Pemetrexed: It’s the counterion that counts

Case No. S2016_004 ¦ Decision of 06 December 2016 ¦ “Abweisung Massnahmebegehren; Bindung an Einschränkung aus Erteilungsverfahren”

Note that Hepp Wenger Ryffel is involved in this matter on behalf of the defendant.

Little time? Read the summary.

Lilly and CompanyThe patent in suit is Lilly‘s EP 1 313 508 B1; see the EPO Register and Swissreg for further details. EP’508 is heavily litigated in many countries. The present decision in Switzerland concerns Lilly’s request for interim injunctive relief in summary proceedings. Main proceedings are still pending (O2105_004).

The independent claims of EP’508 read as follows (emphasis added):

1.   Use of pemetrexed disodium in the manufacture of a medicament for use in combination therapy for inhibiting tumor growth in mammals wherein said medicament is to be administered in combination with vitamin B12 or a pharmaceutical derivative thereof, said pharmaceutical derivative of vitamin B12 being hydroxocobalamin, cyano-10-chlorocobalamin, aquocobalamin perchlorate, aquo-10-chlorocobalamin perchlorate, azidocobalamin, chlorocobalamin or cobalamin.

12.   A product containing pemetrexed disodium, vitamin B 12 or a pharmaceutical derivative thereof said pharmaceutical derivative of vitamin B12 being hydroxocobalamin, cyano-10-chlorocobalamin, aquocobalamin perchlorate, aquo-10-chlorocobalamin perchlorate, azidocobalamin, chlorocobalamin or cobalamin, and, optionally, a folic binding protein binding agent selected from the group consisting of folic acid, (6R)-5-methyl-5,6,7,8-tetrahydrofolic acid and (6R)-5-formyl-5,6,7,8-tetrahydrofolic acid, or a physiologically available salt or ester thereof, as a combined preparation for the simultaneous, separate or sequential use in inhibiting tumor growth.

Pemetrexed disodium (see structural formula below) is marketed by Lilly under the trademark Alimta®. Stakes are high for Lilly: Alimta® generated a worldwide revenue of $2,493 million in 2015; see Lilly’s Annual Report 2015, p F31. The drug is used as a cancer medication that interferes with the growth and spread of cancer cells in the body; see drugs.com for further information.

ActavisThe attacked embodiment is Actavis‘ Amtiris® which makes use of pemetrexed diacid instead of pemetrexed disodium (see structural formula above). Amtiris® had been approved by Swissmedic on 23 March 2016; see Swissmedic Journal 03/2016. Please refer to the interactive 3D structure below to get an idea of how pemetrexed dicacid actually looks like:

Literal infringement was not an issue. The present decision is all about the question of whether or not the use of pemetrexed diacid might constitute an infringement under the Doctrine of Equivalents (DoE).

Note that the wording of the claim had been narrowed down during prosecution in order to overcome the examiner’s objections and to proceed to grant: The broad term antifolate had been more precisely defined as pemetrexed in first place, and finally even further as pemetrexed disodium. The FPC thus assessed whether the DoE is applicable at all to the feature pemetrexed disodium. The FPC notes that the patentee is bound by limitations he had accepted during prosecution in order to obtain the patent, and that he is therefore prevented under principles of good faith (Art. 2 CC) to circumvent this limitation by asserting equivalence. The FPC refers to a decision HG060066 of the Commercial Court Zurich in this respect. This is not to be confused with the Prosecution History Estoppel known in the U.S. — it rather highlights that the prosecution history is not just irrelevant.

Für die Beurteilung der Bedeutung dieser von der Patentinhaberin im Laufe des Erteilungsverfahrens vorgenommenen Einschränkung ist davon auszugehen, dass die Schweiz, wie andere Europäische Länder auch, keine Prosecution History Estoppel, wie sie in USA angewandt wird, kennt. Das heisst aber keineswegs, dass die Erteilungsgeschichte in der Schweiz völlig ausser Acht gelassen werden kann.

The FPC consequently held that the request for interim injunctive relief had to be dismissed for this reason alone.

For the sake of completeness, the FPC additionally assessed infringement under the DoE. The FPC’s 3-step questionnaire has recently been approved by the Supreme Court.

The first question to be answered is whether the replaced features have the same objective function. The FPC essentially relied on the fact that the attacked embodiment is a Swissmedic approved generic version of Alimta®, ie the pemetrexed disodium containing product. The same objective function was thus held to be given.

The second question asks whether the replaced features and their same objective function are made obvious to the skilled person by the teaching of the patent. See also the clarifying headnote of O2014_002 on how the FPC expects this question to be addressed. The FPC held that the skilled person knows that pemetrexed diacid would be at least partially deprotonated under physiological conditions, and that both pemetrexed diacid and pemetrexed disodium will result in the same pemetrexed dianion. Concluding, the skilled person would thus have expected the diacid to have the same effect (based on the anion). The FPC expressly dissents with the judgement of the England and Wales Court of Appeal ([2015] EWCA Civ 555, #71) in this respect.

Finally, the third question asks whether it is evident for the skilled person that the replaced feature has the same effect, starting from the teaching of the patent in suit. Would the skilled person have understood the wording pemetrexed disodium as a strict limitation? The FPC notes that other components are defined more broadly in the claims, ie vitamin B12 or a pharmaceutical derivative thereof. Not so for pemetrexed disodium. The skilled person would thus have understood this as an intentional limitation, in further view of the specification. The patent refers to antifolates in paragaph [0022] as follows (emphasis added):

The terms “antifolate” and “antifolate drug” generally refer to a chemical compound which inhibits at least one key folate-requiring enzyme of the thymidine or purine biosynthetic pathways, preferably thymidylate synthase (“TS”), dihydrofolate reductase (“DHFR”), or glycinamide ribonucleotide formyltransferase (“GARFT”), by competing with reduced folates for binding sites of these enzymes. The “antifolate” or “antifolate drug” for use in this invention is Pemetrexed Disodium (ALIMTA®), as manufactured by Eli Lilly & Co.

The FPC thus answered the third question in the negative, expressly consenting with the judgement of the England and Wales Court of Appeal ([2015] EWCA Civ 555, #72) in this respect. The FPC also sides with the German Federal Supreme Court’s decision X ZR 29/15 in parallel proceedings in that the present matter is not an abandonment in the sense of X ZR 16/09Okklusionsvorrichtung. In Okklusionvorrichtung the replacing feature had been explicitly mentioned in the specification; not so in the present matter. However, the FPC notes that this does not automatically mean that a contrario the third question is to be answered in the affirmative.

Der BGH fokussiert sich bei der Beurteilung der dritten Äquivalenzfrage allerdings sehr auf diese Frage des Verzichts. Dem kann nicht gefolgt werden. Die Tatsache, dass kein Verzicht gemäss Okklusionsvorrichtung vorliegt, bedeutet keineswegs automatisch im Umkehrschluss, dass die 3. Äquivalenz-Frage zu bejahen ist. Das greift zu kurz.

The FPC thus dismissed Lilly’s request for interim injunctive relief in summary proceedings. Main proceedings are still pending (O2015_004).

Reported by Martin WILMING

BIBLIOGRAPHY

Case No. S2016_004 ¦ Decision of 06 December 2016 ¦ “Abweisung Massnahmebegehren; Bindung an Einschränkung aus Erteilungsverfahren”

Eli Lilly and Company ./. Actavis Switzerland AG

Composition of the Board of the FPC:

  • Dr. Dieter BRÄNDLE
  • Dr. Roland DUX
  • Prisca VON BALLMOOS

Reporting Judge:

  • Dr. Roland DUX

Court Clerk:

  • Susanne ANDERHALDEN

Representative(s) of Plaintiff:

Representative(s) of Defendant:

DECISION IN FULL

Download (PDF, 212KB)

WHAT’S GOING ON ELSEWHERE

A comprehensive summary on the current status of proceedings relating to Lilly’s Alimta® can be derived from Lilly’s Form 10-Q (3/2016); see p 24-25.

If you are interested in the fulltext decisions, there is a long series of decisions to read from the UK, ie [2012] EWHC 3316 (Pat), [2013] EWCA Civ 517, [2014] EWHC 1511 (Pat), [2015] EWCA Civ 555 and [2016] EWHC 234 (Pat).

As to Germany, there is the most recent decision X ZR 29/15 of the Federal Supreme Court. Please find the whole course of proceedings through the various instances in Germany here. Interim injunctive relief has been granted by the Regional Court Munich I in matters 21 O 22243/15 and 21 O 5583/16.

SUMMARY

The FPC dismissed Lilly’s request for interim injunctive relief in summary proceedings concerning a generic version of Lilly’s Alimta®, ie Actavis’ Amtiris®. While the claims of Lilly’s EP 1 313 508 B1 specifically require pemetrexed disodium, Amtiris® comprises pemetrexed diacid. The FPC held that limitation from antifolate to pemetrexed disodium during prosecution constitutes an abandonment of subject-matter. But even if it would not be considered an abandonment, the FPC denied an infringement under the Doctrine of Equivalents since the skilled person would have understood the wording pemetrexed disodium as a strict limitation, in view of the claims in view of the specification. Main proceedings are still pending (O2015_004).

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