Written by:Tina TAI ,Yu GUO ,Bin WU（Intellectual Property）[1]
Preface
At the beginning of 2020, we were entrusted by Beijing RDPAC International Consulting Co., Ltd. and conducted statistics and analysis on the status quo of the review of invalidation and administrative litigation for invalidation disputes of compound patents between 2010 and 2019. Combining with the review practices of the United States and Europe, we conducted comparative analysis on the selection of lead compounds in the inventive step problem of compounds, the motivation and enlightenment of modifying the structure of compounds, and the acceptance of supplementary experimental data and brought up with three suggestions as follows.
(1)Judge the eligibility of the closest prior art compound claimed by the petitioner. For the judgment of the inventive step of compound, the lead compound should be selected first, and then the modification direction of the lead compound should be selected. From the perspective of the law or process of scientific research, the basic basis for the selection of lead compounds by ordinary researchers in the medical field should be the overall teaching of relevant compounds in the prior art. After understanding the entire state of the art and comprehensive consideration of known uses, effects, and other physical and chemical properties commonly investigated in the medical field, those skilled in the art should research and develop the most excellent, that is, the most promising compound as a starting point for further structural improvements, that is, as a lead compound.
(2)The structure-activity relationship of the prior art compound can be judged according to the overall teaching of the prior art, then the obviousness of the structure of the involved patent compound can be judged thereby. We suggest to recognize the highly unpredictable structure-activity relationship in the field of medicine, and consider the overall structure-activity relationship taught in the prior art including general formula compounds, specific compounds, descriptions of effects, etc.. Based on the explored structure-activity relationship, it is judged whether there is a motivation to make corresponding structural modifications and whether there is a reasonable expectation of success in the modification of the structure.
(3)The stipulation in the new version of the Patent Examination Guidelines “the technical effects proved by the supplementary experimental data should be obtained by those skilled in the technical field from the disclosure of the patent application” should be flexibly explained. When judging the technical effects of the compound, relevant technical effects that are clearly recorded or inferred in the specification should be reasonably considered. If the relevant quantitative experimental data is not recorded in the specification, the applicant or patentee should have the opportunity to submit relevant experimental data to support the technical effect, so as to provide an objective technical factual basis for the review.
On October 17, 2020, the 22nd meeting of the Standing Committee of the 13th National People’s Congress passed the “Decision on Amending the Patent Law of the People’s Republic of China”. After the amendment, drug patent linkage system is introduced in Article 76 of the Patent Law. On July 4, 2021, State Drug Administration and China National Intellectual Property Administration jointly issued the “Implementation Measures for the Early Resolution Mechanism for Drug Patent Disputes (Trial)”. On July 5, 2021, the Supreme People’s Court issued the “Regulations on Several Issues Concerning the Application of Law in the Trial of Civil Cases of Patent Disputes Related to Drugs Applied for Registration”. On July 5, 2021, China National Intellectual Property Administration (CNIPA for short) issued the “Administrative Adjudication Measures for the Early Resolution Mechanism for Pharmaceutical Patent Disputes”.
According to the newly established drug patent linkage system, in the process of drug marketing approval, if the drug applying for marketing may infringe the patent rights of others, the relevant parties can file a suit before the people’s court or request an administrative ruling from the patent administration department of the State Council, requesting a judgment or a ruling on whether the drug-related technical solution applied for registration falls within the scope of protection of the patent rights of others’ drugs. In this system, compound patents related to listed drugs, that is, compound patents for active ingredients of marketed drugs, are particularly important.
In this context, we hope that to study the stability of compound patents again, and further compare them with the statistical data and review recommendations summarized in the previous research report, in order to accurately grasp the new changes and new trends in compound patent invalidation review.
Part One Statistical Analysis of Chinese Compound Patent Invalidation
This part first searches, analyzes and counts the review of invalidation of compounds and administrative litigation of invalidation disputes in China.
I. Search and analysis methods of invalid cases
As in the previous report, we use the IPC numbers of medicine-related fields (such as C07D, A61K, A61P, C07C, C07F, C07K) as the search point to search for invalidation decisions in the past two years from January 1, 2020 to September 30, 2021, and further screen the invalidation decisions obtained from the search for relevant invalidation decisions whose authorized claims’ subject is related to compounds in the pharmaceutical field , thus 16 invalidation decisions are retrieved from this search. See Table 1 below for relevant basic information about invalidation decisions.
Table 1. Compound patents from 2020 to 2021
Basic information about invalidation decision
| No. | Decision No. | Application No. | Decision Date | Title of Invention |
Law Article (Compound Subject) |
Conclusion (Compound Subject) |
| 1 | 44093 |
2013800 29174.4 |
2020/4/21 | New thienopyrimidine derivatives, preparation method and therapeutic use thereof | A26.4 |
Maintained (part*) |
| 2 | 44182 | 03802556.6 | 2020/4/24 | 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-one |
A26.3/A26. 4/A22.3 |
Maintained (part*) |
| 3 | 44853 |
201210217 024.3 |
2020/6/4 | Bruton’s tyrosine kinase inhibitor | A26.3 |
Maintained
|
| 4 | 44855 |
200680056 438.5 |
2020/6/4 | Bruton’s tyrosine kinase inhibitor | A26.3/A26.4 |
Maintained
|
| 5 | 45381 |
20151029 3269.8 |
2020/7/10 | Deuterated dehydrophenyl asterin compound, preparation method thereof and application in preparation of anti-tumor medicine |
A26.3/A26.4 /A22.2/A22.3 |
Maintained
|
| 6 | 45997 | 00818966.8 | 2020/8/21 | Substituted oxazolidinone and its application in the field of blood coagulation |
A26.3/A26. 4/A22.3 |
Maintained (part*) |
| 7 | 46044 | 00818966.8 | 2020/8/27 | Substituted oxazolidinone and its application in the field of blood coagulation | A26.3/A26.4 |
Maintained (part*) |
| 8 | 46047 | 00818966.8 | 2020/9/1 | Substituted oxazolidinone and its application in the field of blood coagulation | A26.3/A26.4 |
Maintained (part*) |
| 9 | 47328 |
201180056 716.8 |
2020/12/18 | Prodrugs of substituted polycyclic carbamoyl pyridone derivatives | A26.4/A22.3 |
Maintained
|
| 10 | 47569 |
201180035 776.1 |
2021/1/4 | Methods and compounds for treating Paramyxoviridae virus infection |
A26.3/A26. 4/A22.3 |
Maintained
|
| 11 | 47590 |
201380024 470.5 |
2021/1/5 | Lysine-Glutamate Dipeptide Derivatives |
A26.3/A26. 4/A22.3 |
Maintained (part*) |
| 12 | 48183 | 01820481.3 | 2021/2/2 | Novel sulfonamide compounds and their application as endothelin receptor antagonists |
A26.3/A26. 4/A22.3/A29 /R20.1 |
Maintained (part*) |
| 13 | 48855 |
201110006 009.X |
2021/3/23 | Dipeptidyl peptidase inhibitor | A26.3/A22.3 |
Maintained
|
| 14 | 50976 |
200810200 106.0 |
2021/7/14 |
Deuterated ω- diphenylurea and derivatives and pharmaceutical composition containing the compound |
A22.3 |
Maintained
|
| 15 | 51360 |
20068001 1923.0 |
2021/8/4 | Piperazine substituted benzothiophene for the treatment of mental illness | A22.3 |
Maintained (part*) |
| 16 | 51835 |
20058003 3600.7 |
2021/09/09 | Compounds used to inhibit the proteasome | A22.3 | Maintained |
* Maintain the validity of the patent right based on the amended claims of the patentee
On this basis, the texts of the 15 invalid decisions were analyzed, including the reasons for invalidation, the evidence provided by both parties, the amendment of claims in the invalidation procedure, the comments of the collegiate panel, and the final conclusion of the invalidation decision.
Ⅱ.Overall statistical analysis of invalid cases
- Annual distribution of invalid decisions
Figure 1 shows that the number of invalidation decisions on compound patents from 2020 to September 2021 remains at a high level. From the overall data, after 2017, the number of compound patent’s invalidation decisions has been maintained at a relatively high level, about 10 cases per year. The data suggests that the state of generic drug companies challenging the core compound patents of listed drugs has shown an intensified trend in the past five years.
- Distribution of invalid reasons
According to the data in Figure 2, it can be seen that, similar to the period from 2010 to 2019, in the patent invalidation cases with a subject on compounds from 2020 to September 2021, the issue on inventive step is still the main reason for invalidation. Compared with the reasons for invalidation from 2010 to 2019, the most obvious difference is that the proportions involving insufficient disclosure and support issues have increased, while the proportions involving modification of out-of-scope and other clauses have decreased.
In general, the main invalidation reasons for patent invalidation cases involving compound subjects from 2010 to 2021 are issues of inventiveness, insufficient disclosure of specifications and unsupported issues. Among the total 51 invalidation decisions in the statistical analysis, 35 cases involve invalidation grounds on inventiveness, accounting for nearly 70%. In addition, there were 28 cases involving insufficient disclosure of specifications, accounting for 55%, and 19 cases involving the invalid reason of unsupported issues, accounting for nearly 37%.
- Distribution of invalid conclusions
Compared with the data from 2010 to 2019, the changes in invalidation conclusions from 2020 to 2021 are the most obvious. As shown in Table 1 above, from 2020 to 2021, a total of 8 compound patents were declared valid, 8 compound patents were declared partially invalid, while no compound patent was declared invalid. After carefully studying the examination decision of partially invalidated patents, we noticed that all partially invalidated patents were declared valid on the basis of the patentee’s amendment of the claims. In other words, for all 16 compound patents, CNIPA did not voluntarily declare any of these patents invalid, or even invalidate just one claim in them. Therefore, from the perspective of the patentee, during the period 2020-2021, all compound patents involving invalidation process are eventually remained valid.
- Circumstances of claimed subject matter
In view of the fact that compound patent mainly includes general structure of Markush and specific compound, we further count the claims according to their subject matter, and obtain the data in Table 2 below.
Table 2. The subject matter of the claims
*：In Decision No. 48855, although claim 1 of the patent does not adopt the drafting method of Markush claims, it includes more than ten specific compounds, so it is also classified as Markush claims.
**：In Decision No. 44182, claim 1 is amended from a scope of dozens of compounds at the time of authorization to 4 specific compounds, and therefore it’s classified as a specific compound claim.
Based on the above data, it can be seen that in the 16 examination decisions that maintained the validity of patent rights, 9 patents ultimately only protect specific compounds, and almost all of them only protect the active ingredient compounds of listed drugs. Based on this, it is believed that amending the final claims into claims of specific compounds can increase the chance of maintaining the patent rights.
- Reasons for recognizing the inventiveness of compound patents
As mentioned earlier, from 2020 to 2021, creativity is still an important reason for invalidation in compound patent invalidation requests. In view of such a high patent maintaining rate, we carefully read all 16 invalidation decisions, and briefly summarized the main reasons for the final approval of the compound’s inventiveness, as shown in Table 3 and Figure 3 below.
Table 3. Reasons for recognizing the inventiveness of compound patents
| Serial No. |
Decision No. |
Application No. |
The Main Reason of Recognizing Inventiveness |
Whether it Involves Supplementary Test Data |
| 2 | 44182 | 03802556.6 | Achieved unexpected technical effects | |
| 5 | 45381 | 201510293269.8 | Achieved unexpected technical effects | Yes |
| 6 | 45997 | 00818966.8 | Non-obviousness in the structure of the compound of the present invention | Yes |
| 9 | 47328 | 201180056716.8 |
The prior art does not give the technical enlightenment of the technical solution of the present invention (Selection of lead compound) |
|
| 10 | 47569 | 201180035776.1 |
The prior art does not give the technical enlightenment of the technical solution of the present invention (Selection of lead compound) |
|
| 11 | 47590 | 201380024470.5 |
The prior art does not give the technical enlightenment of the technical solution of the present invention (Selection of lead compound) |
|
| 12 | 48183 | 01820481.3 | Non-obviousness in the structure of the compound of the present invention | Yes |
| 13 | 48855 | 201110006009.X | Non-obviousness in the structure of the compound of the present invention | |
| 14 | 50976 | 200810200106.0 | Achieved unexpected technical effects | |
| 15 | 51360 | 200680011923.0 | Achieved unexpected technical effects | |
| 16 | 51835 | 200580033600.7 | Non-obviousness in the structure of the compound of the present invention | Yes |
Regarding the specific reasons for the above-mentioned recognized inventiveness of compound patent, we will explain and analyze it in details later.
III. Relevant judgments of Chinese courts
- Statistics
Use the relevant database to search the invalid administrative litigation in 2020-2021 with the international classification numbers of medicine-related fields (such as C07D, A61K, A61P, C07C, C07F, C07K) as keywords, and further filter the relevant judgments in the search results with the authorized claim subject matter relating to compounds in the pharmaceutical field, and exclude the case of withdrawal of the lawsuit. From this search, the following 5 judgments were obtained.
Table 4. Administrative Litigation on Invalidation Decision of Compound Patent from 2020 to 2021
| Product Name | Patent No.Involved | Patentee | Decision/Judgment No.and Conclusion | Issue Date |
|
Engligliflozin |
ZL201310414119.9 | Boehringer Ingelheim | Invalidation Decision No. 33101 All compound patent rights are invalid | 2017-08-15 |
|
(2018) Beijing 73 Xingchu No. 1097 Maintain decision |
2020-12-15 | |||
| ZL201310379906.4 |
Invalidation Decision No. 33102 All compound patent rights are invalid |
2017-08-15 | ||
|
(2018) Beijing 73 Xingchu No. 1099 Maintain decision |
2020-12-15 | |||
| ZL201310368328.4 |
Invalidation Decision No. 33103 All compound patent rights are invalid |
2017-08-15 | ||
|
(2018) Beijing 73 Xingchu No. 1098 Maintain decision |
2020-12-15 | |||
| Tofacitinib | ZL00816941.1 | Pfizer |
Invalidation Decision No. 36902 All patent rights are invalid |
2018-08-08 |
|
(2019) Beijing 73 Xingchu No. 1460 Maintain decision |
2020-12-18 | |||
|
Tenofovir Alafenamide |
ZL01813161.1 | Gilead |
Invalidation Decision No. 37633 Patent right is valid |
2018-10-18 |
|
Invalidation Decision No. 40981 Patent right is valid |
2019-07-08 | |||
|
Invalidation Decision No. 42586 Patent right is valid |
2019-12-03 | |||
|
(2020) No. 3498, Beijing 73 Xingchu Maintain decision |
2021-04-23 |
Based on the content of the above table, it can be seen that all 5 judgments were first-instance judgments made by the Beijing Intellectual Property Court, and all judgments maintained the invalidity decision made by CNIPA, and none of the judgments were revised.
After careful reading of the above five judgments, we further find that the focus of the dispute in all cases is mainly on the issue of inventiveness, and four of them involve the question of whether the supplementary test data can be accepted (3 cases of Empagliflozin and 1 case of Tofacitinib).
Part Two Invalid reasons for insufficient disclosure and non-support
As shown in Table 1 and Figure 2, among the reasons for invalidation claimed by the petitioner, in addition to inventiveness, the most common reasons for invalidation are “insufficient disclosure of specification” and “the claim cannot be supported by the specification”. Even from 2020 to 2021, 5 patent invalidation requests do not even involve inventiveness issues[2]
After the tofacitinib invalidation decision was issued, among the reasons for invalidity involving insufficient disclosure, except whether the specification have disclosed relevant technical effect data, which have been the focus of attention in the past, they have also begun to pay attention to whether the specifications disclose the preparation methods of relevant compounds and/ or confirm the data.
For example, in the case of invalidation of ibrutinib (Decisions No. 44853 and 44855), the reasons for invalidation only involved insufficient disclosure and non-support. Evidence 1 submitted by the invalidation petitioner is the invalidation decision of tofacitinib. The main reason for requesting invalidation is that the involved patent did not disclose the preparation method and confirm the data of the compound, especially when the final compound involved chiral carbon, the specification did not fully disclose the preparation methods of this chiral compound and confirm the data. In the reply, the patentee submitted more than ten counter-evidences to illustrate the synthetic route, reaction mechanism, and source of reaction raw materials of the relevant compounds. In the end, the collegiate panel accepted the opinions of the patentee and maintained the validity of the patent right.
In addition, in the case of invalidation of maxitentan (Decision No. 48183), since maxitentan was only disclosed as a compound in table in the specification, the invalidation petitioner claimed that the specification did not fully disclose the preparation method and confirm the data. In the reply, the patentee gave a detailed description of the synthetic route of the maxitentan compound based on the contents of the specification, and then pointed out that the maxitentan compound has similar effects based on the three compounds with very similar structures described in the specification. In the end, the collegiate panel accepted the opinions of the patentee and maintained the validity of the patent right.
On these grounds, judging from the results of the invalidation decisions, it is difficult to invalidate compound patents, especially patents for specific compounds (including the picture claim relating to one single compound), solely on the basis of insufficient disclosure or unsupported invalidation grounds.
Part Three About the Selection of Lead Compound
As pointed out in the previous report, for the judgment of compound inventiveness, 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 whether the person skilled in the art has the motivation to choose from the existing technology and the possibility of expected success. From the perspective of the law or process of scientific research, the basic basis for the selection of lead compounds by ordinary researchers in the medical field should be the overall teaching of relevant compounds in the prior art. After understanding the entire state of the art and comprehensive consideration of known uses, effects, and other physical and chemical properties commonly investigated in the medical field, those skilled in the art should research and develop the most excellent, that is, the most promising compound.. On the contrary, especially when those compounds with the smallest structural differences have been explicitly abandoned, those skilled in the art are more likely to choose other compounds with larger structural differences but more promising as the starting point for their invention. If the compound with the smallest structural difference is forcibly selected as the closest to the prior art for inventiveness analysis, and sometimes even inactive intermediate products disclosed in the prior art are used as the closest to the prior art, it is likely to deviate from the general law of the invention, which makes the hypothetical process of inventiveness analysis significantly deviate from the path that may be taken in the real world.
Therefore, in the previous report, we suggested that in the first step of the “three-step method”, the invalid petitioner should be required to explain in detail the reason for choosing a specific prior art compound as the closest to the prior art, and clarify the reason for the “most promising” compound in the prior art. .
Among all invalidation decisions we retrieved, in the invalidation case of rivaroxaban (Decision No. 45997) and the invalidation case of carfilzomib (Decision No. 51835), the patentees both claimed that the compound in the closest prior art claimed by the petitioner is not the compound with the best effect in the reference document, so the selected compound is not suitable as a starting point for structural improvement of the compound, and is not a suitable lead compound. However, the defendant’s decision did not give any comment on the above-mentioned dispute of the patentee.
Judging from these two invalidation decisions, CNIPA still hold a view that the choice of lead compounds will not affect the judgment of compound inventiveness. The Beijing Intellectual Property Court (2018) Jing 73 Xing Chu No. 6483 first-instance judgment gave specific reasons for the above viewpoint. First, in accordance with the application prior rule, CNIPA needs to conduct an examination based on the closest existing technology claimed by the invalidation petitioner. Secondly, even if the closest prior art claimed by the petitioner is not suitable as the closest prior art, then the derivation and conclusions that conform to the “three-step method” of the invention-creation reconstruction process at this time should be that, those skilled in the art starting from the closest prior art claimed by the petitioner, may not find there is a technical problem to improve in the direction of this patent, and has no motivation to improve the technical problem, which makes it impossible to lead to a conclusion that the technical solution of this patent is obvious .
It is precisely for the above reasons that CNIPA and the People’s Court have always ignored the arguments involving the choice of lead compounds.
Among the invalid decisions we retrieved, although there was no invalidation decision that recognized the selection of the lead compound in a true sense, individual decisions mentioned the issue of the selection of the lead compound.
For example, in the invalidation case of mabaloxavir (Decision No.47328), the closest prior art compound claimed by the petitioner was an integrase inhibitor for the treatment of HIV, while the patented compound involved in the case was a cap-dependent endocytosis nuclease inhibitors for the treatment of colds. “To judge whether claim 1 of this patent is inventive, it is first necessary to confirm whether the HIV integrase inhibitor and the cap-dependent endonuclease inhibitor are provided in the prior art and whether there is an internal connection in the mechanism sufficient so that those skilled in the art can determine HIV integrase inhibitors can also function as cap-dependent endonuclease inhibitors.” However, the prior art “does not disclose or teach that integrase inhibitors can also inhibit cap-dependent endonuclease activity”. Therefore, “no matter what kind of teaching and enlightenment is given by the closest prior art on the structure of the compound itself, those skilled in the art have no motivation to make structural improvements to the closest prior art according to such teaching or enlightenment and expect it to be an inhibitor of cap-dependent endonuclease activity”.
For another example, in the case of invalidation of Remdesivir (Decision No. 47569), the closest prior art compound claimed by the petitioner was for the treatment of flaviviridae virus infection, specifically hepatitis C virus infection, while the compound in the patent was used to treat paramyxoviridae virus infections, specifically for the treatment of respiratory syncytial virus infections and parainfluenza virus infections. “paramyxoviridae and flaviviridae belong to different types of viruses, with different biological characteristics and responses to antiviral compounds. Those skilled in the art can hardly predict their antiviral activity on the basis of Evidence 1 that the compound has the use of treating paramyxoviridae virus infections. When facing the technical problems actually solved in this patent, there is no motivation to improve it on the basis of compound in Evidence 1, so as to obtain compounds that can treat paramyxoviridae virus infections.”
The determination in the above decision does not really involve the choice of the lead compound (its essence is that the prior art does not give the technical enlightenment of the present invention), but in any case, these judgments show that, as the patentee, when arguing the inventiveness of the compound, it should be noted whether the compound in the prior art cited by the applicant has the same object of action as the patented compound in question, and even whether it has the same mechanism of action.
Part Four About Non-obviousness
For the judgment of the inventive step of a compound, there are generally two issues to be judged, one is the obviousness of the compound structure, and the other is the obviousness of the compound’s pharmaceutical effect.
Prior to the “Daiichi Sankyo olmesartan medoxomil invalidation case” and the “Ticagrelor compound invalidation case”, when reviewing the inventive step of compound patents, CNIPA emphasized the pharmaceutical effects of the compound more. Even in the examination of some patent applications and patent invalidation, it appears a reviewing way of that “the group or ring on the compound core can be replaced. If the compound of the present invention does not achieve unexpected effects compared with the prior art, it will not be inventive. “At that time, when judging the inventiveness of a compound, the non-obviousness of the compound structure was relatively ignored.
The “Daiichi Sankyo Olmesartan Medoxomil Invalidation Case” corrected the above-mentioned determination method and clarified that “the judgment of markush claims’ inventiveness should follow the basic method of judgment of inventiveness, that is, according to the “three-step method” stipulated in the Patent Examination Guidelines.And unexpected technical effects are an auxiliary factor for inventiveness judgment, and as a backward judgment method, it has particularity and does not have universal applicability. Therefore, only after the “three-step method” review and judgment could not determine whether it is obvious or not, can it be determined whether the patent application is inventive based on the unexpected technical effect. It is generally not suitable to skip the “three-step method” and directly apply the unexpected technical effect to judge whether the patent application is inventive.”
However, even if the compound’s own structure is not obvious when judging the inventiveness of a compound’s patent, some examiners still have the opinion that only the parent nucleus in the compound (generally regarded as the cyclic structure part) has a great influence on the pharmaceutical properties and effects of the compound, while the substituents on the ring have little effect on the pharmaceutical properties and effects of the compound, it is further believed that the substituents on the core of the compound can be replaced at will.
The second-instance judgment of “the invalidation case of ticagrelor compound” corrected the above point of view. The judgment first made it clear that the judgment of inventiveness must be based on the overall teaching of the prior art to determine whether there is a motivation to change the relevant technical features. Secondly, it is clear that “markush claims include immutable skeleton parts and changeable markush elements… Once any part of the skeleton part is changed, whether it is a larger part such as a ring structure or a smaller part such as a carbonyl group, it is impossible to predict whether the same drug activity can still be produced so it is impossible to predict whether the technical effect obtained in Evidence 1 can be achieved.” That is to say, the judgment made it clear that based on the overall consideration of the existing technical content, not only the ring structure of the compound will affect the pharmaceutical activity of the compound, but small groups such as the carbonyl group may also affect the pharmaceutical activity of the compound.
After the second-instance judgment on “ticagrelor compound invalidation case” was issued, in several subsequent compound invalid cases (for example, the invalidation cases of rivaroxaban, alogliptin, maxitentan, etc.), CNIPA is paying more and more attention to judging the structure-activity relationship of the compound in the reference document based on the overall teaching of the reference document, and then judging the obviousness of the structure of the compound of the invention involved in the case based on the above-mentioned structure-activity relationship.
- Invalidation of Rivaroxaban (Decision No. 45997)
In this invalidation case, the structural formula of the rivaroxaban compound and the structural formula of the recent prior art claimed by the petitioner (Compound A in Evidence 3 Example 9) are as follows, respectively.
The study found that Evidence 3 related to factor Xa inhibitors with the following general formula,
Among them, for R1 (the substituent on the benzene ring), specification and claim 1 of Evidence 3 clearly define that R1 is -C(=NH)-NH2 (may have substituents), 5-methyl[1,2,4 ]Oxadiazole or 5-oxo[1,2,4]oxadiazole
Based on the above content, Evidence 3 teaches that only compounds with an amidino group (-C(=NH)-NH2) or a specific structure and specific connection method of oxadiazole and phenyl connection structure can inhibit factor Xa. As shown in the structural formula, [1,2,4] oxadiazole actually includes an amidino structure. Therefore, what Evidence 3 actually teaches is that compounds with a (amidino-phenyl) structure can act as factor Xa inhibitors. This can also be corroborated by the invention name of Evidence 3 “benzamidine derivative”.
On the basis of the above facts, the collegiate panel determined that “for the common-sense Evidence 1-2 provided by the petitioner in the hearing, the replacement of small molecule substituents in the field of medicinal chemistry is a conventional technical means. However, the modification of structures in the above evidence is on a basis that similar drug compounds have same skeleton structure. Based on the above analysis, the compound of this patent is quite different from the compound of Example 9 in Evidence 3, and the relevant evidence shows that for the benzamidine inhibitor in Evidence 3, those skilled in the art chose not to replace benzamidine with other groups, but to improve other structures on the basis of maintaining the structure”. According to this, the collegial panel approved the inventiveness of rivaroxaban compounds.
The Rivaroxaban case is a typical case in which CNIPA was able to examine the overall teaching of the reference document and judge the non-obviousness of the compound structure itself during the examination of the inventive step of the compound patent following the “Ticagrelor invalidation case”. The invalidation decision of this case refers to the review standard established in the second-instance judgment of the “Ticagrelor invalidation case”. Based on the overall teaching content of Evidence 3, the collegial panel determined that when facing with the benzamidine compound of Evidence 3, those skilled in the art know that benzamidine and formamidine are necessary structures to achieve the inhibitory activity of factor Xa, so the selection of the improved site is not to replace benzamidine with other groups, but to improve other sites on the basis of maintaining the structure.
- Alogliptin invalidation case (Decision No. 48855)
In this invalidation case, the structural formula of the alogliptin compound and the structural formula of the latest prior art (compound in Example 14 of Evidence 2) claimed by the petitioner are as follows, respectively.
Study found that Evidence 2 related to DPP-IV inhibitors having the following general formula，
Based on the structure of the compound represented by the above general formula, Evidence 2 teaches that a compound with a purine dione structure has DPP-IV inhibitory activity. Therefore, according to the teaching of Evidence 2, “Purine dione is a fixed structure. Evidence 2 does not give any suggestion that the structure of purine dione can be replaced throughout. Those skilled in the art have no motivation to replace the purine dione in Evidence 2”. Accordingly, the collegiate panel approved the inventiveness of the alogliptin compound.
- Invalidation of Maxitentan (Decision No. 48183)
In this invalidation case, the structural formula of the maxitentan compound and the structural formula of the latest prior art (compound 7k in Evidence 5) claimed by the petitioner are as follows, respectively.
.Combining the evidence in the case, “Comparing the IC50 value of the patent involved moxitentan on ETA and ETB receptors with the corresponding values of compound 7k and its sodium salt in Evidence 5, it can be seen that the effects of the two are basically equivalent. Therefore, relatively based on Evidence 5, the technical problem actually solved by this patent is to provide a compound with a different structure that has antagonistic effects on ETA and ETB receptors”.
In judging whether claim 1 of this patent is inventive, the key lies in whether those skilled in the art based on the Evidence 6, 7, 9, as well as the Evidence 16, 22, and 23 listed by the petitioner to prove common knowledge, have the motivation to change the carbon sulfonamide group (ie “-C-SO2-NH-”) in the compound to an azasulfonamide group (ie, “-NH-SO2-NH-”)
On the basis of researching the content of Evidence 5, the collegiate panel determined that “Evidence 6 and Evidence 7 both disclosed that the sulfonamide group at the 4-position of the pyrimidine ring was a carbon sulfonamide group. Based on the teaching of Evidence 6 and/or Evidence 7, those skilled in the art cannot obtain the inspiration of changing the carbosulfonamide group (ie “-C-SO2-NH-”) in Evidence 5 to the nitrogen sulfonamide group (ie “-NH-SO2-NH-” )”. Accordingly, the collegiate panel approved the inventiveness of maxitentan compound.
- Kafilizomib invalidation case (Decision No. 51835)
In this invalidation case, the structural formula of the carfilzomib compound and the structural formula of the most recent prior art (compound 16 in Evidence 1) claimed by the petitioner are as follows, respectively.
On the basis of researching the content of Evidence 1, the collegiate panel determined that “if Evidence 1 did not provide other compounds with longer structures than the acetyl group, and did not conduct any research on the effect of further lengthening the terminal structure on the activity of the compound, those skilled person in the art cannot predict the effect of further lengthening the terminal structure on the activity of the compound. Evidence 1 did not give a clear and regular guidance. Therefore, based on the comparison of compound 16 and 18, those skilled in the art will not obtain the motivation of further modifying acetyl group to extend its structure, and Evidence 1 did not give such technical enlightenment.” Accordingly, the collegiate panel approved the inventiveness of carfilzomib compound.
After the second-instance judgment of the “Ticagrelor invalidation case” was issued, it caused a huge response in the industry, and was highly appraised by R&D and innovative companies in the pharmaceutical field. The review decisions of a series of cases including the invalidation of rivaroxaban indicate that CNIPA has accepted the method of judging the inventiveness of compound patents determined in the second-instance judgment of the “Tegrelor invalidation case”, and has abandoned the previous simple method of mechanical comparison of whether the structure of the compounds is close, clarifying that in the inventive judgment of a compound, the analysis of the structure-activity relationship is the key to determining the technical problem that the invention actually solves and analyzing whether the existing technology has corresponding technical enlightenment, thereby avoiding mechanical comparison of whether the structure of the compound is closer to the subjective assumptions, so the conclusions drawn on this basis are also more objective.
It can be seen from the above several review decisions that CNIPA began to pay attention to the obviousness of the compound structure in the judgment of compound invalidation cases. However, even if the structure is obvious, it does not mean that the compound is not inventive. It is also necessary to determine whether the compound involved in the patent has achieved unexpected technical effects relativing to the prior art, that is, whether the pharmaceutical effect is obvious. This method of judgment has always been emphasized in the review of compound inventiveness in the past, and it is still maintained. Many of the cases we retrieved were maintained, basing on the non-obviousness of the compound’s pharmaceutical effects. For example, the case of invalidation of pabocoxib (Decision No. 44182), deuterated pranabulin (Decision No. 45381), the first-instance judgment of invalidity of tenofovir alafenamide ((2020) Beijing 73 xing chu No.3498), the invalidation case of donafenib (Decision No. 50976) and the invalidation case of epipiprazole (Decision No. 51360). Therefore, in addition to emphasizing the non-obviousness of the compound structure, the non-obviousness of the pharmaceutical effect of the compound still needs to be paid attention to in the debate on the inventiveness of the compound.
[1]The authors are all patent attorneys of Beijing King & Wood Mallesons Law Firm. Contact: Tina TAI,tinatai@cn.kwm.com，010- 58785132
[2]Among them, the invalidation case No. 44093 only involved clear grounds for invalidation, and after the patent owner amended the claim, the petitioner recognized the amendment and suppose that the grounds for invalidity have been overcome. It is speculated that this case was an invalidation request made by straw-man entrusted by the patentee to amend the claims.