No gift from Santen for SPC holders this year

Why on earth has Patent my French! not reported yet on Santen, I am sure dozens of readers have silently but reproachfully wondered.

After all, SPCs are a frequent topic on this blog, and it is not every day that a CJEU ruling shatters previously established practice. And based on a French referral, no less. Well, you may probably blame it on summertime torpor.

Luckily, Matthieu Dhenne does not mind heatwaves and has kindly sent me a contribution, which I am happy to reproduce below.

Santen owns European patent No. EP 057959306 for an ophthalmological emulsion in which cyclosporin is an active ingredient, plus a marketing authorization (“MA”) for the drug IKERVIS®, an eye drops emulsion containing said cyclosporin, which is intended for the treatment of severe keratitis in adult patients.

On the basis of these patent and MA, Santen filed an application with the INPI for a supplementary protection certificate (“SPC”) for a product entitled “cyclosporin for the treatment of keratitis“. The Director General of the INPI rejected this application, considering that the marketing authorisation on which it was based was not the first for cyclosporin, since another authorisation had already been previously issued for a SANDIMMUN® drug, which included this same active ingredient, in the context of post-graft medication. Faced with the applicant’s appeal against this rejection, the Paris Cour d’appel referred two questions to the CJEU, with a view to determining, in substance, whether an SPC could be granted for a new therapeutic application of a known drug.

The European High Court firstly considered that the definition of the notion of “product” in Article 1 b) of Regulation (EU) No. 469/2009 on SPCs is independent of the approved therapeutic application of said product, which therefore implies that it has a therapeutic effect of its own.

The Court concluded, secondly, that this strict interpretation of the concept of product implies that Article 3(d) of the Regulation must be understood as relating to the first marketing authorisation of any medicinal product incorporating the active ingredient.

The Santen judgment is thus an important turnaround.

As a reminder, an SPC extends the term of protection of a product that is a component of a medicine and is covered by a patent. Its purpose is to compensate for the length of time it takes to obtain a marketing authorization for a drug, because it is particularly significant. The central question raised in the Santen case was therefore whether this certificate only rewards the development of new active substances or whether it also rewards the search for new treatments for known substances.

Initially, the Court of Justice had consistently adopted a literal interpretation of the texts by excluding the grant of SPCs for new therapeutic applications (C-31/03, Pharmacia Italia; C-431/04, MIT; C-202/05, Yissum). However, it reversed its position with its judgment in the Neurim case on 19 July 2012 (C-130/11). It then held that an SPC could be granted despite an earlier marketing authorisation for the same active ingredient, so that the mere existence of a marketing authorisation for the veterinary medicinal product did not prevent an SPC from being granted for a different application of the same product, provided that the said application fell within the scope of protection of the basic patent. However, the Court later restricted the scope of this reversal in Abraxis (C-443/17), by rejecting the protection of new formulations of a known product.

Nevertheless, the interpretation of the Neurim case law has given rise to considerable debate as to whether its application was limited to the case at hand, i.e. from veterinary use to human use or vice versa, or whether Neurim meant that any new therapeutic application was protectable by a SPC. National patent offices took different positions on this question.

In Santen, the Court of Justice unambiguously put an end to SPCs for second therapeutic applications and thus to the legal uncertainty surrounding them.

SPC case law is like a Moebius strip: sometimes, a long and winding path may bring you back to where you started from.

The judgment is thus part of a trend towards a literal reading of Regulation (EU) No 469/2009, in particular after the Abraxis case mentioned above, and should be reaffirmed in the pending Novartis case (C-354/19), which relates to the question whether a new SPC can be granted to the holder of a first SPC concerning the same active ingredient.

This ultimately brings us back to the idea, once developed by Michel de Haas in connection with patents, that a new treatment is not protectable because it was already inherent in the first product.

While legal certainty undoubtedly remains the first social value to be attained, it should not be overlooked that it is achieved here at the cost of a significant reduction in the incentive for research in the pharmaceutical sector. However, despite the insecurity, many SPCs have been granted and exploited in accordance with previous case law and some companies have been built based on the economic model of re-using known drugs (developers of personalized drugs or orphan drugs, or companies using data and artificial intelligence to identify new therapeutic uses, for example). Therefore, although it increases legal certainty, this judgment is nonetheless a loss for many players in the sector, who will ultimately no longer have the incentive to invest in the development of new applications for known medicines.

But perhaps this restrictive approach of the CJEU should be seen as an appeal to the Commission since, as the Advocate General pointed out in Santen, it is for the European Union legislator alone, and not the Court, to decide to extend the scope of protection of SPCs?

Thank you Matthieu for this nice summary. There is no doubt that this ruling must have disappointed a number of stakeholders.

Now, on a purely legal standpoint, I am struck by the unusual clarity of the ruling.

CJEU judgments on SPCs have had this tendency to form an undecipherable patchwork of rules. When a new one is issued, it is generally not an easy task to figure out whether it reverses or qualifies a previous one, or whether it should be interpreted as being limited in scope to very specific facts. This was in particular the problem with Neurim, which was difficult to reconcile with Yissum et al.

Contrast this with the quasi-crystal-clear order in Santen:

[…] A marketing authorisation cannot be considered to be the first marketing authorisation, […] where it covers a new therapeutic application of an active ingredient, or of a combination of active ingredients, and that active ingredient or combination has already been the subject of a marketing authorisation for a different therapeutic application.

Even more remarkable is the way the court explicitly repelled its previous ruling at paragraph 53:

It follows that, contrary to what the Court held in paragraph 27 of the judgment in Neurim, to define the concept of ‘first [MA for the product] as a medicinal product’ for the purpose of Article 3(d) of Regulation No 469/2009, there is no need to take into account the limits of the protection of the basic patent.

This got me thinking though.

Now that we know for a fact that the CJEU sometimes sets aside rules that it previously laid out itself, isn’t this an incentive for litigants to try to challenge other seemingly well-established rules?

Neurim was issued only eight years ago, and it has now already gone the way of the dodo, so why not try this approach again in the future? In other words, is it at least conceivable that an unusually clear ruling may have ultimately increased overall legal uncertainty?

Let’s hope that the next SPC regulation will be intrinsically clearer and leave less room for diverging interpretations.


CASE REFERENCE: CJEU, July 9, 2020, C-673/18, Santen SAS v. Directeur général de la propriété industrielle

Time for the third round

The postman may always ring twice, but Lionel Vial, as a seasoned post-writing man, always rings three times. Here is thus his third foray into the Truvada® litigation.

As our faithful readers surely remember, there have already been two rounds in the Truvada® litigation in France (reported here and here). For the less faithful readers, here is a short reminder.

Truvada® (Gilead) is an anti-HIV drug comprised of the combination of tenofovir disoproxyl fumarate (TDF) and emtricitabine (FTC) approved for Pre-exposure Prophylaxy (PreP) of HIV infection, since it has been shown to allow for a reduction of 86% of the risk of being infected by HIV.

Truvada® was covered until 25 July 2017 by European patent EP 0915894. The effects of the patent have been extended by supplementary protection certificates (SPCs) expiring between 21 and 24 February 2020 depending on the countries.

The SPCs are based on European Union marketing authorization EU/1/04/305/001 and on claim 27 of the basic patent, which reads as follows:

A pharmaceutical composition comprising a compound according to any one of claims 1-25 [N.B. tenofovir disoproxil is claimed in claim 25] together with a pharmaceutical carrier and optionally other therapeutic ingredients. (Emphasis added).

The essential question repeatedly asked to the French courts was whether the use of the expression “other therapeutic ingredients” to refer to emtricitabine (FTC) is indeed sufficient to protect the TDF/FTC combination pursuant to Article 3(a) of Regulation (EC) No. 469/2009 of the European Parliament and of the Council (i.e. the SPC regulation).

Round one saw the rejection, on 5 September 2017, of Gilead’s request for a preliminary injunction under urgency proceedings to prohibit the sale of Mylan’s generic, because the SPC was considered “in all likelihood invalid” by the French judge in charge of the case.

Round two saw the Paris Tribunal de Grande Instance confirm this preliminary ruling by invalidating the SPC on 25 May 2018.

Which brings us to round three, which took place before the Paris Cour d’Appel.

Bam! Wham! … and Pow!

In our previous post on the subject, we had expressed the thought that there was not much suspense left, especially in view of the opinion of the Advocate General (AG) of the CJEU delivered on April 25, 2018 in the then pending case C-121/17, relating to the corresponding UK SPC, and according to which it would not have been obvious to a person skilled in the art that the active ingredient emtricitabine was specifically and precisely identifiable in the wording of the claims of that patent.

Referral C-121/17 yielded a decision on 25 July 2018:

Article 3(a) of Regulation No 469/2009 of the European Parliament and of the Council of 6 May 2009, concerning the supplementary protection certificate for medicinal products, must be interpreted as meaning that a product composed of several active ingredients with a combined effect is ‘protected by a basic patent in force’ within the meaning of that provision 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. For that purpose, from the point of view of a person skilled in the art and on the basis of the prior art at the filing date or priority date of the basic patent:

            • the combination of those active ingredients must necessarily, in the light of the description and drawings of that patent, fall under the invention covered by that patent, and
            • each of those active ingredients must be specifically identifiable, in the light of all the information disclosed by that patent.” (emphasis added)

Let’s see what the Cour d’Appel made of it in its decision handed down on 19 June 2020:

The court, which studied the consultations and scientific articles submitted by the parties, retains that if it is not contested that the person skilled in the art knew that for treating HIV a therapy combining several active principles was more effective than a mono-therapy, nothing establishes that in 1996 the person skilled in the art, given the the general state of its knowledge, necessarily and specifically thought of emtricitabine to combine it to TD upon reading claim 27 which is drafted in very general terms.

The [first instance] judgement will be therefore confirmed in that it retained that no functional formula necessarily and specifically related to emtricitabine and that consequently the combination of the two products TD and emtricitabine could not be made the subject of an SPC on the basis of the EP 894 patent […]” (emphasis added)

Thus, not much suspense indeed, as round three also ends in a knock-down. Time to throw in the towel?


CASE REFERENCE: Cour d’appel de Paris, pôle 5 chambre 2, June 19, 2020, Gilead Sciences Inc. et al. v. SASU Mylan, RG No. 18/15906.

Back to the old normal?

Let me first start by wishing that all readers are safe and well, in these exceptional and difficult times.

As so many of us have to remain home all day in the foreseeable future, with the dreadful pandemic newsfeed as a main distraction, I said to myself, what better way to take my mind off it than to write about… a pharma case?

And so, here is an update on the Inegy® patent dispute (judgment kindly provided by Denis Schertenleib).

Difficult to think about anything else these days.

One year ago, Lionel Vial and I reported on a preliminary injunction ordered against Mylan due to the likely infringement of SPC FR05C0040 owned by Merck Sharp & Dohme Corp. (MSD).

In that post, we expressed some surprise at the decision since, back in April 2018, a judge in charge of emergency interim proceedings had refused to issue a preliminary injunction against another generic drug company, Biogaran, based on the same SPC, because the latter was considered likely invalid, which was confirmed on appeal on June 26, 2018 (see this post).

We wondered whether there was thus a new, more patentee-friendly trend in France with respect to preliminary injunctions in general and pharma patent litigation in particular, which is why the March 2019 post was entitled The new normal.

But now, we seem to be back to the old normal, as the Cour d’appel has overturned the preliminary injunction, and effectively re-raised the bar for pharma patent holders. 

As a reminder, Inegy® is a combination of ezetimibe and simvastatin, which is prescribed for reducing cholesterol levels.

Ezetimibe reduces intestinal absorption of cholesterol while simvastatin (belonging to the family of statins) is an HMG-CoA reductase inhibitor which inhibits cholesterol biosynthesis.

MSD’s SPC protecting Inegy® 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”.

EP’599 specifically claims:

  • a very broad family of compounds in claim 1 (in the form of a Markush formula);
  • ezetimibe as a specific compound in dependent 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 the above compounds, 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 initiated nullity proceedings, to which MSD responded by requesting, on November 30, 2018, that a preliminary injunction to stop selling Mylan’s ezetimibe/simvastatin combination and to pay provisional damages be issued against Mylan.

On March 7, 2019, the judge in charge of case management (JME) granted the preliminary injunction. Mylan appealed, and the JME’s judgment has now been overturned by the Paris Cour d’appel on February 14, 2020.

Like in first instance, Mylan argued 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 does 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 was already the subject of a certificate (i.e. SPC FR03C0028 granted for ezetimibe) in breach of Article 3(c) of the SPC regulation.
  • As is usual in SPC-related cases, the court analyzed the relevant case law from the CJEU. But the court interpreted the Gilead decision (C-121/17, Teva UK Ltd. et al. vs. Gilead Sciences Inc.) differently from the JME at first instance.

According to Gilead:

Article 3(a) of [the SPC regulation] must be interpreted as meaning that a product composed of several active ingredients with a combined effect is ‘protected by a basic patent in force’ within the meaning of that provision 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. For that purpose, from the point of view of a person skilled in the art and on the basis of the prior art at the filing date or priority date of the basic patent:

the combination of those active ingredients must necessarily, in the light of the description and drawings of that patent, fall under the invention covered by that patent, and

each of those active ingredients must be specifically identifiable, in the light of all the information disclosed by that patent.

The Cour d’appel held that the conditions of Gilead are not automatically met merely because the claims of the patent explicitly mention the active ingredients of the combination product. Something more is required.

The court insisted on the the link between the claimed combination and the technical problem at stake, based in particular on reason 48 of Gilead, which reads: “it is necessary to ascertain whether a person skilled in the art can understand without any doubt, on the basis of their general knowledge and in the light of the description and drawings of the invention in the basic patent, that the product to which the claims of the basic patent relate is a specification required for the solution of the technical problem disclosed by that patent“.

The court also turned to earlier decisions of the CJEU, namely Sanofi (C-443/12, Actavis Group PTC EHF & Actavis UK Ltd v. Sanofi) and Boehringer (C-577/13, Actavis Group PTC EHF & Actavis UK Ltd v. Boehringer Ingelheim Pharma GmbH & Co. KG) and found that the facts of the present case are similar to those of these earlier decisions.

Here is the court’s summary of Mylan’s key argumentation:

Mylan argues that the basic patent lists a large number of products, namely all known cholesterol-lowering products to be combined with the new active compound ezetimibe, that it does not contain any information on the specific effects of these combinations, and in particular the one associating ezetimibe with simvastatin, and that this combination is therefore not a product distinct from ezetimibe alone, for which the patentee has already obtained an SPC, which would make it possible for them to prohibit the sale of ezetimibe combined with any other product, so that the [SPC] is likely invalid.  

And here is the summary of MSD’s rebuttal:

MSD argues that [the expressly designated] composition of ezetimibe and simvastatin necessarily pertains to the invention for the skilled person, in keeping with Gilead. They add that this combination product is not a mere juxtaposition of two known active substances; it effectively makes it possible to solve the technical problem stated in the patent, namely the development of more effective drugs in the treatment and prevention of atherosclerosis, avoiding side effects, in view of the complementary modes of action of ezetimibe and simvastatin; and that this is a second invention of the EP’599 patent, covered by this patent under article 3(a) of the regulation, so that this case is different from Sanofi and Boehringer. They add that the combination product of ezetimibe and simvastatin has not given rise to an SPC under article 3(c) of the regulation yet, that several products can be protected as such by a basic patent, and that the condition of article 3(c) is also met so that the SPC is valid. 

In summary of the summaries: for MSD, there are two inventions in the basic patent, namely ezetimibe on its own, and the combination of ezetimibe with other complementary drugs such as simvastatin; for Mylan, the patent is only about ezetimibe itself.

In order to decide between these two propositions, the court looked at the structure of the basic patent, and at the nature of the combined effect of the two active substances.

Concerning the structure of the patent, the court noted that the summary of the invention primarily focuses on the class of compounds to which ezetimibe belongs. And then:

[…] The next paragraphs 15 to 17 which disclose product compositions and notably the association of a hydroxy substituted azetidinone and a cholesterol biosynthesis inhibitor are introduced by the following wording: “in still another aspect, the present invention relates to a pharmaceutical composition” or “the present invention also relates to”, so that the skilled person could consider the combination […] as being another “aspect” of the invention relating to hydroxy substituted azetidinones, and not a distinct invention. 

That sounds like a fair point, but on the other hand, it should scare the hell out of all patent drafters that an apparently innocuous choice of wording can have such dramatic consequences more than 25 years after the patent was drafted.

Concerning the “combined effect” of the active substances (an expression used at paragraph 53 of the reasons of Gilead), the court noted the following:

MSD states in its submissions that the “combined effect” under Gilead of the association of ezetimibe and simvastatin lies in the fact of not having to administer the maximum dose of statin and reducing the risk of side effects. This is not mentioned in the patent, which indifferently mentions that the effect of both hydroxy substituted azetidinones alone and their combination with a cholesterol biosynthesis inhibitor is the “treatment and prevention of atherosclerosis”. Therefore, the skilled person, who knew from the prior art that it was possible to combine two anti-cholesterol substances having different modes of action […] and who knew statins and especially simvastatin, in use since the end of the 80s for the treatment of hypercholesterolemia, would not consider that this combination is a distinct product of the patent (in the absence of any indication at the filing date as to the combined effect of ezetimibe and simvastatin, and the results from later research not having to be taken into account) […].

Consequently, the court seems to consider that, in order for a combo drug to be considered as distinct from a mono drug in a patent, this needs to be stated in the patent itself, and there must be a specific effect for the combination disclosed in the patent.

It remains an open question whether a mere mention of a specific combined effect would suffice or whether the combined effect would have to be plausible at the filing date (by analogy with the requirements of sufficiency of disclosure).

The above will probably be controversial enough, but an additional point made by the court, after concluding that the validity of the SPC was seriously challenged, may be even more controversial. To wit:

At any rate, the proportionality of the measures ordered at first instance is not justified in view of the respective interests relating to originator and generic drugs having obtained marketing authorizations. A financial harm cannot be seen as non-repairable or even poorly repairable, as long as it can later be cured by a damages award, unless under exceptional circumstances which are not justified in the present case, as the SPC at stake expired on April 2, 2019, i.e. less than two months after the preliminary injunction order.   

Just like in the latest post on this blog (in the context of telecom SEP litigation), the proportionality principle has thus been emphasized by the court, which seems to be a tendency on the rise. And just like in this other case, the fact that the expiry date of the IP at stake was nigh was a factor taken into account in the proportionality assessment.

This must be very worrying for originators, as preliminary injunctions have been a powerful deterrent for competitors, and as there are concerns that damages may never completely compensate for the competitive advantage gained by generic drug companies launching before expiry.

The case on the merits is probably going on in parallel, so we will probably get further updates on this case.

As a final note, a very similar decision was issued on the same day, with Sandoz instead of Mylan as the generic defendant.


CASE REFERENCE: Cour d’appel de Paris, pôle 5 chambre 2, February 14, 2020, SAS Mylan v. Merck Sharp & Dohme Corp. & SAS MSD France, RG No. 19/06114.

A travel back in time

Regular readers of this blog are probably aware that Lionel Vial is a frequent contributor.

I am grateful for his thorough reporting on pharma / biotech case law. Today, he once again keeps us apprised of the latest SPC tidbit. As he even provided the illustration, I really have nothing to add but say thanks!

While we are all waiting for the decision of the CJEU in the Santen case (C-673/18) to finally know if, in application of the Neurim (C-130/11) case law, a patented novel medical use in humans of a product having already been authorized for a previous different medical use in humans deserves a supplementary protection certificate (SPC), the decision discussed today will take us back to the pre-Neurim era, a time of uncertainty as we will see.

At that time, the prevailing case law regarding further medical use consisted in Pharmacia Italia SpA (C-31/03) rendered on October 19, 2004, and Yissum (C-202/05) rendered on April 17, 2007.

According to the judgment in Pharmacia Italia SpA:

The grant of a supplementary protection certificate in a Member State of the Community on the basis of a medicinal product for human use authorised in that Member State is precluded by an authorisation to place the product on the market as a veterinary medicinal product granted in another Member State of the Community before the date specified in Article 19(1) of Council Regulation No 1768/92 of 18 June 1992 concerning the creation of a supplementary protection certificate for medicinal products.

On the other hand, the order in Yissum reads:

Article 1(b) of Council Regulation (EEC) No 1768/92 of 18 June 1992 concerning the creation of a supplementary protection certificate for medicinal products […] is to be interpreted as meaning that in a case where a basic patent protects a second medical use of an active ingredient, that use does not form an integral part of the definition of the product.

The DeLorean remains the best way to travel in time with style.

The Regents of the University of Colorado (hereafter the University) was granted European patent No. 1658858 on November 18, 2009 for the use of a botulinum toxin, in particular botulinum toxin type A, in the preparation of a pharmaceutical composition for treating a recalcitrant voiding dysfunction, in particular urinary incontinence.

A corresponding marketing authorization was then granted on August 22, 2011.

The University had six month (that is until February 22, 2012) to file an SPC application. However, since botulinum toxin type A had benefited of previous marketing authorizations and in view of the then prevailing case law, the University considered it impossible to have an SPC granted and therefore no SPC application was filed.

Then the Neurim judgment was rendered on July 19, 2012. It notably provides that:

Articles 3 and 4 of Regulation (EC) No 469/2009 of the European Parliament and of the Council of 6 May 2009 concerning the supplementary protection certificate for medicinal products must be interpreted as meaning that, in a case such as that in the main proceedings, the mere existence of an earlier marketing authorisation obtained for a veterinary medicinal product does not preclude the grant of a supplementary protection certificate for a different application of the same product for which a marketing authorisation has been granted, provided that the application is within the limits of the protection conferred by the basic patent relied upon for the purposes of the application for the supplementary protection certificate.

Neurim has often been considered as a complete reversal of the previous case law.

Besides, for many commentators, it opened the door to SPCs for novel medical uses in humans of products having already been authorized for a previous different medical use in humans.

The University therefore filed an SPC application on September 19, 2012, i.e. within 2 months of the publication of the Neurim judgment, but about 7 months after the end of the deadline for doing so.

The University sought to benefit from the provisions of Article L. 612-16 of the Code de la propriété intellectuelle, according to which:

Where an applicant has not complied with a time limit as regards the Institut National de la Propriété Industrielle, it may submit an appeal for reinstatement of it rights if it is able to give a legitimate reason and if the direct consequence of the hindrance has been refusal of its patent application or of a request or the loss of any other right or means of appeal.

The appeal must be submitted to the Director of the Institut National de la Propriété Industrielle within two months of the cessation of the hindrance. The act that has not been carried out must be accomplished within that period. The appeal shall only be admissible within a period of one year from expiry of the time limit not complied with. […]

However, the INPI (French patent office) was not convinced and rejected the appeal for reinstatement on June 30, 2015.

The University and Allergan (to whom the SPC application and the basic patent had then been assigned) appealed the decision of the Director of the INPI before the Paris Cour d’appel on September 18, 2015.

In a first decision dated September 16, 2016 the Cour d’appel confirmed the decision of the INPI. However, the decision was invalidated by the Cour de cassation, the French Supreme court, on April 5, 2018, for procedural reasons, as the Cour d’appel had neglected notifying observations made by the INPI to the University and Allergan.

The case then came back in front of the Paris Cour d’appel which, albeit with different judges, again confirmed the decision of the INPI on February 12, 2019 in the following terms:

However, according to the terms of article L. 612-16 of the intellectual property code, the legitimate reason must be understood as a “hindrance”;

Even considering that the case law of the CJEU, before the Neurim judgement, did not allow the University to expect obtaining an SPC and could therefore discourage it to file an SPC application, the director of the INPI rightly observes that this situation does not characterize a hindrance according to the previously cited provision, given that the case law, be it that of the Court of justice, evolves, that even with the Pharmacia Italia and Yissum case law other operators have indeed filed SPC applications in relation to further medical uses, one of which having given rise to the Neurim judgment, and that the lack of filing of an SPC application by the University was the result of its free appreciation of the latter and not of an objective impossibility, independent of its will.

In any case, pursuant to article 7 of regulation No. 469/2009 concerning the supplementary protection certificate for medicinal products, the University had a six-month period expiring on February 22, 2012 to file its SPC application; the reference for preliminary ruling to the Court of justice of the European Union was received at the Court on March 16, 2011 and published in the OJEU on June 18, 2011; under these conditions, as is rightly observed by the director of the INPI, the University had to consider a possible reversal of the case law of the Court of justice;

As such, the decision of the director of the INPI is exempt from criticism in having retained that the lack of respect of the deadline imparted to the University for filing its SPC application was not due to a hindrance for which it would benefit from a legitimate reason, but to its will not to proceed with a filing that it did not consider appropriate and this in spite of the reference for a preliminary ruling submitted to the Court of justice duly published on June 18, 2011.

Perhaps, this case is an illustration that too much knowledge is sometimes dangerous, and that we, as counsels, should always be careful when giving opinions on the likely outcome of a filing on the basis of our knowledge of established case law, bearing in mind that there is always a possibility, even a remote one, that a case law can be overturned.

In any case, the University and Allergan should refrain from nourishing regrets on their missed filing at least until the result of the Santen referral (C-673/18) is known, as this latter case precisely arises from a decision of rejection of an SPC application by the INPI in relation to a further medical use.

Well, the way I see it, getting SPC law 100% right is a little bit like having to hit a wire with a connecting hook at precisely eighty-eight miles per hour the instant a lightning strikes a tower. Everything will be fine.


CASE REFERENCE: Cour d’appel de Paris, pôle 5 chambre 1, February 12, 2019, The Regents of the University of Colorado & Allergan Inc. v. Directeur de l’Institut National de la Propriété Industrielle, RG No. 18/14291.

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