The team is joined by Guest Kats Rosie Burbidge, Stephen Jones, Mathilde Pavis, and Eibhlin Vardy, and by InternKats Verónica Rodríguez Arguijo, Hayleigh Bosher, Tian Lu and Cecilia Sbrolli.

Wednesday, 27 September 2017

Pemetrexed pops up in Milan

This GuestKat was delighted to get her paws on a recent decision handed down by the Court of Milan which forms part of the long running multi-jurisdictional battle concerning Eli Lilly's patent protecting its pemetrexed (Alimta) product.  She is doing her best to digest this month's decision of Fresenius Kabi Oncology Plc and Ors v Eli Lilly & Company and Ors (N.R.G. 54470/2016) (available on darts-ip) by reference to an automated online translation of the decision, and so asks that readers bear with her. The gist of the Court of Milan's judgment is as follows.  

Background

Magnifico Milano
Fresenius issued proceedings in the Court of Milan in Oct 2016 for precautionary measures (interim relief).  In its application, Fresenius sought a declaration from the Court that Fresenius' generic product - based on pemetrexed diacid (with tromethamine) - did not infringe the Italian designation of Eli Lilly's patent EP 1313508, which specifies pemetrexed disodium in the claims. By way of reminder, pemetrexed is an oncology treatment, the damaging side-effects of which can be mitigated if given together with vitamin B12.  The applicant argued inter alia that:
  1. the claims of EP '508 are limited to only pemetrexed disodium, because of the unambiguous wording of the claims; 
  2. infringement on the basis of equivalents was excluded in this case, because the file history of EP '508 showed that the patentee had limited the scope of protection to the salt pemetrexed disodium; 
  3. use of pemetrexed diacid (with tromethamine) was not suggested even implicitly in EP '508.  
Eli Lilly counterclaimed, seeking an injunction on the basis of direct and indirect infringement of its patent.

Court of Milan's analysis and decision

The Court examined the EPO file history in detail.  In the text of the original patent application, the claims extended to the entire class of antifolates.  It was subsequently limited by the patentee to 'pemetrexed', and finally to 'pemetrexed disodium'.  These changes to the claims were consistent with changes to the EP '508 description.  The Court noted that these changes were a 'clear delineation of patent protection', for only pemetrexed disodium.  Other compounds, such as pemetrexed diacid were therefore excluded from the scope of the EP '508 claims.  Further, while Fresenius' product has the same therapeutic effect as Alimta, the association of pemetrexed disodium associated with tromethamine could not also be considered an obvious substitution of the expression pemetrexed disodium in combination with vitamin B12.   Any form of direct infringement, including on the basis of equivalents was excluded.  Further, there was no indirect infringement - the SmPC of the generic product indicated that reconstitution and dilution would happen in a glucose solution, rather than a saline solution as specified in the claims of EP '508.

Consideration of UK decision 

Eli Lilly drew the recent decision of the UK Supreme Court in Eli Lilly v Actavis to the Court of Milan's attention.  The UK judgment considered whether the Actavis generic pemetrexed products, which used (a) pemetrexed diacid, (b) pemetrexed ditromethamine, or (c) pemetrexed dipotassium, directly infringed the UK, Italian, Spanish or French designations of the patent claims, which specify pemetrexed disodium. 

Arnold J. had found at first instance in the UK proceedings that under Italian law "the patent clearly demonstrated a conscious intention of the patentee to limit the claims to pemetrexed disodium” and that this was "amply confirmed by the prosecution history". However, both these conclusions were rejected by the Supreme Court which found direct infringement of the Italian designation of the patent by the Actavis variants.  The Court of Milan noted that it was not bound by the UK Supreme Court decision in relation to the Italian designation, because those proceedings concerned different parties, and the generic products in the UK proceedings were not identical in their excipients, ratios, and licensed indications to Fresenius' product. (For anyone in need of a quick recap, Stephen's series of posts on the UK Supreme Court decision can be found here (equivalence), here (EPO file history) and here (consideration of French, Italian and Spanish designations)).   

Although the facts of the Italian and UK cases differ in certain respects, the Court of Milan judgment is an interesting juxtaposition against the UK Supreme Court decision.   Should a doctrine of equivalents go hand in hand with some form of file wrapper estoppel?  Any insights (particularly from Italian patent enthusiasts) are welcome. 


28 comments:

Proof of the pudding said...

Whilst the Court of Milan has tried to "finesse" the issue, there is no doubt that they have reached a decision that directly contradicts that of the UK Supreme Court.

The UK SC found that Actavis' product containing pemetrexed ditromethamine directly infringed the Italian designation of Lilly's patent. The Court of Milan has now concluded that a product containing the same active ingredient does not infringe that designation.

Despite the half-hearted attempt to apply a fig-leaf by pointing to insubstantial differences, it is clear that not only the decision but also the Court's reasoning is irreconcilable with that of the UK SC. It will be interesting to see where we go from here!

Amenda said...

Nice Article.

Kant said...

As a non-chemist, could I ask if someone could indicate if tromethamine has any similarity to vitamin B12?

Eibhlin Vardy said...

Dear Kant - tromethamine is the salt, but vitamin B12 would also be administered during treatment with the Fresenius pemetrexed product.

Proof of the pudding said...

@Kant
"tromethamine" is an amine otherwise known as "Tris". Mixing pemetrexed diacid and tromethamine together in the correct ratio will produce the 1:2 salt (pemetrexed ditromethamine), which was an active ingredient for one of the products under consideration in the UK case.

Anonymous said...

The fact that the products and the parties were different is the reason why the Judge could depart from the outcome of the UK Supreme Court proceedings.
It seems to me that the most convincing and interesting part of the decision is the reasoning about file history wrappel. Why the patent should protect something which - if included in the patent - would have made the claim invalid pursuant to Article 123(2) EPC? To my knowledge the decision appears also consistent with previous decisions of the Courts of Milan and Turin which denied infringement by equivalents in case of limitation of the claims of the patent during the examination procedure.

Anonymous said...

Let's face facts. The Italian court has made the correct decision. Looks like it was simple all along. Lucky for us the UK Supreme Court will be the final port of call for all UK legal decisions in the future, because they were clearly on the ball with this one.

Anonymous said...

In Italian, the name of almost all cities are feminine, so the caption of the photograph should read "Magnifica Milano".

Jean Aymar said...

If I understand well, the Milan Court has denied equivalence by taking into account the prosecution history, while the UK Supreme Court has only considered the wording of the claims in the light of the description.
Maybe this is not so surprising.
In 2012 the AIPPI has studied "The use of prosecution history in post-grant patent proceedings"(Q229)- see the final report at: https://aippi.org/download/commitees/229/SR229English.pdf
It seems that UK Courts are quite unwilling to take into account the prosecution history while assessing infringement, which is not the case of Italian ones. This might explain the different issue of the two cases.

MaxDrei said...

Jean Aymar, what an interesting comment. The EPO file wrapper exposes the drafting slip.

As I suggested in comments on the English Decision, this is a case about how much rope to cut the owner of a patent founded on a less than perfectly drafted patent application.

Who suffers, when the drafting slip is exposed in litigation? Italy deems it to be the owner of the patent. conversely, Lord Neuberger has decided it's the public that shall suffer.

Historically, England was out of line, in setting high drafting standards. That was because patent expert judges sat in judgement on patent expert patent drafting attorneys.In today's world though, life's too short to demand such high levels of professional competence. After all, we're all human. We all Maske mistakes don't we.

Mark Schweizer said...

"Pemetrexed" will be the "Epilady" of the 21st century...

The Swiss Federal Patent Court, similar to the Court of Milano, considered the prosecution history and denied infringement by equivalent means because of the limitation introduced by the patentee during the examination, see https://www.bundespatentgericht.ch/fileadmin/entscheide/O2015_004_Urteil_2017-03-09.pdf

An appeal against the decision is pending before the Swiss Federal Supreme Court.

The German Bundesgerichtshof also took the prosecution history into account, but came to a more nuanced conclusion: equivalent infringement by means excluded by the limitation is not possible if the limitation was introduced to distinguish the claimed subject matter from the prior art. Equivalent infringement is, however, not excluded if the limitation was introduced (or took the form it has) for "formal reasons" (e.g., clarity or EPC 123(2), see para. 68 of http://juris.bundesgerichtshof.de/cgi-bin/rechtsprechung/document.py?Gericht=bgh&Art=en&Datum=Aktuell&Sort=12288&Seite=5&nr=75370&pos=165&anz=599

Anonymous said...

@Mark Schweizer EPA here. Imagine a common scenario in which claim 1 lacks novelty over D1, with claim 2 being novel and inventive. Should all EPAs write their letters like below?

"The applicant submits that claim 1 is novel. However, to address the examiner's clarity issues, claim 1 has been amended to include the features of claim 2".

When I write to the EPO, I don't want to have to write boilerplate rubbish (which seemed persuasive on the UK Supreme Court). Neither do I want to have to pretend I'm amending for clarity reasons when I am not.

Anonymous said...

and the anonymous comment at 13:31 is exactly why patent claims should always be construed literally. Patent attorneys are very adept at playing with the rules and the words, which the Supreme Court judges didn't get, so their patent claims should be construed as written.

Attentive Observer said...

A patent is granted not for the drafting skills of the patent attorney, but for the contribution to the art. That at the beginning of the description, or at the end of it, there are standard gobbledygook sentences attempting to go further than what was actually invented and generalise it, should not be taken later to the benefit of the patentee.

The only mistake the EPO examiner did was not to request the strict limitation to permetrexed disodium, which was the only example to be found in the description. After all, cf. Art 84, the claims should be commensurate with the description and vice versa.

On the the face of the actual content of its application Eli Lilly's contribution to the art was limited to permetrexed disodium and that's it.

There is no file wrapper estopel in Europe, but the way the applicant and later patent owner behaved during examination should be taken into account.

The decision of the Milan court shows perfectly how wrong the UKSC was. It is not because the UKSC made a mistake in the Improver-Epilady case, that it had to compensate it by making a new mistake in the Permetrexed case.

This is worse, when one sees that the UKSC further considered that there was also infringement in Italy. The Milan Court showed what it thought of Lord Neuberger's opinion. That the UKSC is entitled to decide for UK is not disputed, but it should have refrained on deciding for other courts. That the parties are different is one thing, but the discussion on substance was the same.

MaxDrei said...

I feel obliged to reply to the comment of earlier today, from the Attentive Observer.

Both parties asked the court in England to give its opinion on infringement in Italy. Is the court supposed to say it cannot even have an opinion, even after a full briefing from both sides, what the law in Italy is?

And anyway, the court cannot enforce the patent right in Italy, can it? Enforcement is up to the courts in Italy, isn't it?

As to "contribution to the art", the application as filed presents it a use of antifolate. That was too wide. The Applicant's fall back position, claim 9 in the WO, was to use ALIMTA, Lilly's proprietary disodium pemetrexed. The debate is about what would have happened, had the WO contained a dependent claim to pemetrexed (with its salts). Would the EPO have allowed that claim and, if so, would it have survived post-grant attack on its validity?

For is there any doubt, that the skilled reader of the WO, using a mind willing to understand it, would have grasped that the "contribution" included using a pemetrexed antifolate.

Incidentally, I am distressed that my comment from yesterday evening never made it to publication, the one about how different patent drafting practice is, as between the USA (where this case was drafted) and the rest of the world. European practice is the onion layer style, with as many intermediate levels of Generalisation as can be conceived. American style is the "diamond in a balloon" model. Claim 1 impossibly wide. Then nothing till the illustrated embodiment, the worked example, or the best mode, and no supported stand taken, on enhanced patentability at an intermediate level of generality. I see this case as a Poster Child for debate about the two different drafting styles.

Mind you, this case was drafted at least 17 years ago. Perhaps times have changed.

But in that case, this case serves to show, that drafters have to produce what the courts will be looking for, 17 years later than when they write their stuff.

Attentive observer said...

Dear Max Drei,

I did not realise that the parties had required the UKSC to give its view on what was going on in Italy. So please forget this comment and accept my apologies on this point.

As the decision cannot be enforced in Italy, to what avail did the parties ask the UKSC? Trying to influence the courts in other countries? Why should a court play this game? Because it thinks it is big enough? It is a fact, that courts are very keen on their independence, and do not like to be told what to do. And we have seen what the Milan Court decided. They were apparently not impressed with what the UKSC came up with.

The attitude of the Milan Court with respect to file history, reinforce my view that Lord Neuberger should not have attacked the examiner when requesting a limitation. In view of the EPO practice, this limitation was fully justified.

If I can agree on the above point, I cannot agree on the second point. The actual contribution to the art was not using a permetrexed antifolate, but a very specific one: permetrexed disodium, administered in combination with vitamin B12.

The extremely broad claim filed in the US (even ignoring the fact that it was for a method of treatment) had no chance to be granted in Europe due to a clear lack of "substance". It might be interesting to see what was said in the ISR:

https://register.epo.org/application?documentId=EFSTQMY4DHEPLEI&number=EP01948214&lng=en&npl=false

It was the applicant’s duty at the time to show that the teaching was more general, for example by filing experimental data/examples showing that it had indeed a more general concept at hand and could be applied to various kinds of permetrexed antifolates, and not only to the one claimed.

Even if he could not add those further data/examples in his application, the patent could have been published with the mention STIN (Supplementary Technical Information, Guidelines H-V, 2.3).

With at least two examples of different permetrexed salts, the applicant/proprietor could have justified a broader claim with dependent claims relating to specific salts. But it never even attempted to do so. So your question about the kind of claim which would have been needed has received a reply. It might not be what you would like to hear, but this is how it would work at the EPO.

I do however agree again when it comes to drafting. There are clear differences in drafting between Europe and the US, and any attempt to have one size fits all has never been successful. I think it is due to the different way of examining, legal philosophy, and the way the courts look at things on each side of the Atlantic.

I doubt very much the situation has improved in the last 17 years. This is why there are difficulties, especially when it comes to added matter with applications originating in the US.

MaxDrei said...

Dear Attentive Observer, in reply, I have just two points.

Litigation is a last resort, when negotiation has not succeeded. But negotiations continue. Classically, the parties settle in Germany after the LG Decision, before going to appeal. Could it be then, that the parties asked the UK court for its view on other countries in Europe, as a way to stimulate negotiation of a settlement to their dispute? Why look for more complicated explanations, when the easiest one is available?

Second, alas we shall never know how the case would have fared at the EPO regional phase, if the WO had included a claim, wherein the antifolate is pemetrexed or a salt thereof. Would one example, disodium, of that specific and precisely claimed subject matter, that solution to the problem, have been "enough"? I'm not a chemist. What say European patent attorney readers, those who prosecute pharma cases at the EPO?

THE US anon said...

From this outsider's viewpoint, it seems LESS odd that one (or both) of the parties may ASK.

It seems more odd that any reputable court would entertain ANSWERING, given that any such answer could not possibly be binding in that other sovereign (could it?)

Anonymous said...

A claim to pemetrexed in any salt (or free acid) form would have been granted in Europe had here been basis for such a claim and would have survived litigation. The active substance is the pemetrexed ion and the claim is directed to a therapeutic benefit that would have been met by any pemetrexed derivative.

The Lilly patent attorney prosecuting the case should have fought harder for a broader claim. ALIMTA may be considered as supporting only the sodium salt, but an argument that the skilled person would have understood the invention to not be so limited could have been taken further, and through appeal.

I suspect the UK patent office and the German patent office would have allowed such a broader claim, which is why certain national filings should also be considered alongside the EP filing for important pharmaceutical patent cases.

Anonymous said...

The answer to the right of the UK Court to decide on infringement in Italy may be found in the Brussels Regulation.

Jean Aymar said...

@MaxDrei & Abtentive Observer

According to Council Regulation (EC) No 44/2001 there is no exclusive jurisdiction for patent infringement cases. Therefore, it is perfectly possible that the UKSC had jurisdiction for infringement in Italy, and in this case its decision will be binding for Italian Courts. On the contrary, the UKSC cannot decide about the validity of a foreign patent (or a foreign part of an European Patent), because Art. 22 of the Regulation gives exclusive jurisdiction to the Courts of the country of the patent.

Attentive observer said...

I thank the various commenters for their input.

Litigation is always a last resort, and any means to come to an out of court settlement is preferable to a long and tedious legal battle. I understand thus the reason for such a request.

If it is true that according to Council Regulation (EC) No 44/2001 there is no exclusive jurisdiction for patent infringement cases, then why do we need a UPC?

As far as validity is concerned, it could be decided by the EPO, provided the opposition period would not be limited to 9 months post grant. As the proprietor may limit its patent during the whole life of it, why should third parties bothered by a patent be limited to a relatively short period?

This arrangement would also avoid any clash between decisions on validity between the UPC and the Boards of appeal of the EPO. This is to me one of the potential drawbacks of the UPC.

the UPC will not be the only court dealing with infringement/validity in Europe. The EPC has more member states than the UPC, and their courts should not be belittled. There is no mechanism to resolve such conflicts, and claiming like Mr Arnold at the UPC conference in July in Munich, that the UPC will be the leading court in Europe is quite daring. The UPC will not be the only court dealing with infringement/validity in Europe as the EPC has more member states than the UPC, and their courts should not be belittled.

In Milan the parties and the case were not the same, so there was no res judicata. But deep down the problems were the same as in the UK.

If the applicant had made an effort in fighting for a mere general claim, then we would not have ended in the present situation. I can agree that a more general claim would probably have been possible, not as broad as originally, but limited to permetrexed ions and with at least one or two different examples, or the proof that it works for other ones than the one specifically disclosed.

Jean Aymar said...

@ Abtentive observer

Why do we need the UPC? Because of nullity counterclaims/defenses

Everything is well explained here: http://patentmyfrench.com/borderline/

MaxDrei said...

Attentive, you ask why the EPO cannot do the validity side of the litigation.

Of course it can. The Dutch courts used to ask the EPO for an opinion on validity.

The problem is though, that judges think they can do it better. In particular, they think they do obviousness properly. The "no nonsense" Problem/Solution Approach by DG3 is not for them. They like lots of nonsense.

And then there's bifurcation. Can't have one forum construing the claim for validity and another for infringement, can we now? Or perhaps we can, eh?

And then there's the independence issue. Never used to be a problem. But then the EPO President went on a crusade to shut down DG3 and, suddenly, it seems that DG3 is no longer independent.

What irony, when you imagine that Le President's shut-down of DG3 was all done in order to give the UPC in Paris a flying start.

MaxDrei said...

I have a question for the kind commenter who told me (above) over the weekend that a claim to pemetrexed would have got past not only the EPO but also the national courts, and should have been put forward and driven home by the Lilly attorney prosecuting the application at the EPO.

BUT: When prosecuting at the EPO, it can be seen as risky indeed, to put forward the claim you want, and then see it rejected, first by the ED and then by DG3. I often suggest to clients that to try for their wished-for amendment, and fail, might be worse (when it comes to acting against infringers) than not to have tried at all. In particular, the scope of "infringement by equivalent" is often likely to be broader with a clean EPO prosecution record, than one in which Applicant tried and failed to get the claim that matters.

Perhaps cases like this will help Big Corp to realise that, in a First to File world, it makes sense to invest in quality drafting.

Meanwhile, this litigation demonstrates (yet again) how much easier everything is, with the benefit of hindsight.

Attentive observer said...

I can only support Max Drei's view that it makes sense to invest in quality drafting.

It is especially important for files originating from the US to have a high quality drafting. This is especially valid when such a US application serves as priority filing.

Often problems arise due to a very sloppy drafting of the original application. But once filed it is too late. You might improve the second filing, but then you say good by to the priority. What is worse? The problem is that it is difficult to quantify what can be quality drafting, and anything not quantifiable is not worth bothering about in lots of circles.

The legal world is different on both sides of the Atlantic, and while I have sympathy for the fear to owe something in Europe which could be detrimental in the US, but the rule of the game is different in Europe and in the US, and what might be possible in the US is not possible here. The usual comment coming from US applicants: we got this here, so we want it at yours, is not very useful, and even contra-productive.

I know bifurcation is only practised in Germany, but it works. Should the patent be of bad quality, due to more pertinent prior art coming to surface after grant, it is worth waiting to decide upon infringement until validity is settled.

Validity could be settled quickly, even at the appeal stage at the EPO, provided resources are made available. But this is not the agenda of the chap sitting on the 10th floor in the Isar building.

There again, with a properly drafted application and a good examination, one could consider that a EP is a patent with a high presumption of validity, but this is alas not any longer the case at the present EPO. But quality lying in timeliness is increasing says the same chap.....

THE US anon said...

Ao,

"The usual comment coming from US applicants: we got this here, so we want it at yours, is not very useful, and even contra-productive."

Likewise, in the opposite direction with Euro comments being contr-productive with US matters - especially the same when it comes to patent law discussions (along the lines of certain Euro-types that think that US law should be just like Euro law.

Attentive observer said...

To US anon,

You certainly have extremists on both sides of the Atlantic, but let's be honest, the larger number is sitting on the US side.

How often do European representatives utter a sigh of anxiety when they receive instructions from the US counter-part and are not allowed to even change a iota, even if they know very well that it will never go through?

The question of two part form claims is not so much the problem, the problem is more with added subject-matter, and the wish to file affidavits and declarations, for instance from the inventor, stating that the invention is the 7th world marvel. Trees have to suffer for it, and to no avail.

Continuations and continuations in part are a US ways of dealing with some problems, but are totally useless over here.

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