A saga with twists

As promised last week, here is another episode of the ezetimibe SPC saga. Just like last week, Lionel Vial reports on the latest twists.

After having applied, on the basis of European patent EP0720599 (EP’599), for a first French SPC for ezetimibe alone (FR03C0028), then for a second one for ezetimibe in combination with simvastatin (FR05C0040), Merck Sharp & Dohme Corp. (Merck) has sought to secure a third one for ezetimibe in combination with atorvastatin (FR14C0068) corresponding to the medicinal product Liptruzet®.

However, if the first two SPC applications were granted by the INPI (French patent office), the third application was met with a decision for refusal that Merck appealed.

It is the appeal decision, rendered on January 22, 2019, that we will discuss today.

The 1960s, a decade of many twists – now, that’s a far-fetched one.

As a reminder from our previous post, EP’599 specifically claims ezetimibe in claim 8 and a pharmaceutical composition for the treatment or prevention of atherosclerosis, or for the reduction of plasma cholesterol levels, comprising an effective amount of ezetimibe, alone or in combination with a cholesterol biosynthesis inhibitor selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin, CI-981, DMP-565, L-659,699, squalestatin 1 and NB598, in a pharmaceutical acceptable carrier (claim 17).

Cl-981 is atorvastatin, a statin (i.e. an inhibitor of cholesterol biosynthesis) that was known before the filing date of the patent. The patent discloses results of biological tests obtained for ezetimibe alone (compound 6a in the last table of the example section of the patent) but does not disclose experimental results specifically obtained for a combination of ezetimibe and atorvastatin.

SPC application No. FR14C0068 was filed for ezetimibe in combination with atorvastatin or the pharmaceutical acceptable salts thereof, including the calcium salt of atorvastatin.

The INPI rejected the application on February 6, 2018 for lack of compliance with article 3(c) of Regulation (EC) No. 469/2009 (“the SPC regulation”) which provides that a certificate shall be granted if, at the date of the application for an SPC, “the product has not already been the subject of a certificate“.

The INPI mainly based its rejection on the previously granted SPC of ezetimibe alone (FR03C0028) and on the decision of the Court of Justice of the European Union (CJEU) in case C-443/12 (Actavis v. Sanofi, Irbesartan):

Where, on the basis of a patent protecting an innovative active ingredient and a marketing authorisation for a medicinal product containing that ingredient as the single active ingredient, the holder of that patent has already obtained a supplementary protection certificate for that active ingredient entitling him to oppose the use of that active ingredient, either alone or in combination with other active ingredients, Article 3(c) of [the SPC Regulation] must be interpreted as precluding that patent holder from obtaining – on the basis of that same patent but a subsequent marketing authorisation for a different medicinal product containing that active ingredient in conjunction with another active ingredient which is not protected as such by the patent – a second supplementary protection certificate relating to that combination of active ingredients.

Subsidiarily, the INPI considered that even if the combination of ezetimibe with an HMG-coA reductase (i.e. a statin) could be considered to constitute a different innovation from ezetimibe alone, which the INPI denied, then SPC No. 05C0040 (for ezetimibe in combination with simvastatin) would be opposable to the grant of a new SPC.

Merck lodged an appeal against the decision of rejection before the Paris Cour d’appel on May 4, 2018.

During the proceedings, the INPI came to agree with the appellant that the combination of ezetimibe and atorvastatin complied with the requirements of article 3(a) of the SPC.

The only question that the Cour d’appel had to answer was therefore whether the combination of ezetimibe with atorvastatin is a different product from ezetimibe alone or from the combination of ezetimibe and simvastatin.

Let’s see what the Cour d’appel decided:

The combination of the statin atorvastatin with ezetimibe must constitute a product – within the meaning of the regulation – different from the combination of the simvastatin statin with ezetimibe, subject of SPC No. 05C0040, in order for the condition of article 3(c) of the regulation to be fulfilled.

However, claim 17 of the patent gives a list of the different statins with which ezetimibe can be combined indifferently and without distinguishing them, and the combination of ezetimibe with a statin as provided by [claim] 17 has already been the subject of SPC No. 05C0040 granted for the combination of ezetimibe and simvastatin; it is not justified within the terms of the patent that the result of the combination of ezetimibe with atorvastatin constitutes a different product from the combination of ezetimibe with simvastatin.

The 599 patent relates to “hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents in the treatment and prevention of atherosclerosis, and to the combination of a hydroxy-substituted azetidinone of this invention and a cholesterol biosynthesis inhibitor for the treatment and prevention of atherosclerosis” and SPC No. 05C0040 has been granted for the combination of ezetimibe with a cholesterol biosynthesis inhibitor, simvastatin, so that the combination of ezetimibe with another statin, atorvastatin, which is not protected as such by the patent, cannot justify the grant of anew SPC.

The condition of article 3(c) being unfulfilled because of SPC No. 05C0040 “ezetimibe in combination with simvastatin” the appeal of MSD against the decision dated February 5, 2018 of the Director of the INPI will be rejected.

To summarize, the Cour d’appel has decided that the EP’599 basis patent protected as such two different products: (i) ezetimibe and (ii) ezetimibe in combination with a statin.

Besides, the Cour d’Appel has also decided that the various particular statins cited in claim 17 were not protected as such, so that the combination of ezetimibe with atorvastatin could not be distinguished from the combination of ezetimibe with simvastatin, both of them being variations of the same product “ezetimibe in combination with a statin”. Therefore, the combination of ezetimibe with a statin, in particular atorvastatin was already the subject of an SPC (FR05C0040 for a combination of ezetimibe with a statin, in particular simvastatin).

In deciding so, and in relation to the preliminary injunction previously discussed based on SPC FR05C0040 (covering the drug Inegy®), it could be hypothesized that the Cour d’appel has acknowledged that the product ezetimibe in combination with simvastatin is protected as such by the EP’599 patent and is different from the product ezetimibe. However, this would be a dramatic change over the previous decision of the Cour d’appel regarding this SPC (discussed here).

Let’s take this occasion to try to summarize the ezetimibe saga so far:

Product SPC Drug Generic company Decision type Date Result
Ezetimibe + simvastatin FR05C0040 Inegy® Biogaran Appeal following preliminary injunction (CA Paris) 2018/06/26 Preliminary injunction denied (SPC likely invalid)
Ezetimibe + simvastatin FR05C0040 Inegy® TEVA Judgement (TGI Paris) 2018/10/25 SPC valid
Ezetimibe + atorvastatin FR14C0068 Liptruzet® Appeal (CA Paris) 2019/01/22 SPC rejected
Ezetimibe + simvastatin FR05C0040 Inegy® Mylan Preliminary injunction (TGI Paris) 2019/03/07 Preliminary injunction granted (SPC likely valid)

Needless to say, we are eagerly awaiting the next decisions of the Cour d’appel to see more clearly which direction the French case law is taking in matters of combination SPCs.

Many thanks as always Lionel for the thorough summary. This truly is a murky subject.

Lionel’s working hypothesis on the decision is that the court may have acknowledged that the product ezetimibe in combination with simvastatin is different from the product ezetimibe. But this is really a matter of interpretation of the ruling. In my view the ruling states that the product ezetimibe in combination with atorvastatin is the same as the product ezetimibe in combination with simvastatin but does not take a clear position on the product ezetimibe in combination with (any) statin compared with the product ezetimibe alone.

The thing is, during the court proceedings, the INPI simply relied on the existence of the prior combo SPC FR05C0040 and not (i.e. no longer) on the existence of the mono SPC FR03C0028 as a reason for objecting to the second combo SPC. Thus, the court did not have to rule on the comparison with the mono SPC.

Also, it can be noted that the January 22 ruling was issued by exactly the same panel as the one that held that the first combo SPC was likely invalid last June.

It is certainly possible that these judges may have changed their minds in this respect since then but to me the second ruling is inconclusive in this respect.

To be continued, definitely.


CASE REFERENCE: Cour d’appel de Paris, pôle 5 chambre 1, January 22, 2019, Merck Sharp & Dohme Corp. v. Directeur Général de l’INPI, RG No. 18/10532

The new normal

What the heck is going on with preliminary injunctions (PIs) in France right now?

Let’s face it, France is not particularly renowned for its patentee-friendliness. But different winds seem to be blowing these days over the Batignolles. Is this mere happenstance? Could it have anything to do with recent judicial appointments? Is there a feeling among our judges that the pendulum should swing back a little bit towards IP right holders? Or has there been a change in the behavior of third parties?

Preliminary injunctions in France: the new normal?

Hard to tell of course, so readers will have to make their own opinion based on a report kindly provided by Lionel Vial on a PI issued just a few days ago. I will now leave him the floor.

There has been a second high-penalty preliminary injunction in a row in the pharma field that we will comment on today after Renaud’s post on darunavir.

The drug at stake is a combination of ezetimibe and simvastatin (Inegy®, MSD France) which is prescribed for reducing cholesterol levels. Ezetimibe reduces intestinal absorption of cholesterol while simvastatin is a HMG-CoA reductase inhibitor (i.e. a statin) which inhibits cholesterol biosynthesis.

The case opposes Mylan, which has been marketing a generic version of the combination since April 18, 2018, and Merck (Merck Sharp & Dohme Corp. & MSD France) before the Paris Tribunal de Grande Instance (TGI).

Merck Sharp & Dohme Corp. holds French Supplementary Protection Certificate (SPC) FR05C0040, of which MSD France is a licensee. The SPC is based on European patent EP0720599 (EP’599) for the product “ezetimibe optionally in the form of its pharmaceutical acceptable salts in combination with simvastatin” and is set to expire on April 2, 2019.

EP’599 specifically claims ezetimibe in claim 8 and a pharmaceutical composition for the treatment or prevention of atherosclerosis, or for the reduction of plasma cholesterol levels, comprising an effective amount of ezetimibe, alone or in combination with a cholesterol biosynthesis inhibitor selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin, CI-981, DMP-565, L-659,699, squalestatin 1 and NB598, in a pharmaceutical acceptable carrier (claim 17).

On October 17, 2017, Mylan started nullity proceedings against the SPC, to which Merck responded by requesting, on November 30, 2018, that a preliminary injunction to stop selling the ezetimibe/simvastatin combination and to pay provisional damages be issued against Mylan.

Mylan countered that the SPC was invalid because:

    • It was granted for a combination which is not protected as such by the basic patent, in breach of Article 3(a) of the SPC regulation (No. 469/2009), since it would not form the core inventive advance of the patent, which is centered on ezetimibe, in particular in the absence of any research conducted on the ezetimibe/simvastatin combination.
    • The product protected by the basic patent had already been the subject of a certificate (i.e. SPC FR03C0028 granted for ezetimibe) in breach of Article 3(c) of the SPC regulation.

However, principally applying C-121/17 (Teva UK Ltd. et al. vs. Gilead Sciences Inc.), the judge in charge of case management (JME) decided on March 7, 2019 that:

The Court of Justice of the European Union thus considers that a product which is a combination of active ingredients is “protected by a patent in force” where, even if the combination of active ingredients of which that product is composed is not expressly mentioned in the claims of the basic patent, those claims relate necessarily and specifically to that combination. The product must, from the point of view of a person skilled in the art and in the light of the description and drawings of the basic patent, necessarily fall under the invention covered by that patent and each active ingredient must be specifically identifiable.

As such, a product which is a combination of active ingredients pursuant to the first article of regulation (EC) No. 469/2009, necessarily relates to the invention covered by the patent if each of these ingredients is specifically identifiable according to the claims of the patent, without it being necessary that the second active ingredient of the combination be a new compound taught by the patent and protectable on that basis.

In this regard, in view of the GILEAD decision, the Court of Justice of the European Union does not require that the active ingredients, the combination of which is intended, should be an invention of the basic patent, provided [these ingredients] are identifiable. [The Court] only holds that the combination must necessarily relate to the invention covered by that patent.

This thus applies to a novel composition relating at least to an active ingredient taught by the patent.

[…]

Claim 17 of the patent claims a pharmaceutical composition according to claim 16 (which relates to the pharmaceutical composition according to any of claims 9, 12 or 15 wherein the cholesterol biosynthesis inhibitor is selected from the group consisting of HMG CoA reductase inhibitors), wherein the cholesterol biosynthesis inhibitor is selected from a group to which simvastatin belongs.

The association ezetimibe/simvastatin, which is thus taught, therefore necessarily relates to the invention deriving from the basic patent, simvastatin being specifically identified by the patent.

The product sold under the trademark INEGY®, which is a combination of the active ingredients ezetimibe and simvastatin, therefore appears to be “protected by a basic patent in force”, pursuant to article 3(a) of regulation (EC) No. 469/2009.

It is reminded that pursuant to article 3(c) of this regulation, the SPC can only be granted if the product has not already been the subject of a previous SPC.

The condition provided by article 3(c) of regulation (EC) No. 469/2009 therefore also appears to be fulfilled.

As such, the arguments put forward by MYLAN to demonstrate that there is a doubt as to the validity of SPC No. 05C0040 appear to be lacking seriousness, this SPC obviously fulfilling the requirements of article 3 of regulation (EC) No. 469/2009. It can neither be seriously argued against the sufficiency of disclosure nor against the inventive step, since these conditions are not envisioned by article 3 of the regulation for obtaining a SPC, due note being taken that the disclosure of the ezetimibe/simvastatin combination allows the one skilled in the art to easily reproduce it, while this combination was not known at the filing date of the basic patent.

It follows that by marketing, since April 18, 2018, the generics “EZETIMIBE/SIMVASTATIN MYLAN” comprising a combination of ezetimibe and simvastatin, in violation of SPC No. 05C0040 granting the market exclusivity of this combination to MSD, MYLAN likely infringed.

Too bad for what appears to have been a test by Mylan of the application in France of Justice Arnold’s proposal that, in order to be granted an SPC, a product must infringe the basic patent because it contains an active ingredient, or a combination of active ingredients, which embodies the inventive advance (or technical contribution) of the basic patent.

It is also very surprising that there has been a complete change of appreciation of the validity of this SPC, since on April 5, 2018 the judge in charge of urgency proceedings refused to issue a preliminary injunction against Biogaran on the basis of the same SPC because the latter was considered likely invalid, which was confirmed on appeal on June 26, 2018 (see Renaud’s post on the subject here). But then, C-121/17 (July 25, 2018) had not been issued yet and the Cour d’appel mostly relied on C-443/12 (Actavis Group PTC EHF & Actavis UK Ltd v. Sanofi).

However, perhaps the interpretation of the evolving case law of the CJEU by French judges is not the most notable part of this decision.

Indeed, the following substantial damages were awarded:

    • 2,901,779 euros to MSD France
    • 1,460,889 euros to Merck Sharp & Dohme Corp.

As a reminder, in the darunavir case (GD Searle LLC et al. v. SAS Sandoz) the judge in charge of urgency proceedings ordered on January 11, 2019 a preliminary injunction against Sandoz, under a 50,000 euro-penalty per violation of the injunction (Renaud’s post on the subject).

Before that, on June 7, 2018, the judge in charge of case management awarded 5,846,628 euros to Novartis Pharma AG and 7,308,285 euros to Novartis Pharma SAS as provisional damages in the valsartan/amlodipine patent infringement case (see here for a report).

Besides, a preliminary injunction was also recently issued on July 6, 2018 against a potential infringer in a chemistry case, but without provisional damages (see here for a report by Renaud).

Therefore, we may be currently observing a new trend setting in that could make France a very attractive forum for preliminary injunctions, in particular in the pharma field.

An open question is whether this trend could weigh in favor of Paris in relation to the still undecided relocation of the London UPC central division, which is in particular competent for pharmaceuticals.

Out of luck for the time being (the decision on the merits is yet to come) with the ezetimibe/simvastatin combination, maybe Mylan could consider a combination of ezetimibe with atorvastatin, since a recent decision from the Paris Cour d’appel rendered on January 22, 2019 has upheld the decision of the Director of the INPI (French Patent Office) to reject French SPC application No. 14C0068 for “ezetimibe in combination with atorvastatin or pharmaceutically acceptable salts thereof, including the calcium salt of atorvastatin”. But that will be our next post on Patent My French, so stay tuned for more on SPCs!

As always I would like to thank Lionel for this thorough report. The story does indeed need to continue with this appeal ruling of January 22, 2019, which in my view is closely connected to today’s decision – and (spoiler alert) there is a new twist in the saga.


CASE REFERENCE: Tribunal de grande instance de Paris, 3ème chambre 1ère section, ordonnance du juge de la mise en état, October 17, 2017, Mylan v. Merck Sharp & Dohme Corp. & MSD France, RG No. 17/14664.

Red tape on a dyesheet

Let’s start with the dyesheet first – the red tape part of the title will become self-explanatory only at the end of this post I am afraid.

European patent No. EP 2035233 is co-owned by a French company, Evolis SA, and a U.S. company, Illinois Tool Works Inc. The patent is entitled Thermal Transfer Dyesheet and Method of Manufacture. The corresponding Korean patent was asserted against a local competitor, Digital Printing Solution. This action was dismissed by the Korean court in April 2016.

In the meantime, in November 2015, the Korean company presented some of its products in an international trade show in Villepinte – just one stop before CDG airport, for those familiar with RER line B… The patent proprietors obtained a court order so as to perform an infringement seizure at the professional fair. A few weeks later, they filed their complaint for infringement of the EP’233 patent.

Today, I will skip the validity part of the judgment on the merits issued by the Paris Tribunal de grande instance (TGI). Suffice it to say that the defendant’s nullity objections were rejected.

The infringement part of the judgment, on the other hand, contains a couple of interesting points.

First, the defendant challenged the validity of the infringement seizure report.

For the most part, this challenge failed, except on one aspect. As a reminder, the report is drafted by a bailiff who investigates on behalf of the patent proprietors, according to the court order which precisely sets out his or her mission and the limits thereof.

During the seizure, it turned out that the bailiff was unable to find any pricing, invoicing or ordering information in relation with the products at stake. This was established in the report – and not found to be objectionable by the court. However, the court did take offense at one sentence in the report, per which the defendant’s representative present at the trade show did not know the amounts of the allegedly infringing dyesheet that were produced “despite his status of CEO of the company Digital Printing Solution”.

The court held that the bailiff “should limit himself to material observations without issuing an opinion or taking an active part which may orient the outcome of the operation”. In other terms, the above remark in the report was held subjective and inappropriate.

This is an interesting reminder that the seizure team should remain as neutral and impartial as possible – despite the fact that they act at the patentee’s request.

However, in this case the patent proprietors did not suffer any serious consequence as only the remark at stake was held void by the court, but the rest of the report was not affected.

The second interesting point relates to the definition of acts of infringement of a product claim in article L. 613-3 a) Code de la propriété intellectuelle:

Making, offering, putting on the market, using, importing, exporting, transshipping or detaining for the above purposes the product which is the subject-matter of the patent.

There was a discussion as to whether the presence of some allegedly infringing products on the trade show amounted to an act of importation or not. The court answered yes, because an importation according to the above provision “is realized due to the sole introduction of the goods at stake on the territory on which protection is claimed”. Thus, it is irrelevant whether the introduction aims at using, offering, putting the goods on the market or not – unlike an act of mere detention of goods.

Importation can take any form and be carried out with any possible vehicle.

In fact, the formulation of article L. 613-3 a) changed in March 2014. The prior version read:

Making, offering, putting on the market, using or importing or detaining for the above purposes the product which is the subject-matter of the patent.

According to the court, importation acts used to follow a similar rule as detention acts, namely they used to require a certain purpose in order to be acts of infringement – but this is no longer the case since the 2014 reform.

This explanation in the judgment is notable because, although the same interpretation of the pre-2014 statute was made by some authors, such as professor Jérôme Passa in his book Droit de la propriété industrielle, to the best of my knowledge it was not universally shared. In fact, the pre-2014 paragraph was drafted in a somewhat ambiguous manner. That said, whether the 2014 reform merely clarified the rule applicable to importation acts or whether it actually changed the rule will anyway become less and less relevant as there are fewer and fewer pre-2014 importation acts involved in litigation over time.

In passing, the court also held that the presence of commercial documentation in the defendant’s booth amounted to an offer on the French territory, even though this documentation was in English, as French professionals in this sector usually speak English.

So far so good for Evolis and Illinois Tool Works, but the French-American alliance stumbled on the finish line, i.e. they failed to prove that the products at stake implemented the technical features claimed in EP’233.

The infringement seizure report itself did not contain any meaningful analysis of the products at stake. This is not surprising: in many cases, it is simply impossible to analyze whether claimed features are present or not just based on an external inspection of the products or on available documentation.

So the bailiff seized some samples; and in July 2017, another bailiff’s report was drawn up, when the samples were analyzed in Evolis’ premises. But this report was not taken into account by the court:

[…] These operations were made in Evolis’ premises, under its full supervision, in the presence of its CTO and using measuring tools the settings of which were not checked. Besides, the method used and the measurements made were not systematically explained, and notably it is not mentioned why the light adjustment is not the same for examining Evolis’ product and the allegedly infringing one.

In the absence of any other analysis evidence on file, these observations made without any other technical and logistic assistance than that provided by the claimants themselves do not make it possible for the court to appraise whether the [seized products] implement the features of claims 1 and 4 to 7 of [EP’233].

Readers will note that the defendant did apparently not offer any counter-experiments.

However, raising some very broad and general criticisms was good enough for the court.

Clearly, when it comes to an experimental demonstration of infringement, the doubt – any doubt, even a slight one – systematically benefits the defendant.

Or, to put it otherwise, French judges are extremely reluctant to take into account any experimental report made on behalf of one party.

For another example commented on this blog, see here.

This approach is certainly in the interest of fairness for the defendant, but one can wonder whether it is not excessively strict, as it puts the parties in a very asymmetrical situation. Namely, the plaintiff files experimental data, and the defendant can simply raise doubts regarding this data, without providing data of its own to prove that these doubts have merit.

Anyway, what the judges would certainly have preferred in this case is a request by the plaintiffs for the appointment of an expert by the court in order to perform the tests in a neutral environment. Or to put it otherwise: there was not enough red tape on these dyesheets. But the red tape approach is much more complex and cumbersome on a procedural standpoint – and more costly of course.


CASE REFERENCE: Tribunal de grande instance de Paris, 3ème chambre 2ème section, December 14, 2018, Evolis SA & Illinois Tool Works Inc. V. Digital Printing Solution Co. Ltd., RG No. 15/18744.