The Korean Supreme Court had previously ruled that a novel crystalline form invention of a known compound met the inventiveness standard only when such crystalline form invention exhibited an effect qualitatively different from, or quantitatively remarkable over, that of the known compound (hereinafter, “superior effect”), absent special circumstances (see Supreme Court Case No. 2010 Hu 2865 rendered on July 14, 2011).

 In a recent decision, the Supreme Court first clarified that the inventiveness of crystalline form inventions in previous cases was determined mainly based on the presence of superior effect of the crystalline form invention primarily because such superior effect was strong indicia of the difficulty to conceive the invention in the field of pharmaceutical compounds (Supreme Court Case No. 2018 Hu 10923 rendered on March 31, 2022). In the recent 2022 decision, however, the Supreme Court upheld the inventiveness of a specific crystalline form invention without requiring corroboration of the presence of a superior effect of the crystalline form invention. The Court found that it was not obvious to conclude, in view of the ordinary level of skill as of the filing date, that a person skilled in the art would have easily conceived such a crystalline form exhibiting certain beneficial effects (superior thermodynamic stability and low hygroscopicity) from the teachings of a prior art reference that disclosed a compound having the same chemical structure but failed to specify its crystalline form.

▶Background of the Case

A. Prior Art Reference

The prior art reference disclosed 20,23-dipiperidinyl 5-O-mycaminosyl-tylonolide (hereinafter, “tylosin”) as a macrolide antibiotic for use in the treatment or prophylaxis of pasteurellosis of mammalian livestock or poultry.

B. Subject Invention

The claimed invention of the subject application related to a novel crystalline form I of tylosin (hereinafter, “Form I”), characterized by a powder X-ray diffraction spectrum comprising peaks 5.0, 9.0 and 10.5 degrees 2θ. According to the specification of the subject application, the object of the subject invention was to provide Form I, which possessed greater stability at an ambient temperature, exhibited advantageous thermodynamic properties, and showed less water uptake than other solid-state forms of tylosin. In addition to the disclosures in the specification, experimental data submitted during prosecution further showed that, among the novel crystalline forms of tylosin (i.e., Forms I to IV) obtained, Form I specifically was found to be thermodynamically more stable and less hygroscopic than amorphous or other crystalline forms.

C. Prosecution History

In response to the Examiner’s final rejection for lack of inventiveness over the prior art reference, the applicant filed an appeal with the Trial Board. The Trial Board, however, dismissed the appeal for the reason that the subject invention would have easily 1 been conceived from the prior art reference and thus lacked inventiveness. The decision was subsequently appealed to the Patent Court. 

▶The Patent Court Decision

The Patent Court denied the inventiveness of the subject invention for the following reasons:

A person skilled in the art would easily recognize the possibility that the tylosin compound disclosed in the prior art reference may exist in a variety of crystalline forms, and thus it would be obvious for such a skilled person to try to obtain, thermodynamically, the most stable crystalline form by way of investigating all tylosin polymorphs through crystallization techniques known in the art. Therefore, Form I of the subject invention is merely the most stable crystalline form identified as a result of formulation processes routinely carried out in the relevant technical f ield. Further, the superior physical stability and low hygroscopicity of Form I are not recognized as qualitatively different or quantitatively remarkable effects that would not have been expected by a person skilled in the art.

▶The Supreme Court Decision

On appeal, however, the Supreme Court reversed the Patent Court decision. In doing so, the Supreme Court first clarified that, although polymorph screening is routinely performed to investigate whether a pharmaceutical compound has various crystalline forms in the course of formulation design of the compound, such routine practice cannot be the sole basis to deny a determination of difficulty to conceive a crystalline form invention. In this regard, the Supreme Court set forth the standard for determining the inventiveness of a crystalline form invention by examining whether a person skilled in the art would have easily conceived the crystalline form invention from prior art based on overall consideration of various factors including: whether polymorphism of a compound disclosed in the prior art was known or predictable; whether the prior art provided teaching, suggestion or motivation that would have led to the specific crystalline form of the claimed invention; whether the specific crystalline form of the claimed invention is a polymorph that would have been identified through routine polymorph screening of a compound disclosed in the prior art; and whether the specific crystalline form of the claimed invention exhibits beneficial effects unexpected from the prior art.

Under such standard, the Supreme Court noted that the prior art reference failed to specify whether the solid compound of tylosin disclosed therein had a crystalline form or amorphous form; it was not known at the time of the filing date of the subject application whether tylosin had a variety of crystalline forms; the starting materials and specific variables for the crystallization processes (such as solvent, temperature, and time) employed in deriving the tylosin compound disclosed in the prior art reference and Form I of the subject invention were different from each other. As such, the Supreme Court found that it was not clear whether a person skilled in the art would have easily conceived Form I from the prior art reference by way of making appropriate adjustments to the variables of the crystallization process or performing routine polymorph screening.

Further, the Supreme Court indicated that it was difficult to conclude that the effects of Form I could be expected from the prior art reference in view of the fact that the specification of the subject application provided concrete experimental results showing superior thermodynamic stability and low hygroscopicity of Form I, whereas the prior art reference did not describe any experimental results comparable to the effects of Form I.

Judging from the totality of the circumstances, the Supreme Court held that a person skilled in the art would not have easily conceived Form I from the prior art reference without the benefit of hindsight knowledge of the subject invention; and, accordingly, reversed the Patent Court decision.