Pemetrexed - Italy

On Sep 10, 2017, Court of Milan issued decision in pemetrexed case & found Fresenius pemetrexed ditrometamine product non-infringing. In this proceedings Fresenius sought declaration of non-infringement with respect to their product - pemetrexed ditrometamine before expiration of EP1313508 patent. EP’508 patent is expiring in Jun 2021 which claims use of pemetrexed disodium in combination with vitamin B12 for treatment of cancer.

Fresenius argued that the EP’508 patent claims were limited to pemetrexed disodium alone. Specifically, "File history" of EP'508, from which it appeared that Eli Lilly had limited the scope of protection to only salts of pemetrexed disodium from broad antifolate after Examiner’s objection during prosecution. In addition, the replacement of pemetrexed disodium with pemetrexed ditrometamine was not obvious, because it was not suggested, not implicitly, by the EP’508 patent of Eli Lilly. Also Fresenius product is intended to reconstitute with glucose solution and not with saline solution. Therefore, no source of sodium was introduced at any stage of production or preparation for administration.

Eli Lilly in counter statement said that the replacement of the pemetrexed diacid and tromethamine compound by the Fresenius was an obvious solution that could be achieved by routine experimentation. Eli Lilly also argued that the marketing of the Fresenius product would be a case of indirect infringement even if it required dilution in glucose, as the manufacturer's prescriptions would not be followed by the oncologist's physician and pharmacist whom they are referring to, they would be expected to use saline instead of that glucose, prescribed in the Fresenius product.

Court of Milan after hearing both the parties said that the interpretation of the claim, the description, of the entire patent text, the examination of the modifications made during the patent granting procedure, uniquely and independently, for the clear delimitation of patent protection to pemetrexed disodium alone, excluding that it may extend to other compounds. In the present case, in the absence of a restriction on pemetrexed disodium, the patent would have been granted and, if granted, it would have been declared null under the provisions of art. 123(2). In order to overcome this invalidity profile, the inventor has limited the patent patent to sodium pemetrexed, explaining in the description that "antifolate medicinal products of which the invention refers exclusively to Pemetrexed Disodium (Alimta)”.

After a thorough and in-depth analysis, court stated that the pemetrexed diacid in combination with trometamine, which characterizes the FRESENIUS product, can not to be considered a vice-versa equivalent to what is covered by EP'508, in the light of patent instruction "strictly limited” to the use of pemetrexed disodium alone in combination with vitamin B12 always in the antitumour treatment. Also Fresenius product exclusively would dilute in a 5% glucose solution, which is non-chemically different, and not equivalent, to the saline solution. In the presence of manufacturer's opposite instructions in drug label, replacement is not foreseeable.

This Court of Milan’s decision directly contradicts with the recent UK supreme court’s judgment where UKSC found Actavis product infringing. The UK SC also found that Actavis' product containing pemetrexed ditrometamine directly infringed the Italian designation of Lilly's patent. This difference is mainly because Milan court gave more preference to “file history” and applied estoppel.