​With regard to a sustained release pharmaceutical composition formulated by combining the teachings given in two prior art references, the Supreme Court held that the inventiveness thereof cannot be denied, even if all of the technical features of the composition are disclosed in these references, if it is found that a skilled person in the art would have difficulty predicting the effects of the combined composition, and if the technical characteristics of the prior art technologies differ from each other, rendering it difficult to combine them (Supreme Court Case No. 2019 Hu 11756 dated April 8, 2021).

▶Background of the Case 

Korean Patent No. 1245919 (“subject patent”) relates to a sustained release pharmaceutical composition for treating acromegaly, malignant carcinoid tumors and vasoactive intestinal peptide tumors, allowing for the prolonged release of the known active ingredient, octreotide, over a period of more than three months so that the plasma level of octreotide is maintained within the therapeutic range during the entire period.

Specifically, the subject invention is directed to a sustained release pharmaceutical composition in the form of microparticles comprising octreotide (a peptide drug) and two different polylactide-co glycolide polymers (PLGAs), wherein the lactide (L):glycolide (G) monomer ratios of the two PLGAs are different from each other, and there are two different microparticles in terms of the lactide:glycolide monomer ratio of the PLGA (e.g., L:G = 75:25 and L:G = 100:0).

In 2013, a competitor filed an invalidation trial against the subject patent, but the Trial Board upheld the validity of the subject patent. On appeal, however, the Patent Court decided that the specification failed to satisfy the description requirement. In an appeal against the Patent Court decision, the Supreme Court held that the specification providing animal experimental data alone satisfied the description requirement and remanded the case to the Patent Court (for more information, please refer to the FirstLaw IP News article, entitled “Animal Experimental Data in Pharmaceutical Invention Held to Meet Description Requirement,” Issue No. 2018-04, December 2018).

On remand, the competitor submitted a new prior art reference (D6) and argued that the subject patent was invalid for lack of inventiveness over D6 and D1, the main prior art reference that had already been submitted during the invalidation trial proceeding.

▶The Patent Court Decision

The Patent Court noted that, while D1 disclosed a sustained release composition in the form of microparticles comprising octreotide as an active ingredient and two different PLGAs where the L:G monomer ratios of the two PLGAs were both 50:50, D1 was different from the subject invention in that the microparticles in D1 were prepared by supplying various concentrations of the two PLGAs through a gradient pump, meaning there were a variety of different microparticles in the composition due to the use of the gradient pump. The Patent Court, 1 however, found that the subject invention and D6 were identical in terms of the technical idea, and were different only in terms of the active ingredient contained in the microparticles. Specifically, Example 4 of D6 described a pharmaceutical composition in the form of microparicles for a prolonged release of three months or more where leuprorelin, an analog of leutenizing hormone releasing hormone (LHRH), was contained in two types of microparticles having different lactide:glycolide monomer ratios as recited in the subject invention.

The Patent Court determined that the subject invention, and D1 and D6, when read in combination, were substantially identical in their technical field and object of the invention, and there was no indication in any of the prior art that taught away from combining the disclosures of D1 and D6. Therefore, the Patent Court denied inventiveness of the subject invention when viewed by combining D1, relating to a sustained release formulation in the form of microparticles containing octreotide, and D6, disclosing a sustained release formulation with the same composition as the subject invention in connection with another active ingredient (leuprorelin) and its prolonged release effect.

▶The Supreme Court Decision

On appeal, however, the Supreme Court determined that a person skilled in the art would not have easily conceived the subject invention by combining D1 and D6 because it would be difficult to expect that the sustained release effect of D6 would still be obtained when combined with D1, and the technical characteristics of D1 and D6 were different from each other.

Specifically, the Supreme Court found that it would be difficult for a person skilled in the art to expect that the same sustained release effect as shown in D6 would also be exhibited when the method of preparing the sustained release composition of leuprorelin was applied to the octreotide formulation of D1 because the leuprorelin of D6 was different from the octreotide of the subject invention in physicochemical properties and structures directly affecting the release rate of the formulation, such as molecular shape, reactivity with PLGA, half-life and minimum effective concentration, initial burst release, etc. Further, the Supreme Court stated that a person skilled in the art would not have easily expected an in vivo prolonged release of a drug over a period of about three months, as shown in the subject invention, because more than 30% of octreotide was released in 7 days in an in vitro release test of the octreotide formulation disclosed in D1, and the relationship between in vitro release effect and in vivo release effect of octreotide was not clear at the time of the filing date of the subject patent. Moreover, the Supreme Court noted that it would not have been obvious for a person skilled in the art to combine D1 and D6, whose technical characteristics were different from each other in that, while multiple microparticles were individually prepared and then mixed in a certain ratio so as to provide a formulation of microparticle mixtures exhibiting a desired release pattern in D6, D1 aimed to provide a preparation method of sustained release microparticle formulation having various compositions using a single continuous process for the purpose of improving the method of D6, which was deemed complex and economically unsound.

Accordingly, the Supreme Court reversed the Patent Court’s decision by holding that a person skilled in the art would not have easily conceived the subject invention by combining D1 and D6 without hindsight knowledge from the subject invention.

The validity of the patented invention was subsequently confirmed in the proceeding remanded to the Patent Court (Patent Court Case No. 2021 Heo 2663 dated October 8, 2021; final and conclusive).