The patent in suit is Lilly‘s EP 1 313 508 B1; see the EPO Register and Swissreg for further details. In a nutshell, EP’508 relates to combination of pemetrexed disodium and vitamin B12. See this Blog here for a discussion about earlier infringement proceedings concerning the same patent.
Now, nullity is at stake.
An Opposition Division of the EPO had maintained the patent as granted with decision of 27 December 2010; an appeal had initially been lodged but withdrawn later. Related decisions in civil proceedings elsewhere had also addressed the validity of EP’508, e.g. in
USA (Court of Appeals for the Federal Circuit, 2015-2067, decision of 12 January 2017 relating to the corresponding US patent 7,772,209 and maintaining the patent);
Japan (IP High Court, 2015 (Gyo-Ke) 10249 et al., decision of 2 February 2017 relating to the corresponding JP patent 5102928 and maintaining the patent).
Thus, it was an uphill fight for the plaintiff. And even though the FPC took the parallel decision of the German FPC into account, it explicitly disagreed. It is held on p 19 (penultimate and lastparagraph), that the German FPC erred with the finding that
[…] bei einer Pemetrexedgabe durch die Blockierung der drei Schlüsselenzyme Thymidylatsynthase (= TS), Dihydrofolatreduktase (= DHFR) und Glycinamidribonukleotidformyltransferase (= GARFT) im «DNA- Zyklus» nicht nur dieser Zyklus, sondern auch der «Methylierungszyklus» blockiert wird.
Consequently, the FPC did not put much weight (if any) on the parallel decision in Germany.
On the contrary, the decision holds that the claimed subject-matter was novel over Worzalla et al. since mere reference to a diet ‘Purina Chow #5001’ did not implicitly, yet clearly and unambiguously, disclose the presence of vitamin B12 (or folic acid).
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 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, 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.
It’s all about a combination of the antifolate pemetrexed disodium, vitamin B12 and, optionally, folic acid. Briefly, pemetrexed is an antifolate that inter alia inhibits synthesis of thymidine and thus de novo DNA synthesis. Evidently, antifolates are quite toxic. But according to EP’508, toxicity can be successfully controlled by co-administration of pemetrexed with vitamin B12 and, optionally, folic acid.
EP’508 had already been litigated in infringement proceedings in Switzerland, resulting in a landmark decision of the Supreme Court on the Doctrine of Equivalents and how amendments of the patent during prosecution are to be dealt with in this respect; see this Blog here.
This time, validity of EP’508 is being challenged, based on a lack of novelty or, at least, lack of an inventive step; and added matter. Only inventive step has been pleaded in the hearing. With respect to the other grounds of nullity, the Sandoz merely referred to the written submissions.
It was evident from the pleadings that the opinion of the judge-rapporteur had been in favour of the defendant. This interim opinion is in line with the decision of an EPO opposition division, the Rechtbank Den Haag (Case No. C/09/533354 / HA ZA 17-581; judgment available as Dutch original and inofficial English translation), the IP High Court of Japan and the U.S. CAFC. On the other hand, the German Federal Patent Court had revoked the German part of EP’508; an appeal before the Supreme Court is still pending.
Sandoz started from Jackman as closest prior art in the assessment of inventive step. With reference to Worzalla et al., Jackman describes experiments in which pemetrexed was administered alongside with folic acid. Further, phase I clinical trials had been reported in which pemetrexed was administered together with folic acid (Hammond et al.). In consideration of the biochemical pathways, Sandoz argued that it had been obvious to add vitamin B12 to said known combination.
Eli Lilly of course disagreed. In Lilly’s view, the skilled person would not have pursued a combination of pemetrexed and folic acid, let alone to add vitamin B12. In real life, phase II clinical trials began with pemetrexed alone, irrespective of the experiments of Hammond et al. Toxicity of pemetrexed had intially been deemed controllable. It was only in the course of phase II clinical trials that the therapy scheme was switched because toxicity was found to be too severe.
A significant point of discussion was whether a skilled person would have been motivated to add vitamin B12 in light of some marker experiments. Niyikiza, the main inventor of the patent in suit, had published a report that described a correlation of pemetrexed toxicity with an unspecific marker (homocysteine), but not with the vitamin B12-specific marker MMA (methlymalonic acid). Accordingly, in Lilly’s view, a skilled person would not have been prompted towards the invention.
Note that Hepp Wenger Ryffel is involved in this matter on behalf of the plaintiff.
Pemetrexed revisited, once again:
As reported earlier on this Blog here, the Supreme Court had remitted the case to the FPC with the order to dismiss the suit with respect to the requested declaratory judgment of non-infringement for the diacid, and to also assess the two other salts that had initially been at stake in first instance proceedings.
Well, the first part is a no-brainer. The FPC is bound to the legal assessment of the Supreme Court, and it thus dismissed the suit with respect to the diacid.
As to the two other salts, i.e. pemetrexed dipotassium and pemetrexed ditromethamine, the FPC briefly assessed infringement under the doctrine of equivalents.
The first question to be answered in the assessment of infringement under the DoE is whether the replaced feature and the replacing feature have the same objective function. The decision holds that it is only the cation that is different, and that the dianion is the same in any event. Further, it is held that both the dipotassium and the ditromethamine salt will be dissociated under physiological conditions, and everything suggests that the mode of action is determined by the dianion.
Pemetrexeddikalium unterscheidet sich von Pemetrexeddinatrium bzw. Pemetrexeddisäure lediglich durch das Kation. Das Dianion ist in allen Fällen identisch. Pemetrexeddikalium liegt bei physiologischem pH dissoziiert in Kation und Dianion vor. Es spricht alles dafür, dass die Wirkungsweise durch das Pemetrexed-Dianion gegeben ist.
Aus diesen Gründen ist eine Gleichwirkung für Pemetrexeddikalium gegeben ist.
One may like or dislike the outcome as it is. Be this as it may. What is troubling me is that this reasoning is only focused on the mode of action of the dianion. Note that the dianion neither is the replaced feature nor the replacing feature. Does this reasoning actually address the first question of the FPC’s questionnaire for the assessment under the DoE at all?
Does the replacing feature objectively fulfil the same function? (‘Gleichwirkung’)
Is there a need to rephrase the first question? Time will show, I guess.
The FPC answered the second and third question in the affirmative, too. It did so by mere reference to the considerations of the Supreme Court.
In sum, all three pemetrexed forms (diacid, dipotassium and ditromethamine) are held to infringe the patent in suit.
In a nutshell, the FPC had taken a stepwise approach in O2015_004. In first place, it was held that limitation from antifolate to pemetrexed disodium during prosecution constitutes an abandonment of subject-matter. In an auxiliary assessment, i.e. if one were to consider the limitation not as an abandonment, the FPC denied an infringement under the Doctrine of Equivalents (DoE) since the skilled person would have understood the wording pemetrexed disodium as a strict limitation, in view of the claims and in further consideration of the specification.
As you were! The Supreme Court did not agree with either of these two findings.
1. Abandonment of subject-matter
The wording of the claims had been narrowed down during prosecution: The broad term antifolate had been amended in the claims to pemtrexed in first place and finally to pemetrexed disodium, to restore novelty while at the same time complying with Art. 123(2) EPC.
This limitation is also reflected in the description. The definition in paragraph  of EP’508 had only been introduced during prosecution:
The FPC had held that the patentee is bound by the limitation that 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 now circumvent this limitation by asserting equivalence as if the limitation had not been made.
The Supreme Court notes that behavior in contradiction to one’s prior acts is not generally prohibited under the principle of good faith, but only if the prior act gave rise to a legitimate trust of others which then is frustrated by the later act (BGE 125 III 257, r. 2a). The Supreme Court further holds that the limitation of a claim feature does not readily constitute an abandonment of the protection against infringement under the DoE for that feature without taking the reasons of the limitation into account.
Die Einschränkung eines Merkmals stellt nicht ohne weiteres und unbesehen des Grundes für diese Einschränkung eine Erklärung des Verzichts auf den Schutz gegen Nachahmung dar.
The Supreme Court did not identify any special circumstances that would justify the use of the makeshift of Art. 2 CC to prevent gross injustice, either.
2. Infringement under the DoE
The Supreme Court held that the pemetrexed anion is the active substance with anti-cancer effect and agreed with the FPC’s finding that the diacid and the disodium salt objectively fulfil the same function.
The second question (accessibility / ‘Auffindbarkeit’) is somewhat tricky, again. The Supreme Court recites the FPC in that accessibility of the replacing feature had been answered in the affirmative; ¶5.4.
Die Vorinstanz hat die Auffindbarkeit der abgewandelten Form für den Fachmann bejaht.
This is not very precise. The second question, in the FPC’s approach, asks for the accessibility of the same effect when the skilled person is confronted with both the claimed variant and the replacing variant. The FPC’s second question is not about how to get to the replacing variant; it’s already there.
Anyway, the Supreme Court held that the skilled person had a reasonable expectation that the replacing variant would work. The necessity of some routine experiments to confirm this expectiation is of no avail. Accessibility was thus confirmed, too.
The Supreme Court also answered the third question (same value / ‘Gleichwertigkeit’) in the affirmative. The skilled person had no reason to believe that the patentee had only intended protection for the literal meaning of the claim, i.e. pemetrexed disodium.
Der Fachmann […] hatte keinen Grund zur Annahme, die Patentinhaberin habe Schutz nur für die wortsinngemässe Ausführung beansprucht.
Even though it is noted in paragraph  of the patent (see marked-up excerpt above) that
[t]he ‘antifolate’ or ‘antifolate drug’ for use in this invention is Pemetrexed disodium (ALIMTA®), as manufactured by Eli Lilly & Co.
the Supreme Court held that there is no apparent reason why the patent would expand on the properties and ways of action of antifolates in general if it was intended to limit the claimed scope to the product manufacted by the patentee; ¶5.5.6.
Wenn zudem in der Beschreibung erklärt wird, das für die Erfindung verwendete Antifolat sei das von der Patentinhaberin hergestellte Pemetrexed-Dinatrium der Marke ‘Alimta’, so ergibt sich daraus bei objektiver Betrachtung eine Beschränkung ausschliesslich auf dieses Antifolat im Gesamtzusammenhang der Beschreibung nicht. Denn es ist nicht erkennbar, weshalb im Patent die Eigenschaften und die Wirkungsweise von Antifolaten allgemein beschrieben werden sollte, wenn das von der Erfindung beanspruchte tumorhemmende Produkt ausschliesslich das von der Patentinhaberin hergestellte Markenprodukt sein sollte.
Concluding, the Supreme Court held that use of pemetrexed diacid instead of pemetrexed disodium infringes the patent under the DoE.
The case has been remitted to the FPC with the order to dismiss the suit with respect to the requested declaratory judgment of non-infringement for the diacid, and to also assess the two other salts that had initially been at stake in first instance proceedings.
Reported by Martin WILMING
For ease of reference, here is a list of some corresponding decisions of highest instance available elsewhere, based on the same European patent:
I will update the list when more decisions are available.
Lawyers and patent attorneys are having a hard time nowadays when advising clients on infringment under the DoE.
Maybe it should not be me to overly analyse this decision since my firm has been involved in this matter, as noted above. But I was taken aback by some key elements of the decision which are of relevance far beyond the subject-matter at stake in the present matter, and I will briefly address those aspects on a general level only, to the extent possible.
So, here is some food for further thought:
i) The gist of the DoE?
The Supreme Court comes up with a very pronounced gist of the DoE; see ¶5.5.3:
Der Schutzbereich wird – mit Ausnahme der nachfolgend zu erörternden bewusst gewählten Beschränkung – über die genaue wörtliche Anwendung der Patentansprüche hinaus gewährt in der Erkenntnis, dass es auch bei sorgfältiger und umsichtiger Redaktion unmöglich ist, in einer technischen Anleitung alle möglichen Ausführungen zu benennen. Der Schutz soll daher auch gewährt werden, wenn die technische Anleitung den Fachmann über den zu engen Wortsinn hinaus anweist, wie die Erfindung zu verwirklichen ist.
This can be loosely translated as follows:
With the exception of a deliberately chosen limitation the scope of protection shall extend beyond the literal meaning, in appreciation of the fact that it is not possible to specify all potential embodiments even when the text is redacted with all due care and diligence. Protection shall thus also be granted when the technical teaching instructs the skilled person how to work the invention beyond the overly limited literal meaning.
I do not agree.
This rationale would actually excuse each and every mishap in drafting / prosecution of an application, be it a minor negligence, a gross error or just blatant foolery. All of this could not reasonably be considered deliberately chosen (‘bewusst gewählt’) and would thus not be covered by the exception.
Now, as long as the skilled person nevertheless understands that the teaching of the patent is applicable beyond the literal meaning, it shall still be covered by the scope of the claim under the DoE?
Is this the right balance between legal certainty for the public and forgiveness of drafting / prosecution failures?
The Protocol on Interpretation of Art. 69 is not that strict. It only requires that due account shall be taken of any element which is equivalent to an element specified in the claims when determining the scope of protection. Does ‘due account’ really mean that the only exception is an express and deliberatly chosen limitation?
I am in doubt.
One of the best pieces on the various situations where the DoE is typically invoked that I have come across still is in Arnold J’s judgment at the High Court of Justice in the corresponding matter in the U.K.,  EWHC 1511 (Pat), in ¶104 ff.:
[E]xperience shows that patentees resort to arguments about equivalents in three main classes of case. The first is where, with the benefit of hindsight, it can be seen that the patent was unfortunately drafted, whether because of poor instructions from the inventor or poor drafting by his patent attorney or a combination of these things. […] The second class is where technology has moved on since the priority or filing date of the patent. […] The third class is where the patentee now regrets a decision taken during the course of prosecution of the patent application, whether by himself or by the examiner, and is trying to avoid the consequences of that decision.
Arnold J went on in his assessment of the first and the third class of cases in ¶105 and ¶107, respectively:
In the first class of case, the law recognises that drafting patent claims is a difficult and imprecise art and that third parties should not be allowed to exploit infelicities of drafting where it is reasonably clear that those infelicities should not affect the scope of the claim. This is in order to provide ‘fair protection for the patent proprietor’. The law also recognises, however, the countervailing consideration that third parties are entitled to rely on the drafting of the claim when deciding on a commercial course of action. There is no tort of avoiding a patent claim. Thus it is also necessary to provide ‘a reasonable degree of legal certainty for third parties’. The problem, of course, is that what is fair protection to one person is legal uncertainty to another. Conversely, what is reasonable legal certainty to the second person is a denial of protection to the first. The courts have to strike a balance. […]
In the third class of case, there is no reason why the law should be sympathetic to the patentee. Not only do applicants generally rely on skilled professional advice, but also they can appeal against adverse decisions of examiners during the course of prosecution if they consider that those decisions are wrong. If the courts allow decisions as to claim scope made by the examiner during the course of prosecution which have not been successfully appealed effectively to be overturned by decisions on claim construction, the courts undermine the important role of the examiner. This is still more so if the courts allow decisions as to claim scope made by the applicant during the course of prosecution effectively to be reversed by decisions on claim construction.
ii) The more apparent the replacing feature (but not too much, please!), the more likely the third question would be answered in the affirmative?
There has been a guiding principle in the assessment of equivalents according to the German Federal Supreme Court since the ‘Okklusionsvorrichtung‘ decision (X ZR 16/09):
If the description discloses several possibilities regarding how a specific technical effect can be attained but only one possibility has been included in the patent claim, the use of the other possibilities generally does not constitute an infringement under the doctrine of equivalence.
So, an explicit mentioning of two alternatives in the specification while only one of these alternatives is recited in the claim rules out an infringement under the DoE. Fine.
But what if there is explicit disclosure of a generic class of compounds (‘antifolate’) and only a single specific variant (‘pemetrexed disodium’) in the claims and specification? Luckily, the German Federal Supreme Court had to assess the parallel case in Germany, too (X ZR 29/15): It concluded that this is not sufficient per se. But if there were further indications that the skilled person reads the other variants along in his head (‘unmittelbar mitlesen’), then ‘Okklusionvorrichtung’ might well be applicable. Fine, too.
Now, this is the chemist in me speaking to the other chemists out there: Imagine you readily appreciate the below as a preferred embodiment of a group of compounds (¶5.5.7), can you avoid reading along in your head some very close relatives of this compound?
The chemist in me has a hard time to not think of some close relatives in the upper right of the molecule.
Safeguarding legal certainty for the public has always been an issue. The following is taken from Miller v. Bridgeport Brass Co. of ancient 1881:
[I]t must be remembered that the claim of a specific device or combination, and an omission to claim other devices or combinations apparent on the face of the patent, are, in law, a dedication to the public of that which is not claimed. It is a declaration that that which is not claimed is either not the patentee’s invention, or, if his, he dedicates it to the public.
In my perception, this still holds true nowadays; equivalence must not extend to what is apparent on the face of the patent, but remained unclaimed.
I have been a strong believer in the power of the questionnaires. But, frankly, I am getting more and more frustrated. When cases come up where the result based on just two questions appears to be inappropriate, a third one is added (Germany and Switzerland). If the result with three questions appears to be inappropriate, the questions are amended (UK). Still, judgments on equivalence are frequently reversed even in one and the same jurisdiction, and are rarely consistent across jurisdictions. So, what is it all worth? The questionnaires apparently only provide an illusion of certainty, don’t they? And they are not the law. (If you catch me red-handed when using the questionnaire nevertheless, don’t blame me for this paragraph. I am just conforming with the landmark case law …)
iii) What about inventive equivalents?
The Supreme Court elaborates on the second criterion (accessibility / ‘Auffindbarkeit’) in the assessment of equivalents in ¶5.4 ff. It is held in ¶5.4.1:
Der Fachmann […] muss aufgrund seines Allgemeinwissens durch die patentierte Erfindung zur Abwandlung angeregt werden; beruht die Abwandlung ihrerseits auf erfinderischer Tätigkeit, ist die Auffindbarkeit ausgeschlossen (vgl. BGE 125 III 29 E. 3b S. 32 mit Verweisen).
Loosely translated as follows:
The skilled person must be prompted to the replaced feature by his common general knowledge and based on the patented invention; accessibility is ruled out if the replacing feature itself is based on an inventive step ([…]).
The decision suggests in ¶5.4.1 that this is common ground for the Supreme Courts of the UK, Germany and Switzerland.
The second test applied by the German courts, as I understand it, at least sometimes appears to require the variation not to be inventive, but I am not sure that that is an appropriate requirement, although it is unnecessary to decide that point on this appeal. If the variation represents an inventive step, while it may render it less likely that the patentee will succeed on the second reformulated question, I find it hard to see why that alone should prevent the resultant variant from infringing the original invention. It may entitle the infringer to a new patent, in the same way as the invention of a novel use for a patented invention can itself be patented, but like such a novel use I see no reason why the variant should not infringe the original patent.
I am not even sure if this holds true for Switzerland. The Supreme Court’s own landmark ruling ‘Urinalventil’ (4A_131/2016) marches to a different drummer, in my perception. In that later case, the replacing feature in the attacked embodiment was in fact patented by the EPO, with the patent in suit being explicitly acknowledged as closest prior art. The attacked embodiment had nevertheless been held to infringe the patent in suit under the DoE. See this Blog here for a detailed review of the ‘Urinalventil’ case.
Moreover, the second question in the FPC’s questionnaire in no way excludes inventive equivalents; see this Blog here. The headnote in O2014_002 reads as follows:
The assessment of accessibility is not to be confused with the assessment of inventiveness. Starting point for the assessment of accessibility is not the general state of the art, but the patent in suit. Therefore it is not to be assessed whether the replaced feature is inventive in view of the state of the art. It is rather to be assessed whether, starting from the teaching of the patent in suit, it is evident for the skilled person that the replaced feature has the same effect (r. 22.214.171.124).
(Clarification of the case law with respect to S2013_001, decision dated 21. März 2013)
iv) Should one care (more) about the title?
There are multiple references to the title of the patent in particular in the reasons of the Supreme Court’s decision (p. 2, section A; ¶5.5.5; ¶5.5.6:
[…] Patent[s] […] dessen Gegenstand umschrieben ist als “Combination containing an antifolate and methylmalonic acid lowering agent” […];
In der Beschreibung ist – wie im Titel des Patents – allgemein von Antifolaten die Rede.
This emphasis on the title puzzles me. It is required by the EPC that the title of the invention must be contained in the request for grant form and that it shall clearly and concisely state the technical designation of the invention (R. 41(2) lit. b EPC), no doubt about it. However, the title is not part of the description (R. 42 EPC) which shall be used to interpret the claims (Art. 69(1) EPC) in accordance with the Protocol on Interpretation of Art. 69.
I am not aware of any relevant decision on equivalents that has put this much emphasis on the title.On a personal note, I couldn’t have cared less about the title by now. A negligence?
v) Final thoughts
There were times (in particular in Germany after introduction of the third criterion (‘Gleichwertigkeit’)) when the DoE effectively was dead. In my perception, the pendulum now swings back and we see decisions more to the contrary. Over time, the ‘truth’ will be somewhere in between. Hopefully.
Exhausted from equivalents, I remain
If you came here on a shortcut, you missed a lot. Anyway, I will assume this was your ‘delibarately chosen limitation’ of information. The decision holds:
Limitation of ‘antifolate’ to ‘pemetrexed disodium’ during prosecution did not constitute an abandonment of subject-matter.
A composition comprising pemetrexed diacid infringes a claim specifying pemetrexed disodium under the DoE.
The case is remitted to the FPC to with the order to dismiss the suit with respect to the requested declaratory judgment of non-infringement for the diacid, and to also assess the two other salts that had initially been at stake in first instance proceedings.