Pemetrexed - Italy

On Oct 15, 2018, The Court of Milan reversed first instance decision regarding method of use patent & found infringement.

Previously, by order of Sep 10, 2017, first instance Judge issued a declaration of non-infringement that antitumor drug “Pemetrexed Fresenius Kabi 100 mg” and “Pemetrexed Fresenius Kabi 500 mg” powder for concentrate for solution did not infringe the Italian portion of patent EP 1313508 owned by ELI LILLY. In short, in the first instance preliminary proceedings the Judge held that the literal wording of claims 1 and 12 showed that the patent claimed a specific chemical compound, i.e. the disodium salt of the antifolate pemetrexed (pemetrexed disodium), and this was confirmed by the description of the patent (whereby “the antifolate or antifolate drug for use in this invention” was exclusively “pemetrexed disodium (ALIMTA) as manufactured by ELI LILLY”), so that the alleged infringement by the petitioners’ product had to be excluded, on the grounds that it includes another component, i.e. pemetrexed diacid. In support of the above conclusion, the first instance Judge also relied on the file history of EP 1313508 and, in particular, on the progressive limitations introduced by the patent holder following the objections raised by the Examiner against the original wording of the patent application, which initially claimed the entire class of antifolates, was subsequently limited to the antifolate pemetrexed and then further limited, in its final version, to pemetrexed disodium alone. Therefore, the Judge concluded that this construction of the scope of protection of EP 1313508 excludes its infringement by equivalents because patentee limited the claim scope to pemetrexed disodium only.

Court of appeal however disagreed & said that in the present case, the reconstruction of the examination phase of EP 1313508 carried out by the Panel of Experts confirmed that an objection was raised against the first limitation submitted by ELI LILLY & Co., according to which the compound pemetrexed – which had replaced the wider term “antifolates” used in the original wording of claim 1 – could be challenged under Article 123, paragraph 2, EPC. In fact, this remark did not imply any objection of lack of novelty or lack of inventive step. It must be acknowledged that in such event – unlike limitations arising from prior art objections – a limitation introduced further to an objection of added matter cannot materially affect the application of the doctrine of equivalents, since such objection only concerns formal issues regarding the literal wording of the amended claims, as compared to the patent application as filed. Thus, in present case it can thus be safely ruled out that the amendment made by the applicant and introduced in the text as granted may per se be considered to restrict the interpretation of the patent’s scope of protection in such a manner as to exclude compounds that are equivalent to pemetrexed disodium.

Moreover, according to reply filed by Eli Lilly there was no intention to restrict the scope of protection to the pharmaceutical form of pemetrexed disodium. There is absolutely no hint of any such exclusion, especially considering that the invention does not regard the selection of a pemetrexed salt but is rather aimed at reducing the toxic effects of the active moiety of said active ingredient, i.e. the anion. As confirmed by the Panel of Experts, at the filing date of EP 1313508 the person skilled in the art was aware that the active moiety of the ingredient pemetrexed – i.e. the one capable of penetrating inside the cells and exerting both its inhibiting but also its toxic effects – is the anion & not salt. Therefore, the person skilled in the art would not attach any particular significance to the fact that the antifolate pemetrexed was in the disodium salt form. The person skilled in the art would treat this as a clearly non-essential element of the invention, since the invention is aimed to solve a clinical issue of toxicity by associating vitamin B12 to the active (and toxic) moiety of pemetrexed disodium, i.e. the anion.

The Panel of Experts thus next conducted the so-called “Triple Test” to assess whether – once literal infringement has been excluded – infringement by equivalents exists between pemetrexed fresenius and the pemetrexed disodium of EP 1313508. The Panel established that both have the same therapeutic function, highlighting the SmPC (Summary of Product Characteristics) portion of the Fresenius. The administration of Pemetrexed Fresenius according to the methods described in the SmPC – after reconstitution in 5% glucose solution and subsequent dilution of a powder containing also mannitol, hydrochloric acid and trometamol – necessarily leads to forming the anionic species having trometamol (or tromethamine) as a counterion instead of sodium. Since the active moiety is the same both in Fresenius’ pemetrexed diacid and in ELI LILLY & Co.’s pemetrexed disodium, and since such active moiety is used in combination with vitamin B12 and folic acid, the Panel of Experts concluded that the mechanism of action of Pemetrexed Fresenius is the same as pemetrexed disodium according to the medical use defined in EP 1313508.

The Panel of Experts thus concluded that Pemetrexed Fresenius infringes the scope of protection of patent EP 1313508 by direct equivalence.