Executive Summary
Supreme Court Decision No. 2021 Hu 10343 rendered on March 28, 2024
1) Factual grounds
With respect to the α-form crystal of mirabegron, the descriptions “since the α-form crystal of the present invention is stable without showing hygroscopicity, it can be used as a pharmaceutical and is useful as a pharmaceutical,” “while mirabegron dihydrochloride showed a sharp increase in weight from about 80% relative humidity, and retained about 14% moisture at 90% relative humidity, showing strong hygroscopicity, the α-form crystal of mirabegron has a water retention of 0.2% or less and exhibits no hygroscopicity in the entire range of 5% to 95% relative humidity, and the β-form crystal of mirabegron increased in weight from 20% relative humidity and retains about 3% water up to 95% relative humidity,” are found in the specification of the present invention.
Mirabegron is described in Claim 6 of Cited Reference 1, and [Table 3] in the original ruling, and the method of preparing mirabegron dihydrochloride is disclosed in Example 41.
2) Legal principles of judgment
Polymorph screening, which examines whether a compound has various crystal forms, i.e. polymorphs, is commonly performed for the purpose of a formulation design of a pharmaceutical compound. In the field of pharmaceutical compounds, when considering whether a specific crystalline compound having the same chemical structure as a compound known in prior art with a different crystal form, i.e., a crystalline form invention recited in the claims, involves inventive step, the special circumstances shall be taken into account. However, the description is not sufficient to deny the difficulty in constitution of the crystalline form invention. This is because polymorph screening being a commonly performed experiment is one issue, while whether a specific crystalline form of a crystalline form invention can be easily accomplished based thereon is another.
Meanwhile, since effects of an invention that belongs to the field of pharmaceutical compounds, such as a crystalline form invention, could not have been easily anticipated based only on the constitution, the effects of the invention are required to be taken into account when considering the difficulty in constitution. Also, when the effects of the invention exhibit remarkability over prior art, they may be materials from which the difficulty in constitution can be inferred.
When determining the difficulty in constitution of a crystalline form invention, the difficulty should be recognized based on material showing the technical significance and unique effects of the crystalline form invention, the specific crystalline structure claimed in the invention and the preparation method thereof, the subject matter of prior art and characteristics thereof, and the general polymorph screening method, and the constitution of the crystalline form invention could have been easily derived by one of ordinary skill in the art based on prior art by comprehensively taking into account whether a crystalline polymorphic form of a compound disclosed in prior art is known or could have been anticipated, whether any teaching or suggestion indicating that the specific crystalline form could have been accomplished is found in the crystalline form invention or any motivation is found in prior art or a prior art document, whether a specific crystalline form invention falls within the range of crystal polymorphs that can be examined through general polymorph screening for prior invention compounds, and whether the specific crystalline form exhibits advantageous effects that could not have been anticipated.
When the effects of the crystalline form invention exhibit a significant difference in quality and quantity compared to the effects of the compound disclosed in the prior art, the crystalline form invention is not considered to lack inventive step. The remarkability of the crystalline form invention should be considered based on effects that are disclosed in the specification of the invention to be recognized or inferred by one of ordinary skill in the art. In a patent invalidation trial based on lack of inventive step and a subsequent lawsuit to cancel a decision based thereon, the responsibility of proving the grounds for invalidation is borne by the party asserting the invalidation, but when the effects of the crystalline form invention are in doubt, the holder of the patent right is allowed to argue and prove the effects in detail by submitting additional experimental data after the filing date. Here, the additional experimental materials must be within the scope of the subject matter disclosed in the specification of the invention (refer to Supreme Court Decision No. 2018 Hu 10923 rendered on March 31, 2022).
3) Detailed consideration
Cited Reference 1 discloses in the specification that the compound of formula I containing mirabegron is isolated and purified by a vitreous body, salt, hydrate, solvate or polymorphic crystals, etc., and Cited Reference 1 comprises the compound represented by Formula I, salts thereof, hydrates, geometric and optical isomers, and polymorphs, and thus suggests a polymorph form of a crystal.
According to the experimental results in which the hygroscopicity of the α-form crystal of mirabegron was compared with mirabegron dihydrochloride and additional experimental data submitted after the filing date, while the α-form crystal of mirabegron exhibits no hygroscopicity in the range of 5% to 95% relative humidity at a temperature of 25 °C, mirabegron dihydrochloride showed a sharp increase in weight from about 80% relative humidity. The weight change was measured after storage for 24 hours at a temperature of 25 °C and a relative humidity of 80%, the weight change of the α-form crystal of mirabegron was −0.03% and that of mirabegron dihydrochloride was 0.7%, which is not a significant difference. In addition, no significant difference in hygroscopicity between the α-form crystal of mirabegron and mirabegron dihydrochloride was found at less than 80% relative humidity, and thus a significant difference in hygroscopicity is observed only under harsh conditions of a relative humidity of less than 80%. As previously stated, when the relative humidity is about 80% or lower, and no difference or an insignificant difference in hygroscopicity is found between the α-form crystal of mirabegron and mirabegron dihydrochloride, it cannot be concluded that the α-form crystal of mirabegron has advantageous hygroscopicity as a material for manufacturing pharmaceuticals or as a pharmaceutical over mirabegron dihydrochloride.
Even though, with respect to hygroscopicity between the α-form crystal of mirabegron and mirabegron dihydrochloride, a quantitatively significant difference in effects is found, the α-form crystal of mirabegron is different from mirabegron dihydrochloride in view of formation of salts. Accordingly, it is not known whether the difference in effects is brought on by the difference in formation of salts or the difference in formation of a polymorph form, and the experimental results showing the comparison with mirabegron dihydrochloride are not sufficient to consider that the α-form crystal of mirabegron exhibits a quantitatively significant difference in effects over the compound disclosed in Cited Reference 1. Therefore, Claim 3 of the subject case could have been easily conceived of by one of ordinary skill in the art based on Cited Reference 1, and thus lacks inventive step.
4) Implication
This Supreme Court ruling is significant in that it specifically applies the criteria for determining the patentability of a crystalline form invention, following Supreme Court Decision No. 2018 Hu 10923 rendered on March 31, 2022.
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