In a continuing saga reflecting the court's struggle to define or rationalize the patentability criteria for a novel crystalline form invention of a known compound, in a recent decision, the Korean Supreme Court, while maintaining the applicability of the "totality of factors" test fashioned in a 2022 decision (discussed infra), still denied the inventiveness of a crystalline form invention, in view of the prior art reference implying the possibility of obtaining the crystalline form and a conflicting disclosure in the specification which tends to undermine the presence of any superior effect of the invention (Supreme Court Case No. 2021 Hu 10343 rendered on March 28, 2024; hereinafter, "2024 decision").

▶ Pre-2022 Decisions: Superior Effect Test 

Prior to 2022, the courts had ruled that a crystalline form invention would meet the inventiveness criterion only when such a crystalline form invention exhibited an effect qualitatively different from, or quantitatively remarkable over, that of a known compound (hereinafter, "superior effect"), absent special circumstances (see, e.g., Supreme Court Case No. 2010 Hu 2865 rendered on July 14, 2011). In accordance with the superior effect test, presence of superior effect had been used practically as the sole barometer for gauging the inventiveness of a crystalline form invention in Korean patent practice.

▶2022 Decision: Totality of Factors Test

In its 2022 decision referred to above, the Supreme Court expanded the test for determining the inventiveness of a crystalline form invention by way of taking into consideration the totality of all relevant factors, such as: whether the disputed crystalline form of a compound disclosed in the prior art was known or predictable; whether there was teaching, suggestion, or motivation in the prior art that would have led to the specific crystalline form of the claimed invention; whether the claimed crystalline form fell within the range of polymorphs that would have been identified through routine polymorph screening of the compound disclosed in the prior art; and whether the claimed crystalline form exhibited beneficial effects unexpected from the prior art (Supreme Court Case No. 2018 Hu 10923 rendered on March 31, 2022; hereinafter, "2022 decision").

▶2024 Decision

A. Subject Invention

The specification of the subject patent described that a dihydrochloride salt of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (hereinafter, "mirabegron") disclosed in the prior art reference (discussed below) had strong hygroscopicity and was unstable; and that such hygroscopicity problem was solved by two (2) crystalline forms of mirabegron provided by the subject invention, i.e., (i) the α-form crystal having a moisture content of not more than 0.2% over the entire range of relative humidity from 5% to 95%, and (ii) the β-form crystal maintaining a moisture content of approximately 3% from a relative humidity of 20%, in a metastable crystalline form suitable for use as a pharmaceutical.

The granted claims of the subject patent covered both the α-form and the β-form crystals.

B. Prior Art Reference

The prior art reference, cited during the prosecution of the subject patent application, disclosed the general formula of compounds useful for diabetes treatment in the Markush type, providing working examples by preparing one hundred thirteen (113) compounds, one of which was a dihydrochloride salt of mirabegron.

Further, the prior art reference mentioned that a compound falling within the scope of the general formula could be isolated and purified as a free compound, a salt, a hydrate, a solvate, or a polymorphic crystal, even though no crystalline form of mirabegron was specifically disclosed.

C. Invalidation Actions

Eleven (11) generic pharmaceutical manufacturers lodged invalidation actions against the subject patent with the Trial Board for lack of inventiveness of the α-form crystal and the β-form crystal over the prior art reference. In response, the patentee cancelled the claims drawn to the β-form crystal, thereby retaining only the claims directed to the α-form crystal having lower hygroscopicity. The Trial Board, however, invalidated the subject patent for lack of inventiveness of the α-form crystal over the prior art reference. The decision was appealed to the IP High Court.

D. The IP High Court Decision

The IP High Court also denied the validity of the patent, in accordance with the pre-2022 criterion set forth by the Supreme Court, based on the finding that the low hygroscopicity of the α-form crystal was not considered to be a superior effect.

E. The Supreme Court Decision

On appeal, the Supreme Court clarified that the criterion articulated in the 2022 decision would also apply to the subject case. Nevertheless, the Supreme Court concluded that the crystalline form invention of the subject patent lacked inventiveness over the prior art reference, primarily on the following grounds:

First, the prior art reference taught that the compounds represented by the general formula could be isolated and purified as polymorphic crystals. This would have provided sufficient motivation for a person skilled in the art to identify specific crystalline forms for designing mirabegron formulations. Moreover, the process from the dihydrochloride salt of mirabegron disclosed in the prior art reference for obtaining the α-form crystal of mirabegron involved applying conventional neutralization and crystallization processes typically used in the field of pharmaceutical compounds, and, thus, a person skilled in the art would have easily come up with the α-form crystal of mirabegron from the prior art reference.

Second, the specification of the subject patent described the α-form crystal of mirabegron as having exhibited substantially no hygroscopicity over the entire range of relative humidity from 5% to 95%, whereas the dihydrochloride salt of mirabegron showed a significant increase in weight under conditions exceeding 80% relative humidity. However, since the difference in hygroscopicity appeared only under harsh conditions exceeding 80% relative humidity, it was difficult to consider the α-form crystal of mirabegron to be advantageous as a pharmaceutical in terms of the moisture absorption. Furthermore, it was unclear whether the difference in moisture absorption at over 80% relative humidity was due to crystalline polymorphism or the formation of dihydrochloride salt. Hence, in comparison with the dihydrochloride salt of mirabegron, the α-form crystal of mirabegron could not be considered to exhibit a superior effect.

Third, the specification of the subject patent mentioned that the α-form crystal of mirabegron exhibited approximately 2.8% lower moisture absorption than the β-form. However, considering that the β-form crystal was also admitted in the specification as suitable for pharmaceutical use as a metastable crystalline form, it was difficult to assess the 2.8% difference in moisture absorption as patentably significant.

Having taken into account all of the above factors, the Supreme Court upheld the lower court's decision that the α-form crystal of mirabegron lacked inventiveness over the prior art reference.