Tuesday, June 16, 2020

Pemetrexed – Netherlands


On Jun. 12, 2020, Supreme Court of Netherlands followed Advocate General’s Opinion and upheld preliminary injunction (PI) decision of lower court by dismissing the appeal.

The heart of the issue was the scope of the EP (NL) 1313508 patent which is held by Lilly. The patent entitled, “Combination containing an antifolate and methylmalonic acid lowering agent”. This second medical indication patent claims treatment of cancer with pemetrexed disodium in combination with vitamin B12 & folic acid. The patent is valid in the Netherlands until Jun. 14, 2021. Lilly markets the medicine Alimta® (Pemetrexed disodium). The active ingredient in Alimta® (after solution) consists of pemetrexed anions. In Alimta®, the anions are bound to sodium ions to form the pemetrexed disodium salt. The active substance in Fresenius Kabi's Pemetrexed for injection is Pemetrexed diacid with tromethamine instead of Pemetrexed disodium as in Alimta 100 mg / 500 mg powder for concentrate for solution for infusion. When reconstituted and diluted for administration, the active moiety remains the same irrespective of the salt form. The marketing authorization for Pemetrexed Fresenius was granted on July 22, 2016.

On Aug. 03, 2017 Lilly has claimed an infringement prohibition & argued that Pemetrexed Fresenius falls under the scope of protection of EP 508. Preliminary Relief Judge of the District Court of The Hague on Oct 24, 2017 issued an injunction against Fresenius Kabi’s pemetrexed product.  Court of Appeal of The Hague on May 08, 2018 affirmed the decision. Fresenius then appealed the decision. Advocate General Van Peursem provided opinion on Apr. 01, 2020 on the said matter. The actual assessment was done to see whether Pemetrexed Fresenius falls within the equivalent scope of protection of EP 508. Specifically, the question was whether the limitation of the claims introduced by Lilly during prosecution could preclude infringement under equivalence. During prosecution Lilly amended claims from antifolate to pemetrexed disodium. AG opined that in the eyes of the average skilled person, there is no conscious choice based on a technical reason, which would lead them to understand that the intention here is to claim only the disodium salt. According to the court, this technical choice cannot be deduced from the description by the person skilled in the art nor does the person skilled in the art read any indications that a salt study was carried out on which the choice for disodium salt. The average skilled person would see that disodium was just a suitable salt form. The disodium salt was only mentioned because it already existed (Alimta). The professional does not see such a deliberate limitation as intended by Fresenius on the basis of his general professional knowledge.

Moreover, the inventive idea of EP 508 lies in the use of vitamin B12 and optional folic acid in combination with the antifolate pemetrexed (not limited to pemetrexed disodium), thereby reducing the serious toxic side effects of the pemetrexed anions while the efficacy of the pemetrexed anions in the inhibition of tumor growth is maintained. The person skilled in the art knows that only the anion is responsible for the efficacy (and toxicity) of pemetrexed, he also finds confirmation for the insight that the invention relates rather to the active form of pemetrexed after administration and not to the specific disodium salt form disclosed therein , in the description of the mouse model.

Court of Appeal correctly considered that amendment to claims made during the granting procedure at the direction of the Examiner does not prevent a patent holder from relying on the application of Article 2 of the Protocol (equivalence) when determining the scope of protection. Claims were amended to avoid Art. 123(2) rejection (added matter) raised by Examiner. Added matter and scope of protection are clearly distinguishable issues. A limitation of the claims under Article 123 paragraph 2 EPC would result in the patent holder never being able to claim protection of equivalents. This could lead to too limited scope of protection.

Therefore, the appeal in cassation was dismissed & PI upheld.

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