Can results of a compound from in vitro experiments be evidence supporting medical use of the same

by Wei Yang, Partner, Patent Attorney

Depression is a psychological disorder that can cause serious harm. According to the previous survey data of the World Health Organization, there are about 350 million people suffering from depression in the world. The incidence rate of depression is 6.16% in Sweden, 4.45% in the United States, and 3.02% in China; and such incidence rate is yearly increasing. In China, there are over 100 million patients suffering from various mental illnesses, including about 40 million depression patients. Therefore, more and more attention has been paid to the care and treatment of depression patients.

Votixetine is an antidepressant developed jointly by Lundbeck and Takeda Pharmaceutical and also one of the most expensive antidepressants at present. Votixteine has been given marketing license in 95 countries and regions around the world as of 2022 and achieved global sales of 4.2 billion yuan in 2022. The huge economic benefits of Votixteine in the world have been drawing many pharmaceutical enterprises to make challenge against its related series of patents. Since 2018, in China, many pharmaceutical enterprises have made challenge against the series patents related to votixetine, including invention patent No. ZL02819025.4 entitled "Phenyl-piperazine derivatives as serotonin Reuptake inhibitors".

On July 8, 2021, the petitioner, Chengdu Kanghong Pharmaceutical Group Co., Ltd., filed a request for invalidation against the patent with the China National Intellectual Property Administration (CNIPA), on the grounds that claims 1-7 of the patent are not sufficiently disclosed in the description and therefore are not supported by the description, and that claims 1-7 of the patent do not possess inventiveness over the prior arts.

In response to the request for invalidation made by the petitioner, and taking the observations submitted by the patentee into consideration, the CNIPA made a Decision on Invalidation maintaining validity of patent No. ZL02819025.4 on March 16, 2022.

Before further interpreting the Decision on Invalidation, it is necessary to provide a brief summary of the claims of the patent in question and the content of the description.

Independent claim 1 of the patent seeks to protect a compound represented by general formula I or a pharmaceutically acceptable acid addition salt thereof, claims 2-4 further define Markush options involved, and claim 5 defines 22 specific compounds or their pharmaceutically acceptable acid addition salts.

The description of the patent recites that the claimed compound is an serotonin reuptake inhibitor and can be used for the treatment of affective disorders, such as depression. The description of the patent also recites general methods of preparing the compound represented general formula I, the methods of preparing 24 specific compounds and salts of several compounds, the characterization data of multiple compounds, the method of testing the compounds with respect to their serotonin reuptake inhibiting effect and IC50 value measured.

One of the focuses of this case is to what extent the use and/or effect of a drug compound shall be disclosed so as to meet the requirements for sufficient disclosure of the invention in the description.

The petitioner submits that: (1) the technical problem claimed to be solved by the patent is to provide a novel compound that can effectively treat affective disorders, including depression, anxiety and obsessive-compulsive disorder through the dual action mechanism of serotonin reuptake inhibition and 5-HT2C receptor antagonism, but the description does not provide specific experimental data to show that the compounds in claims 1-7 are compounds having said dual action mechanism; (2) the technical effects of the compounds should be identified and considered based on indications, the results of the in vitro experiments given in the description cannot directly correspond to presence or absence of antidepressant activity; the mechanism between serotonin reuptake inhibition and successful treatment of depression is still unclear, and thus it is not sufficient to show that the compounds in the patent are selective serotonin reuptake inhibitors and thus have potential as antidepressant if only in vitro results of serotonin uptake inhibition are provided in the description.

The patentee holds that the technical problem to be solved by the patent is to provide a serotonin reuptake inhibitor, and the patent has proved through experiments that the claimed compounds in the patent have serotonin reuptake inhibitory activity, and the serotonin reuptake inhibitor has anti-depression effect.

As can be seen from the above, the main disputes between the petitioner and the patentee lie in the following two aspects: (1) What is the technical problem to be solved by the patent? (2) Based on the prior arts and the experimental results as recited in the description of the patent, can those skilled in the art reasonably anticipate that the claimed compounds in the patent can be used for anti-depression treatment?

(1) What is the technical problem to be addressed by the patent?

The CNIPA holds the following remarks.

Firstly, when determining the technical problem to be solved by an invention, it is necessary to take all the content of the patent into comprehensive consideration, from the perspective of those skilled in the art. In this case, as can be seen from the invention title, the technical field and other sections of the patent, one of the aims of the patent is to provide a novel compound as serotonin reuptake inhibitor. Moreover, taking all the content of the description into consideration, those skilled in the art can get to know that the technical problem to be solved by the invention is to provide a compound as serotonin reuptake inhibitor.

Secondly, where the description recites that the invention can solve technical problems at multiple levels, in principle, the description shall be considered to meet the requirements for sufficient disclosure, as long as those skilled in the art can determine that the technical problem at a level has been solved. In this case, the description recites "some of the compounds also have a combined effect of serotonin reuptake inhibition and 5-HT2c?receptor modulation", which, from the literal expression or from the drafting logic of the description, can at most be understood as some compounds in the patent have 5-HT2c receptor modulation effect in addition to the serotonin reuptake inhibition effect. The recitation in the description that these compounds have a "dual effect" does not necessarily mean that the technical problem to be solved by the patent must be determined as the technical problem at said second level. On the basis of all the content of the description, if those skilled in the art can determine that the invention can solve the technical problem of inhibiting serotonin reuptake, then the description cannot be deemed as failing to sufficiently disclose the invention, no matter it verifies that the compounds additionally have 5HT2C receptor modulation effect or not.

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(2) Can those skilled in the art reasonably anticipate that the claimed compounds in the patent can be used for anti-depression treatment?

To answer this question, it is necessary to understand the relationship between the serotonin reuptake inhibitor and the antidepressant firstly. According to multiple copies of evidence provided by both parties, those skilled in the art can reach consensus that serotonin is one of several neurotransmitters closely related to depression, and there are a series of antidepressants that have been developed based on the pharmacological effects of serotonin, including not only selective serotonin reuptake inhibitors, but also serotonin and norepinephrine reuptake inhibitors. Although the selectivity of serotonin is very important to anti-depression activity, it does not mean that only compounds selectively inhibiting serotonin reuptake can finally be used for anti-depression treatment. That is to say, based on the understanding of the antidepressants in the prior art, those skilled in the art can anticipate that compounds having serotonin reuptake inhibitory activity can be used as potential compounds as antidepressant.

Secondly, it is necessary to understand the relationship between in vitro experiments and the anti-depression treatment.

(1) It is not explicitly stipulated in the Patent Law, the Implementation Regulations of the Patent Law and the Guidelines for Patent Examination that the technical issues related to or effects of drug compounds must rely on verification at indication level. It is true that direct verification of a compound’s medical use at indication level is more in line with the requirements for direct manufacturing or use in the industry. However, it does not mean that validation of medical use must be performed at indication level. On the one hand, the criteria for protecting invention-creations under the patent law are different from those for drug marketing review and approval. Taking the legislative intent of the Patent Law into consideration, if those skilled in the art are capable of anticipating a drug compound’s medical use based on the prior art and the content recited in the description, especially the relationship between the indication and the mechanism of action, the protection of such drug compound is in line with the legislative purpose of encouraging invention-creations and promoting scientific and technological progress, even if the verification of the medical use is not treatment directly related to a particular indication in a human body. On the other hand, if there is certain consensus regarding the relationship between the mechanism of action and an indication in this field, and those skilled in the art, by verifying the mechanism of action of a compound, can reasonably expect that the compound has potential as a drug capable of being ultimately applied for treatment of the indication, the description shall be considered to meet the requirements for disclosure of use and/or efficacy of a chemical product as stipulated in the Patent Law.

(2) In vitro experiments have their unique significance. The screening of drug compounds usually needs to go through in vitro experiments, animal in vivo experiments, and clinical trials at different stages, so as to select out the drug compounds that can be marketed in the end. Different experiments play different roles at different stages, in vitro experiments performed at an early stage can narrow the scope of compounds to be screened and provide basis for subsequent research, and clinical trials cannot replace in vitro experiments or animal in vivo experiments due to high cost thereof and ethical issues. As the subjects for testing are different, some compounds that are effective in in vitro experiments might have no potential for drug development according to results of in vivo experiments, but this cannot completely negate the significance of in vitro experiments. Specifically, as far as this case is concerned, the prior art has clearly taught the relationship between serotonin reuptake inhibitory activity and the anti-depression, and thus those skilled in the art can totally understand the manner of verifying the compounds’ anti-depression activity by verifying serotonin reuptake inhibitory activity of the compounds in in vitro experiments. It is not necessary to accept the research value of this experiment only when the relationship between serotonin reuptake inhibitory activity and the anti-depression effect reaches the indisputable level as claimed by the petitioner. The difference between the results of compounds in in vitro experiments and in animal in vivo experiments in the evidence submitted by the petitioner cannot overturn effectiveness of the in vitro experiments for serotonin reuptake inhibitory activity, and the effect that can be verified based on the results in the in vitro experiments should also be considered as the technical effect of the technical solution in the sense of the Patent Law.

(3) The method of testing serotonin reuptake inhibitory activity of candidate compounds by measuring their ability to inhibit the uptake of [3H]serotonin into whole rat brain synaptosomes in vitro is an existing method in the prior art. This method has tested a variety of compounds, including antidepressants that have been marketed. Thus, based on the experimental results provided in the description, those skilled in the art can anticipate the prospect of the compounds in the patent in the antidepressant field.

In view of the above, the description of the patent clearly recites that the problem to be solved is to provide a novel compound having serotonin reuptake inhibitory activity and provides technical content regarding verification of specific compounds’ activity through experiments, and thus those skilled in the art can anticipate that the present invention is capable of solving the above technical problem based on the description. At the same time, on the basis of the fact that the prior arts have disclosed the close relationship between serotonin reuptake inhibitory activity and the anti-depression treatment, those skilled in the art can anticipate that compounds having serotonin reuptake inhibitory activity can be used for anti-depression treatment. Therefore, based on the content recited in the description, it can be determined that the claimed compounds meets the requirements for use and/or effect of drug compounds as provided in the Patent Law, and the description is in line with the requirements for sufficient disclosure as provided in the Patent Law.

In summary, the core of "disclosure for protection" of the patent system is to ensure the realization of value exchange, which is "disclosure for rights" in essence. It is stipulated in the laws that the applicant shall disclose an invention that is practical, novel, and inventive in a clear, complete, and enable manner; in exchange, the government grants the applicant exclusive rights - patent rights- having a certain term.

The drug development usually takes a long time and involves multiple stages such as in vitro experiments, animal in vivo experiments and clinical trials. The timing of applying for a compound patent is crucial to protection of drug innovation. Applicants shall not be required to file a patent application for compound until the results of in vitro experiments or clinical trials are available, which is not conducive to the legislative purpose of encouraging invention-creations and promoting scientific and technological progress. For sufficient disclosure of drug compounds’ medical use, if those skilled in the art can anticipate a compound’s medical use based on the prior art and the content recited in the description, such compound should be patented. The medical use in sufficient disclosure of drug compounds should not be narrowly understood as the use at indication level. If there is consensus regarding the relationship between mechanism of action and the indication in the art, and based on verification of the mechanism of action of compounds, those skilled in the art can reasonably anticipate such compounds’ potential as drugs for a certain indication, then the description should be considered to meet the requirements for disclosure of use and/or effect of chemical products as provided in the description.