Dolce vita for Amgevita®

Judgments on preliminary injunctions are uncommon, and thus particularly interesting.

So are judgments on prior user rights. Thus, when a case combines both aspects, things get truly exciting.

Fresenius Kabi Deutschland acquired the biosimilars activity of Merck KgaA in April 2017. European patent application No. EP 3145487, filed in May 2015, was part of the deal. The patent was later granted, on August 22, 2018.

The patent relates to a pharmaceutical composition which is a biosimilar of the drug Humira®, based on the antibody adalimumab as an active ingredient.

Humira® is what people call a blockbuster drug. It has a number of therapeutic indications, including rheumatoid arthritis, psoriasis, Crohn’s disease and other inflammatory conditions.

Humira® was developed by Abbott and, according to the court, the SPC which protected the originator’s product expired in France on October 16, 2018.

Several biosimilar drugs were developed and obtained a marketing authorization (MA) from the European Medicines Agency (EMA), including the Californian group Amgen. See here for a news report on the Humira® biosimilar landscape. Amgen’s drug is called Amgevita®. It was the first biosimilar approved by the EMA in March 2017. Its price was set in France the day after the expiry of the Humira® SPC, and my understanding is that Amgevita® was then immediately placed on the market.

Meanwhile, as mentioned above, the EP’487 patent was granted to Fresenius on August 22, 2018. Fresenius was really on the starting blocks with this patent: looking at the EPO file wrapper, the communication under R. 71(3) EPC on the intent to grant was dated July 6, 2018, and the applicant replied by paying the prescribed fee and filing the claim translations… on July 6! This is as responsive as you can be.

But Fresenius’ impatience was quite understandable, in view of the imminent expiry of the Humira® monopoly; and because they were of the opinion that Amgevita® infringed EP’487.

A number of exchanges between Fresenius and Amgen took place in October-November 2018. And since Amgen would not bend, Fresenius initiated infringement proceedings in front of the Juge des référés, i.e. the judge in charge of urgency proceedings in the Paris Tribunal de grande instance, on November 14, 2018. Fresenius notably requested a preliminary injunction (PI) against Amgen.

In parallel, Amgen filed an opposition against the patent at the EPO in December 2018.

The French hearing took place on January 14, 2019, and the judge issued her decision one month later – ruling in Amgen’s favor.

Tutto bene per Amgen.

Amgen challenged Fresenius’ request for PI by stating that such a measure would be unwarranted given that Fresenius itself does not have a product on the market; and by arguing that the patent is invalid and that there is no infringement.

In the decision, the judge first summarized the standard to be applied as follows:

[The judge] must rule on the challenges raised by the defendant, including regarding the validity of the patent itself. She must appraise the seriousness of the challenges, and at any rate should assess the proportion between the requested measures and the infringement alleged by the claimant and take the decision to ban the marketing of the infringing product or not, in view of the risks taken on one side and the other. 

A few years ago, there was a controversy regarding the standard to be applied with respect to validity challenges to PIs. Was a “manifest” invalidity the only acceptable defense to a request for PI? Recent case law is much more defendant-friendly (and probably much more reasonable, for that matter), as the above quote shows, in particular with the reference to a control of the proportionality of the requested measures.

The judge then turned to the assessment of Amgen’s non-infringement defense, which, as mentioned in the introduction, was based on a prior user right. Or rather, on a “prior personal possession” of the invention, as it is known under French law.

The judge summarized the conditions to be met for such a defense to be effective:

          • the possession [of the invention must be] before the filing date of the patent or its priority date;
          • the possessed technology [must be] identical with the patented invention; 
          • the possession [must be] on the French territory; 
          • those claiming such possession [must have acted] in good faith.

The judge also clarified that, based on longstanding case law, the possession of the invention does not require a commercial exploitation of the invention. Possession, in this context, rather corresponds to the knowledge of the invention.

Let’s now turn to claim 1 of Fresenius’ patent:

An aqueous pharmaceutical composition comprising:
(a) adalimumab;
(b) an acetate buffering agent (or acetate buffer system);
(c) a sugar stabiliser, wherein the sugar stabiliser is a non-reducing disaccharide selected from the group including trehalose and sucrose; and
(d) polysorbate 80; and
wherein the composition:
• has a pH between 5.0 and 5.5;
• is either free of arginine or comprises arginine in a concentration of at most 0.1 mM;
• is either free of phosphate buffering agents or comprises a phosphate buffer system in a concentration of at most 0.1 mM;
• is either free of amino acids or comprises one or more amino acids in a (collective) concentration of at most 0.1 mM; and
• is either free of surfactants, with the exception of polysorbate 80, or comprises one or more of surfactants excluding polysorbate 80 in a collective concentration of at most 0.001 mM.

The other claims depend on or otherwise indirectly refer to claim 1.

Amgen Inc. had applied for an authorization to run clinical trials on the product designated as ABP 501, in front of the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM), and the authorization was granted on August 13, 2013. This was before the priority date of EP’487.

The ABP 501 formulation was described in the request for authorization as adalimumab “at 50 mg/ml […] formulated with 10 mM sodium acetate, 9.0% (weight/volume) sucrose, 0.1% (w/v) polysorbate 80, pH 5.2“.

The judge noted that those are the essential features of the claimed invention – which seems to be a reasonable conclusion to draw; and that Amgen’s good faith did not appear to be questionable.

Thus, the only remaining point to be discussed, which in my view was the most tricky one, was whether the possession was “personal” and had taken place on the French territory.

This is potentially a major stumbling block to a prior user right defense in this country, especially in large group of companies. Under French law, a very strict distinction is usually applied between various companies, even if they are affiliated. Therefore, if company A “possessed” the invention, this does not necessarily imply that its affiliate B also “possessed” it. Even more so if A is a foreign company, and B a French one.

In this case, the request for authorization to run clinical trials was filed by the U.S. company Amgen, Inc. But the defendant to the lawsuit was a different company, namely the French subsidiary Amgen SAS.

Here is how Amgen passed the hurdle:

In view of the specific organization of the Amgen group, it is reasonable to consider (especially in urgency proceedings) that Amgen SAS, like the other European subsidiaries of the group, had direct access to the document relating to the clinical trials, and thus to the formulation of the biosimilar product ABP501, owing to the “EPIC” platform of the group, as early as March 2013. In fact, part of the clinical trials were performed in France. It must therefore be held that the possession of the formulation which is identical to the patented one, although originating from the U.S., was realized in France. 

Thus, the judge concluded that the prior user right defense raised by Amgen was a serious challenge to the likelihood of infringement.

By way of overkilling, the judge noted that the lack of novelty argument based on prior art document US 2014/0086930 was also serious.

Consequently, Fresenius’ request for PI was dismissed.

I often conclude my posts by stating how much I look forward to the next developments in the litigation (judgment on the merits, appeal…). But in this particular instance, I don’t think there is anything to look forward to, really.

Indeed, we can see on the online European patent register that Amgen withdrew its opposition a few days ago on May 8, 2019. This certainly means that a settlement has been reached. We thus likely will not hear about this dispute anymore.

By the way, the 9-month opposition time limit has not expired yet – it will on May 22. I’m somewhat curious to know whether others will oppose.

One take-away message from this ruling is that the sharing of information between the various companies of the Amgen group via a dedicated platform was crucial in securing the French affiliate’s right to use the invention despite the patent. This may be a point to keep in mind for other multinational companies.

Although on the other hand it may also be difficult to put into place as a general rule, in view of the necessity to actively protect trade secrets.


CASE REFERENCE: Tribunal de grande instance de Paris, ordonnance de référé, February 14, 2019, Fresenius Kabi Deutschland GmbH v. Amgen SAS, RG No. 19/50489.

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.

The “pays” of the PIs?

A hardly understandable question, I know.

“Pays” is the French word for “country”. As for PIs, this term refers of course to preliminary injunctions. A PI is the most dreaded weapon of right holders.

But this legendary prize is also famous for being extremely hard to seize, notably in France. Although… could the trend have recently changed?

One ruling in particular which was issued last June in a prominent pharma case gave rise to a lot of comments. But another ruling issued just one month later also followed a somewhat similar path.

French chemical company Minakem sued two companies of the M2i group, namely Melchior Material and Life Sciences France (MMLS) and M2i Salin (M2i). MMLS owns a patent family on a method for making bromo methyl cyclopropane and bromo methyl cyclobutane. Minakem claimed ownership of this patent family and also complained that MMLS and M2i infringed its own patent No. FR 3010997, filed a few months before the priority date of the MMLS patent family. The two actions were joined as a consolidated case.

The ruling reported today does not contain much information on the context of Minakem’s ownership claim. It is an order issued by the judge in charge of case management, who was presented with a motion for PI by the plaintiff. MMLS and M2i raised invalidity and non-infringement as means of defense – but both grounds of defense were rejected.

Let’s start with validity first. The defendants argued that claim 1 of the Minakem patent lacks inventive step over a so-called Bayer document.

Now seems like a good time to have a look at the claim, which is quite straightforward:

A method of preparing bromo methyl cyclopropane comprising a step a) of reacting cyclopropylcarbinol with a complex of triphenylphosphite and bromine. 

Making reference to the problem and solution approach for the inventive step reasoning, the judge first noted that all parties agreed that the Bayer document was the closest prior art. According to this document, bromo methyl cyclopropane is prepared by reacting triphenylphosphine with cyclopropylcarbinol, and, after cooling, adding bromine.

The judge then held that there are two differences between the claimed invention and the teaching of the Bayer document, namely:

  • The use of triphenylphosphite instead of triphenylphosphine as a reactant: this is a one-letter difference in the name, and more importantly, three additional oxygen atoms in the molecule.
  • The use of a complex of triphenylphosphite and bromine, instead of adding bromine in a subsequent step.

Two documents were offered as secondary references, designated as D.G. Coe and Eli Lilly.

D.G. Coe teaches that triphenylphosphite can be used as a reactant to make alkyl halides (a class which encompasses the bromo methyl cyclopropane at stake here). But the judge noted that, according to the document, the reaction does not work similarly with all alcohols, and in particular that it provides very unsatisfactory results with cyclohexanol. Since cyclohexanol is a cyclic compound, just like cyclopropylcarbinol, the judge was convinced that the skilled person would have been dissuaded by D.G. Coe from reacting a triphenylphosphite complex with cyclopropylcarbinol, as claimed.

As for the second reference, Eli Lilly, it also discloses complexes of the type triphenylphosphite / halogen (e.g. bromine), as well as their potential use for a reaction with aliphatic alcohols, for making alkyl halides. But the document also emphasizes a new use for making vinyl halides by reacting these complexes with enol compounds. The judge concluded that Eli Lilly rather teaches to react the claimed complex with other compounds than aliphatic alcohols such as cyclopropylcarbinol. I am not sure I quite understand why the fact that the document both refers to a traditional use and to a new use of a chemical complex makes the traditional use less obvious than the new use. But on the other hand, it is true that the focus of the document is not on the preparation of alkyl halides.

What I actually found to be perhaps the most instructive in the judge’s reasoning is a mention of two side arguments.

First, the judge noted the following, regarding the sequence of steps in the claimed invention (first, formation of the bromine / triphenylphosphite complex, and then reaction with cyclopropylcarbinol):

This sequence is all the more important as MMLS and M2i precisely insisted on it in order to justify the inventive step of their own patent application filed in the United States, so as to discard the Bayer document which was cited as a prior art, since it disclosed a different order of introduction of reactants. They notably argued that “the particular order of the steps is essential to avoid a side reaction resulting in the opening of the tight ring, thus leading to the formation of a brominated alkene (bromobutene)” and that “this method is advantageous relative to the state of the art”.

This has the flavor of a file wrapper estoppel, and one based on a foreign file wrapper, at that.

But as is usually the case, this only comes as an additional consideration at the end of the reasoning in the ruling.

Second, the judge emphasized that both of the proposed secondary references were fairly old. D.G. Coe was dated 1954, and Eli Lilly was dated 1980.

A strong flavor of secondary indicia of inventive step, if you will.

Some fairly old prior art.

The other defense raised by MMLS and M2i was non-infringement.

The judge in charge of case management thus had to decide whether the existence of infringement was likely or not.

The process implemented by the defendants was known owing to an infringement seizure report.

The main non-infringement argument was that, in the defendants’ process, bromine is used in excess in the reaction with triphenylphosphite (TPP). This leads, they said, to the formation of bromo triphenoxy phosphonium bromide as an intermediate. This is not a TPP / bromine complex as recited in claim 1 of the Minakem patent, they argued, because of the presence of the bromide ion in the intermediate. In contrast, the TPP / bromine complex does not comprise a bromide ion and, according to the description of the patent, it is obtained with an excess of TPP (rather than an excess of bromine). They also insisted that the difference is significant, as their own process leads to a lower proportion of bromo butene by-product than the claimed one.

The judge was not convinced. He noted that the starting materials of the MMLS / Mi2 process are the same as those of the Minakem patent. So is the order of the reaction steps. The judge was not convinced either by the alleged difference in molar proportions of reactants:

[…] The scope of claim 1 of the FR’997 patent is not limited by any proportion, so that it does not necessarily and only cover a process limited to equivalent amounts of bromine and [TPP], and anyway the bromine excess alleged by MMLS and M2i is only low in view of the figures which were communicated. 

It is noteworthy that Minakem filed an affidavit from a chemistry professor that challenged the influence of the relative amount of bromine on the purity of the product.

The judge also noted that the different bromo triphenoxy phosphonium bromide intermediate relied upon by the defendants was not mentioned by the employees who were interrogated during the infringement seizure. And that this intermediate is not mentioned in MMLS’s own patent applications either.

As a conclusion, the infringement of the Minakem patent was found to be likely. The judge thus granted Minakem the PI that they requested, without security in view of Minakem’s financial health. However, the judge rejected Minakem’s request for provisional damages. This is because the evidence for the proposed computation of damages offered by Minakem, based only on an affidavit of their CFO without any external auditing corroboration, was insufficient.

To be continued on the merits! MMLS and M2i have their work cut out for them: it seems like they need to find new arguments if they want to turn the tables and ultimately prevail. I am especially curious to see how the ownership claim in relation to the defendants’ patent family will unfold.


CASE REFERENCE: Tribunal de grande instance de Paris, ordonnance du juge de la mise en état, 3ème chambre 2ème section, July 6, 2018, Minakem v. Melchior Material and Life Science France & M2I Salin,RG No. 17/15019.