The flip side of the coin

Pharma-savvy readers are probably well aware of the pan-European pemetrexed litigation.

Eli Lilly’s patent No.EP1313508 is probably one of the most litigated patents in Europe. A nice summary, which is a little bit more than one year old, can be found here but there have been more recent developments, in particular in the Netherlands and in Germany.

In this context, France was late in the game, but here we are, with a remarkable judgment by the Paris TJ (tribunal judiciaire) issued a few days ago. Many thanks to Loïc Lemercier at Clifford Chance for providing a copy!

The French decision seems to be overall aligned with the rulings issued in most other jurisdictions: in a nutshell, it is a (big) win for Eli Lilly.

The patent was upheld as valid and infringed. A permanent injunction was ordered against the defendant, Fresenius, and provisional damages amounting to 28 million euros were awarded – pending final determination.

There are certainly several noteworthy aspects in this decision, but the most interesting one is probably the interpretation of the claims and the infringement finding.

Claim 1 of EP’508 is a Swiss-type claim, which is drafted as follow:

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.

The claimed invention thus relates to a cancer combination therapy based on the administration of pemetrexed disodium, the main active substance, in association with vitamin B12 (or the like).

As summarized by the court in the judgment, pemetrexed disodium is a known anticancer agent marketed by Eli Lilly under the trade name Alimta®. This agent is toxic and has significant side effects. According to the patent, these undesirable side effects may be reduced owing to the co-administration of vitamin B12, which lowers the level of methylmalonic acid (a predictor of toxic events in patients) without impairing the efficacy of pemetrexed. The two substances may be administered as a single composition or separately.

Fresenius obtained a marketing authorization for a generic of Alimta®, called Pemetrexed Fresenius Kabi®, in 2016, and has been marketing this generic in France.

According to the summary of product characteristics of Pemetrexed Fresenius Kabi® (NB: for some reason, you have to use another navigator than Google Chrome to open this link), there is a mandatory pre-medication regimen: “patients must also receive an intramuscular injection of vitamin B12 (1000 micrograms) in the week preceding the first dose of pemetrexed and once every three cycles thereafter“.

In other terms, Pemetrexed Fresenius Kabi® is intended for the combination therapy recited in EP’508.

But there is a hitch: the active substance in Pemetrexed Fresenius Kabi® is not in the same saline form as Amlita®. The generic drug contains pemetrexed diacid, whereas the originator’s contains pemetrexed disodium. And, most importantly, claim 1 of EP’508 refers to pemetrexed disodium. Fresenius’ non-infringement defense was based on this difference.

When analyzing the scope of the patent, the court made reference to article 69 EPC (the claims must be interpreted in the light of the description and drawings) and its protocol on interpretation. As a reminder, according to this protocol, claim interpretation must stay away from the extremes of an excessively literal interpretation and an excessively extensive interpretation. Besides, any element equivalent to an element specified in the claims must be taken into account.

A claim is like an iceberg: there is more to it than you can see.

Interestingly, the court cited the file history as an additional source of interpretation:

The scope of the claims is determined in the light of the description and drawings, and also if appropriate by taking into account elements from the file wrapper of examination proceedings, such as the amendments and arguments made by the patentee, which are factual elements, to be considered among others. 

The court turned to the description of the patent and noted that it makes reference to the general class of antifolate drugs, of which pemetrexed disodium is an example. This seems to be because, in the application as filed, an antifolate was originally claimed, which was later restricted to pemetrexed disodium.

The court then noted that the crux of the invention is the combination of pemetrexed with vitamin B12, and that the disodium form of the active is inconsequential:

The skilled person knows that the active part of the pemetrexed active substance is the anion (which causes the therapeutic effects as well as the unwanted side effects) combined with vitamin B12 […] and understands, without focusing on the literal wording of the claims, that the invention resides in the combined administration of the active agent, whatever its form, with the other substances claimed in the patent. 

The court added that the existence of other patents owned by the same company and claiming an active in more general terms (with the notion of “pharmaceutically acceptable salts“) is irrelevant.

The court also added that the file wrapper, in the present case, did not need to be taken into account. Anyway, it merely showed that the restriction to the disodium salt form was not necessary to distinguish the invention from the prior art. It was necessary because there was no support in the application as filed for pemetrexed in general, therefore omitting the disodium feature would have resulted in an extension of subject-matter by intermediate generalization:

[…] The examination procedure in front of the office [provides] a simple optional tool of interpretation, it has no effect on the scope of the patent, and is not binding on the court or the patent proprietor. The behavior of the patent proprietor, who accepted a modification requested by the examiner, cannot be interpreted as an admission which is binding on the court and it has no consequence on the scope of the claim. […] Especially so in the present case, as Lilly meant to designate a preferred embodiment, without intending to modify the scope of its right, even if they did not object to the examiner’s argumentation. In fact, this modification due to added matter under article 123(2) EPC was not meant to overcome a prior art prejudicing the validity of the patent, and was only made for purely formal reasons. The modification due to added matter may not prevent the patent proprietor from relying on infringement by equivalence, since it is a formal condition relating to the substance of the inventive contribution and the literal content of the specification, prohibiting the patentee from adding any element which cannot be directly and unambiguously derived from the patent [sic]. It does absolutely not alter the base on which the interpretation must be performed, and it has no bearing on the extent of protection which is conferred. 

On the contrary, with respect to assessing the scope of the patent, article 69 EPC […] demands that equivalents be taken into account. Therefore, adding matter during examination proceedings is not a bar to relying on infringement by equivalence, provided that the specifically claimed means or combination of means (here, the combined used of vitamin B12 […] with the active substance) have a novel function (namely the reduction of toxic effects without impairing therapeutic efficacy) […]. 

The technical problem to be solved consists in reducing the toxicity of the pemetrexed antifolate, without impairing therapeutic efficacy. The solution recommended in the patent, despite the restrictive formulation of the claims, is the combined administration of the pemetrexed anion and the other substances mentioned in the patent, the form in which this antifolate is administered being irrelevant. The scope of the patent thus extends to all forms of pharmaceutically acceptable forms of pemetrexed (salt or others) employed in combination with the […] other substances

There is a lot to digest here.

First, although the file history was generally presented as a source of interpretation, it is rated as a secondary, “optional” one.

My take is that file history is duly taken into account when it confirms the interpretation that the court wants to adopt, but it is disregarded when it does not fit the court’s reasoning.

Second, a primary reason for accepting that the patent covers more than pemetrexed disodium is the fact that the description of the patent generally refers to an antifolate drug.

What if the description had been more thoroughly adapted to the amended set of claims during prosecution, and if all generic mentions of the antifolate class had been removed? Would the court have reached a different conclusion, or would it have made it harder for the court to reach this conclusion? If so, this is a red flag for patent attorneys: do not underestimate the importance of this sometimes boring phase of examination proceedings at the EPO, namely the adaptation of the description.

Third, the court draws a clear distinction between two types of amendments made during prosecution: amendments introduced to distinguish the claimed invention from the art and amendments which are not necessary to distinguish the invention from the art.

Only the former type of amendment affects the actual scope of the patent.

Let’s now turn to the assessment of infringement:

Fresenius’ generic drug is composed of the same active substance pemetrexed, and its administration must be combined, as recommended in the EP’508 patent, with vitamin B12 […]. It is therefore irrelevant whether the [incriminated] compound uses a diacid solution so as to enable its administration, since this does not have any specific technical effect. It should be added that it has been admitted that a formulation specialist is able to offer a number of possible counter-ions other than sodium, to form a free acid or a number of well-known pharmaceutically acceptable salts. The selection of the salt form is thus irrelevant. Only the therapeutic effect of the pemetrexed anion combined with the other substances matters. The defendants claimed that it was not obvious to use this particular salt, which ranks 10th among frequently used salts. This is a criterion for the validity of an invention, not for the assessment of infringement. Fresenius obtained patents […] on this form of salt. But all of this is immaterial. 

The variant directed to the use of a different salt is totally incidental. Pemetrexed Fresenius Kabi® is administered according to the use provided in the invention. It is meant to treat the same cancer conditions, with the same technical effect. It was authorized as a generic drug of the originator’s drug. 

Infringement by reproduction is established. 

Since infringement by reproduction is established, in view of the scope of the patent as determined above, infringement by equivalence does not need to be decided upon. 

This latter part is a bit confusing. By “infringement by reproduction” is probably meant “literal infringement“. So the court seems to say that there is literal infringement when the claims are properly interpreted in the light of the description, so that “pemetrexed disodium” is understood to actually mean “pemetrexed“.

On the other hand, the court did cite the French equivalence test (different means, same function, function must be novel) when determining the scope of the patent (see the passages quoted above). This wavering is mostly inconsequential, though.

I personally think it would be much cleaner to consider that there is no literal infringement because the wording of the claims is crystal-clear, but that there may be infringement by equivalence when considering that the claims could have been drafted in a broader manner in view of the inventive concept. That said, literal infringement and infringement by equivalence both mean infringement, and it does not make any difference in terms of outcome or legal consequences.

To finish this post, I would like to go back to the rosuvastatin case commented on this blog a couple of years ago. In this case, the main claim was directed to the active compound rosuvastatin in the form of an acid or a non-toxic pharmaceutically acceptable salt thereof. The alleged infringement was a zinc salt of rosuvastatin. The court decided that there was no infringement because the claim, when properly interpreted in the light of the description, only covered salts in which the cation is an alkaline metal ion, an alkaline earth metal ion or an ammonium ion – and therefore excluded the zinc salt.

Rosuvastatin and pemetrexed are two sides of the same puzzling coin. On the one hand, an embodiment literally covered by the wording of the claims is found to be excluded from the patent’s scope. And on the other hand, an embodiment explicitly excluded from the claims during prosecution is found to still be covered.

I am not questioning that the outcome in both cases might be the right or “fair” one. But frankly, this is a nightmare for legal certainty.

One can also wonder whether the gap between patent prosecution and patent litigation has not become too deep. In front of the patent office, you have to argue based on the claims, the whole claims and nothing but the claims. In front of a French court, you might as well forget about the wording of the claims: it is all about what the description teaches.

CASE REFERENCE: Tribunal judiciaire de Paris, 3ème chambre 3ème section, September 11, 2020, Eli Lilly and Company & Lilly France v. Fresenius Kabi France & Fresenius Kabi Groupe France, RG No. 17/10421.

5 thoughts on “The flip side of the coin”

  1. It happens that I know the file quite well. I will therefore allow myself some comments.

    Up to today it is only the District Court of The Hague who was consequent and took the behaviour of the applicant during examination to refuse a broad interpretation of the claim as has been done in other jurisdictions.

    The original disclosure went on about the combination of any antifolate with vitamin B12. As the only example properly documented in the application, was pemetrexed disodium, the examiner invited the applicant to limit its claims to pemetrexed disodium.

    In reply the applicant claimed pemetrexed in general. The ED raised, in my opinion quite rightly, an objection under Art 123(2) as the only example was that of pemetrexed disodium. Lord Neuberger was in my opinion wrong when he criticised the ED for raising the objection under Art 123(2). The examiner had no choice.

    All along, the applicant was only interested in a quick grant and accepted the limitation. At no time the applicant tried to defend a broader claim, for instance by showing the possibility of using other anions or by filing a divisional in which a broader claim was pursued.

    The examiner required that the description was to be limited to the example disclosed, but the applicant refused and the examiner gave up. This could be considered as a fault, but in view of the attitude of the applicant I have some understanding.

    So you are quite right when you raise the question: “What if the description had been more thoroughly adapted to the amended set of claims during prosecution, and if all generic mentions of the antifolate class had been removed?” The proprietor would have had more difficulty in claiming equivalents he never thought of.

    Indeed, the barely adapted description was the loophole by which the then proprietor attempted to broaden the scope, although this broadening was never envisaged and supported during the original examination. I suspect the applicant did at the time only have data for pemetrexed disodium. If the examiner had insisted upon a proper limitation of pemetrexed disodium in the description we would not be in the situation we are now.

    The problem with this case is reliance on Art 69 and Art 2 of the Protocol on equivalents, especially by Lord Neuberger, which led us to the present situation. A definition of equivalents was proposed by the EPO, but refused by the contracting states during the diplomatic conference.

    All positive decisions for Eli Lilly are an encouragement for slap dash drafting of claims and description. It is enough to put some speculative considerations at the beginning of the description and then to simply disclose one specific embodiment. With some luck, the speculations may turn to be correct. How can a freedom to operate study be carried out when such drafting practices are encouraged?

    If the UKSC wanted to overcome the blunder it made years ago with the Epilady/Improver decision, it should have chosen a different case.

    In my opinion, other courts followed the decision of the UKSC by fear of being left behind. Only the District Court of The Hague had the guts to say no. I hope the decision will be confirmed in appeal.

    I fully agree with you “that file history is duly taken into account when it confirms the interpretation that the court wants to adopt, but it is disregarded when it does not fit the court’s reasoning”. But this is not correct. Although there is no file-wrapper- estoppel in the meaning of the US, the behaviour of an applicant during examination should be taken into account, especially in such cases.

  2. Hi Renaud,
    Two thoughts on this decision and your interesting report.
    The first is that the reasoning of the court could be viewed as amounting to consider that pemetrexed diacid is a technical equivalent of pemetrexed disodium (it seems that all the criteria for doing so are respected) (of course it would have been preferable that the court says so).
    The second is that I am not sure the claim as granted by the EPO would have been considered valid by the French patent office (INPI), since it would likely have been considered as covering a method for treatment.

  3. Thank you for having shared (and commented) this very interesting decision !

    I will try to bring my contribution to your analysis of the decision.

    Even if the decision rules with a literal/by reproduction infringement, the notion of equivalent is not that far. As mentioned in the quotes you made by refering to the construction part of the ruling, the judges heavily relies on Art. 69 EPC and its protocol, and notably art. 2 of the protocol. And the court not only cite “the French equivalence test (different means, same function, function must be novel) when determining the scope of the patent”, as you mentioned, but seems to have indeed applied this test : at least for the criterion of the novelty of the function, which is the most stringent one. the court even checked this criterion by applying it to a combination of means (which is not simplest application of the doctrin of equivalence) : quote of the decision “adding matter during examination proceedings is not a bar to relying on infringement by equivalence, provided that the specifically claimed means or combination of means (here, the combined used of vitamin B12 […] with the active substance) have a novel function (namely the reduction of toxic effects without impairing therapeutic efficacy)”

    In others words, it seems that the court applied a kind of doctrin of equivalence when construing the claim, allowing the court to rule in a “literal/by reproduction” infringement without applying the doctrine of equivalent down the road when analysing the infringement.

    By the way, as for the wording infringement “by reproduction”, one could wonder what is a infrigement by non-reproduction exists…
    This wording is possibly a periphrase (even possibly made by the attorney in its writings) avoiding to use the doctrin of infringement by secondary diffrences (“The Doctrin-Who-Must-Not-Be-Named).

    Further, avoiding to use the doctrin of equivalent at the infringement step of the ruling delivers a powerful message particularly in view of another “interesting/surprising” outcome of the decision :
    The fact that the court denied to recall the infringing products expliclty because of the choice of the patentee not to have file a preliminary injunction (and thus to let the possible infringement last during the time of the proceedings on the merits).
    This is ironic : the patentee is likely to have consider its case as an infringement by equivalent case (as conforted by the other European rulings) and then he probably restrained itself to seek for a preliminary injunction in France (consistently with a Januar 24, 2017 ruling from the previous famous president of the Paris first instance Court, Saint Gobain v/ Knauf, the preliminary injunction has been denied on the principle that infringement by equivalent prevents the grant of the preliminary injunction).

    Finally, considering the provisional damage, it seems that, at least for the pharma case, one could easily get that Paris is now a pro patentee place.
    Right on time with Milan applying for the phamarceutical branch of the central division of the UPC.

Leave a Reply

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.