining inventiveness of compounds, the lead compound should be selected first, and then the modification direction of the lead compound should be selected. In the selection of the lead compound, it is necessary to specifically analyze the motivation for those skilled in the art to select from the prior art and the expected possibility of success. From the perspective of the rule or process of scientific research, the fundamental basis of ordinary researchers in the medical field in selecting lead compounds should be the overall teaching of related compounds in the prior art. After understanding of the prior art in its entirety, what can enable those skilled in the art to conduct research and development should be the most excellent (i.e., the most promising) compound after comprehensive consideration of known uses, effects and other physical and chemical properties commonly evaluated in the medical field. In contrast, especially when those compounds with the smallest structural difference have been explicitly rejected, those skilled in the art are more likely to choose other compounds that have larger structural differences but are more promising as the invention starting point. If the compound with the smallest structural difference is forcibly selected as the closest prior art for inventiveness analysis (sometimes even the inactive intermediate products disclosed in the prior art are used as the closest prior art), then it is very likely to deviate from general rule of invention creation, which causes the hypothetical process of the inventiveness analysis to significantly deviate from the approaches that may be adopted in the real world.
Therefore, we suggest that in the first step of the “three-step method”, the invalidation petitioner should be required to explain in detail reasons for selecting the specific prior art compound as the closest prior art and to illustrate why it is the “most promising” compound in the prior art. When the patentee submits evidence showing that there is a prior art compound that is evidently better or that the compound proposed by the invalidation petitioner has obvious defects, examination should be conducted on whether or not the compound proposed by the invalidation petitioner is suitable as the closest prior art. In practice, we suggest leaving room for discussions and debates on the issue of selecting the closest prior art the invention starting point, rather than necessarily using the compound selected by the invalidation petitioner as the starting point.
2. Motivation and Teaching for Structural Modification in Determining Inventiveness of Compound Patents
The evaluation of inventiveness (non-obviousness) in the United States also attaches great importance to the motivation and teaching for structural modification from the lead compound after selection of the lead compound. According to the “ordinary inventive ability” of those skilled in the art determined by the U.S. Supreme Court in the KSR case, those skilled in the art can refer to the ordinary means of structural modification in the same field. However, all motivations for structural modification should have a reasonable expectation of success. That is, it can be expected that the modified compound can improve activity or solve the known defects of the prior art compounds without loss of the advantages of the known compounds. Therefore, such motivation shall not be based solely on hypothetical approximations or broad structural similarities, but should be proved by clear scientific rules or experimental evidence.
The European Patent Office in the inventiveness evaluation presupposes that any structural change to a compound should affect its properties, unless there is clear evidence showing that the change is not likely to cause significant change in the properties of the compound. In the examination practice of the European Patent Office, it is clear that such evidence can be the teaching given by compounds of general formula in the prior art. However, such teaching should not exceed the structural definition of the compounds of general formula, including the unchangeable part, the position of the substituent, and the type of optional substituent. In particular, the European Patent Office has clearly determined that the methods that may be considered in the design of drugs such as “bioisosteres” are empirical rules rather than scientific theories, so that when there is no clear verification that these empirical rules can be applied to the structure of the specific compound, it should also be assumed that changes in the structure will affect the properties.
In the practice of inventiveness examination in China, determination is mainly based on “whether or not the structure is close”. Specifically, when the compound of the present invention is “not close in structure” to the compound of the prior art, the compound is usually inventive; on the contrary, when the compound of the present invention is “close in structure” to the compound of the prior art, then unexpected technical effect is usually required to prove inventiveness. However, the Guidelines for Patent Examination does not give a specific and clear standard for determining whether or not the structure of the compound of the present invention is close to that of a known compound. The Guidelines only gives examples of a few specific circumstances (e.g., “compounds with similar structures have the same basic core moiety or basic ring”, but there is no further definition of the concepts of the “basic core moiety” and the “basic ring”. This causes examiners in different cases to have different understanding in determining whether or not the structure is close to the prior art, leading to different determination standards. This is reflected in the tendency of compound patents to focus more on technical effects and experimental data than patents in other fields of chemical medicine.
We believe that the underlying reason why simply unexpected technical effect of compounds with similar structures is required in the inventiveness determination is that those skilled in the art already know that such compounds have a certain structure-activity relationship, so that they can reasonably expect that the compounds obtained after certain structural changes also have roughly equivalent technical effects. Therefore, the compounds can be inventive only when they break said expectation. For example, in the field of organic chemistry, the general physical and chemical properties of compounds (including melting point, boiling point, acidity and alkalinity, etc.) usually have certain regularities. When the structure of the compound is changed according to these regularities, it may simply require unexpected technical effects in the inventiveness determination.
However, it is still highly unpredictable in the pharmaceutical field regarding whether or not a compound has pharmacological or therapeutic effects. The reason is that therapeutic effect concerns biological macromolecules in the human body, and these biological macromolecules are more complicated in structure. For example, in the field of medical research and development, the “lock-key” model can usually be used to simplify the mechanisms of drug action. That is, only when the drug structure can complementally bind to the target (such as the receptor) responsible for the desired biological effect, can it play its due role. This complementary combination is the result of multiple interactions (including covalent bonds, electrostatic interactions, hydrogen bonds, hydrophobic interactions, van der Waals forces, etc.). This makes the binding site likely to involve a larger part such as the conjugated ring structure of the compound, or a smaller part such as a hydrogen bond donor acceptor group and an ionizing group. These interactions are difficult to predict in advance.
In the actual field of pharmaceutical research and development, researchers usually study the structure-activity relationship of a specific type of compounds, and summarize this structure-activity relationship in the literature, which is embodied in the general formula compound or the classification description of the specific compounds. This includes unchangeable structural moieties, the position of substituents, and the scope of optional substituents. Said description together constitutes the boundary of the research and development personnel’s exploration of the structure-activity relationship of pharmaceutical compounds. Area within the boundary represents compounds that the researchers have verified through experiments or reasonable speculation, and area outside the boundary represents fields that have not yet been explored and whose structure-activity relationship is not clear. Therefore, it is still highly unpredictable whether or not these unexplored compounds have technical effects such as the related activity.
Therefore, we suggest that in the third step of the “three-step method”, the general laws of scientific research should be respected; the high unpredictability of the structure-activity relationship in the medical field should be recognized; and the structure-activity relationship taught by the description of the general formula compound, the specific compounds, and the effects, etc. in the prior art as a whole should be comprehensively considered; and the explored structure-activity relationship should be used as the basis in determining whether or not there is a reasonable expectation of success for structural modification and whether or not there is motivation to make the corresponding structural modification. In fact, in the CNIPA Decision No. 42407 (the Sunitinib compound invalidation case, the top ten reexamination and invalidation cases in 2019), Decision No. 45997 (the Rivaroxaban compound invalidation case), and the Supreme People’s Court (2016) Xing Zai No. 41 (the Olmesartan Medoxomi I compound invalidation case, the top ten intellectual property cases in Chinese courts in 2017), the Beijing Higher People’s Court (2018) Jing Xing Zhong No. 6345 (the Ticagrelor compound invalidation case, the 50 typical IP cases in Chinese courts in 2018), etc., both the CNIPA and the People’s Courts are trying to specify that the motivation and teaching for structural modification are determined based on the known structure-activity relationship taught by the prior art. In practice, we suggest that this method should be further determined, and a specific determination method for determining the known structure-activity relationship taught by the prior art should be given. This will help unify the examination standards and provide guidance for patent applicants.
 The authors are all patent agents at King & Wood Mallesons (Beijing).
Contact Person: Tina Tai, firstname.lastname@example.org, 010- 58785132