PART II— Five Patent Invalidation Challenges- CSPC Succeeded in invalidating Mitsubishi Tanabe Pharma Corporation’s Novastan® HI injection 10 mg/2mL Patent
Date: 2 December 2022
【Volume 96】
Previously, we introduced the “three-step method” adopted by the China National Intellectual Property Administration (CNIPA) to determine the inventive step of a patent and the main technical features of Mitsubishi Tanabe Pharma Corporation’s ‘612 patent. We also analyzed how the CNIPA views the closest prior art, the distinguishing technical features of the ‘612 patent, and the technical problem actually solved by the invention. In this part, we continue to discuss the technical problem solved by the ‘612 patent, the obviousness of the technical means, and offer our suggestions.
III. The Technical Problem Actually Solved by the Invention
2. Stability
The CNIPA did not recognize that the ‘612 patent exhibits the technical effect of resistance against crystallization and precipitation at a low temperature for the following reasons:
(1) According to the description and Examples 5, 6 and 8 of the ‘612 patent, the stability mentioned therein refers to the chemical stability that other substances are not generated after heating. However, the patentee has admitted that the chemical stability is a regular performance.
(2) The stability at 4°C cannot be directly recognized as resistance against crystallization and precipitation at a low temperature. The specification of the ‘612 patent only mentions the stability at 4°C in Table 3 and does not make any detailed description of it. Moreover, Table 5 of the ‘612 patent only discloses the viscosity and solubility suitable for drawing up into a syringe without mentioning resistant to crystallization and precipitation at a low temperature. Further, the decrease of solubility does not directly lead to crystallization and precipitation at a low temperature. Compared with the pharmaceutical composition 16 in Table 5, although the pharmaceutical composition 15 is not within the scope of the claims, the difference in solubility between them at 2°C is not significant. Thus, it cannot be directly concluded that the pharmaceutical composition 16 does not crystallize and precipitate while the pharmaceutical composition 15 does.
(3) In any case, even if the stability at 4°C is regarded as the resistance against crystallization and precipitation at a low temperature, it cannot be concluded that the ‘612 patent has the effect of resistance against crystallization and precipitation at a low temperature. The expert testimony mentioned that crystallization and precipitation occurs in the Argatroban injection commercially available in the U.S. at a low temperature after one to two months, while the stability at 4°C described in the ‘612 patent is observed only within 24 hours. Thus, it is impossible to determine whether crystallization and precipitation appears after one to two months.
(4) According to Exhibit 3, it is known that “Argatroban injection 250 mg:2.5 ml is physically and chemically stable for up to 48 hours under storage at 2~8°C in the dark”. However, the physical and chemical stabilities do not directly represent the property of resistance against crystallization and precipitation at a low temperature. In addition, the conditions of the stability test include light, temperature and storage time, and thus it is impossible to determine what factors actually affect the stability. Based on this, it cannot directly correspond to the problem of the temperature-determined crystallization and precipitation. Thus, it cannot be concluded that the ‘612 patent shows the resistance against crystallization and precipitation at a low temperature.
In summary, according to the technical effect of the ‘612 patent compared to the ‘052 patent, the CNIPA considered that the technical problem actually solved by the ‘612 patent is to provide a different specification of Argatroban pharmaceutical composition with a suitable viscosity for injection.
IV. Whether It is Obvious:
The CNIPA deemed that combining the ‘052 patent with Exhibit 3 and the common knowledge in the art can prove that Claim 1 lacks an inventive step.
1. The Distinguishing Feature (1)
The ‘052 patent has disclosed the solubility of the Argatroban in different solubilizers. For example, the content of the Argatroban in ethanol-glycerol-water system is greater than or equal to 100 mg/ml as described in Example 3, and the content of the Argatroban in ethanol-glycerol-sorbitol-water system is 100 mg/ml as described in Example 6. As a result, a person having ordinary skill in the art can select the content of the Argatroban lower than the aforementioned solubility depending on the needs of drug administration. In addition, Exhibit 3 (Argatroban Injection 250 mg/2.5 ml, the U.S. specification) has disclosed that the Argatroban Injection (250 mg: 2.5 ml) can be used at a concentration of 1 mg/ml. Therefore, a person having ordinary skill in the art can easily come up with choosing the dosage of the Argatroban such as 1 mg/ml.
2. The Distinguishing Feature (2)
It is known that the convenience of suction is related to the viscosity of the preparation which is mainly related to the presence of solubilizers. The ‘052 patent has disclosed that glycerol-ethanol-water system and glycerol-ethanol-sorbitol-water system can achieve the high solubility of the Argatroban and also teaches that sugar is not a necessary solubilizer; Hsieh Jin-song (1984). Glycerol. China Light Industry Press Ltd. (“Hsieh”) has disclosed that the physical properties of glycerol-ethanol-water system include viscosity values. Therefore, by referring to the ‘052 patent and Hsieh, a person having ordinary skill in the art has the motivation to choose glycerol-ethanol-water system which is free from sugars and adjust the composition ratios thereof to obtain a viscosity suitable for injection.
In summary, combining the ‘052 patent with Exhibit 3 and the common knowledge in the art can prove that Claim 1 lacks an inventive step.
Wisdom Suggested Strategies
According to the examination records of the CNIPA, at least five invalidation requests for the ‘612 patent have been filed, and CSPC succeeded in invalidating Mitsubishi Tanabe Pharma Corporation’s Argatroban preparation patent with the sufficient and convincing evidence.
In the invalidation requests for the ‘612 patent, the CNIPA especially pointed out that the objective basis for determining the technical problem actually solved depends on the technical effect achieved by the invention compared to the closest prior art. When the specification discloses multiple technical effects, it does not necessarily mean that these effects actually solve the corresponding technical problems compared to the closest prior art. It should be considered whether these effects are conferred on the invention by the distinguishing technical features.
Specifically, when the specification describes the multiple technical effects, the following points should be noted:
- The correspondence between the technical effect and the technical means of the invention should be considered, and it should be determined whether a person having ordinary skill in the art can directly perceive each corresponding technical effect on the basis of the specification. If part of the technical effects cannot be achieved, it should not be considered as the basis for determining the technical problems.
- It is necessary to note whether the multiple technical effects are closely related to each other and should be considered as a unified effect.
- It should be noted that the technical effects conferred on the invention are achieved by the distinguishing feature rather than the technical effects unrelated to the distinguishing feature, wherein the technical problem unsolved by the closest prior art, or a better technical effect compared to the closest prior art is appropriate as a basis for determining the technical problems actually solved.
Differences in the level of determination of the technical problems actually solved will lead to different levels of obviousness of the technical means, and thus the conclusion may be different. Therefore, the technical effect is the key basis for determining the technical problems and the conclusion of inventive step. In the process of reconstructing the concept of the invention according to the “three-step method” starting from the closest prior art, both the patentee and the invalidation petitioner shall pay full attention to the objective determination of the technical effects achieved by the distinguishing features.
