Sunset for Cynrise

Easter always brings back chocolaty memories. The question as a child growing up in the Northeastern part of France on Easter morning was whether eggs had been brought by the Easter bunny. And the question as a child also growing up in the Southeastern part of France was whether eggs had been brought by the Easter bells.

It has been a while since the Easter bunny and the Easter bells stopped feeding me with chocolate. But this year there was an even better surprise on Sunday morning, in the form of an SPC-related guest post by Lionel Vial. And as all readers will probably acknowledge, SPCs are a delicacy of their own.

Rush of nostalgia: Easter eggs are no longer what they used to be.

Here is to Lionel.

The case discussed on this Easter day relates to a ruling of the Paris Cour d’appel dated January 20, 2017 which upheld a decision of the French patent and trademark office (INPI) to reject an application for a supplementary protection certificate (SPC) for a biological medicinal product.

French SPC application No. 11C0054 was filed on December 14, 2011 by Laboratoire Français du Fractionnement et des Biotechnologies (hereafter LFB), a French company specializing in medicinal products purified from human blood. The SPC application was based on French patent No. 2722992 filed on July 28, 1994, which claimed a method for the manufacture of a C1-esterase inhibitor concentrate (claim 1), as well as the concentrate obtained by the method (claim 11).

The SPC application was further based on marketing authorization (MA) No. EU/1/11/688/001 for Cinryze® comprising “C1 inhibitor, human (INN)” as active ingredient.

For those whose curiosity goes beyond patent law, C1 is one of the proteins forming the complement system, which itself is part of the innate (i.e. non-adaptive) immune system. The C1 inhibitor is a natural protein, found in blood, the role of which is to regulate the activation of the complement system. The C1 inhibitor is especially useful for individuals suffering from a rare autosomal dominant disease, caused by a deficiency of functional endogenous C1 inhibitor, which manifests itself in the form of angioedema attacks.

The SPC application was rejected on December 22, 2014 by the INPI for not complying with Article 3(d) of Regulation (EC) No. 469/2009 (hereafter the SPC regulation), i.e. the MA for Cinrize® was considered not to be the first authorization to place the product on the market as a medicinal product.

This was because a prior MA had been issued on June 28, 1999 for Esterasine comprising “human C1 esterase inhibitor” as active ingredient.

LFB lodged an appeal against the decision of the INPI before the Paris Cour d’appel and essentially argued that the human C1 inhibitors of Cinrize® and Esterasine were in fact two different products.

The precise arguments used by LFB are not very clearly summarized in the decision.

But it appears that LFB stressed that the way biological medicinal products, such as Cinrize®, are manufactured has an impact on their molecular structure, which, in the present case, was evidenced by a half-life of 56 hours for Cinrize® vs. 30 hours for Esterasine.

This did not convince the Cour d’appel which considered that:

The regulation relating to SPCs does not provide for exceptions to the definitions of a “product” and a first MA for biological medicinal products or blood products which would allow defining them as a function of their methods of manufacture or under their commercial names; it is therefore irrelevant that the SPC application is based on an MA for the “Cinryze” drug since the product protected by the basic patent is “the C1 inhibitor, human”; [besides] if LFB, after having initially claimed the latter, has amended the application by claiming “the C1 esterase inhibitor of the Cinryze drug”, this limitation made after the objections of the INPI cannot be effective since either the patent or the MA only relate to the “C1 inhibitor” as active ingredient of the Cinryze drug. 

To put it more clearly, the Cour d’appel took a very formal approach of Article 3(d) of the SPC regulation and simply considered that, if the names of the active ingredients mentioned in two different MAs are the same, then both MAs in fact relate to the same product, without further consideration as to the true physicochemical identity between the two products, as in the case of biological medicinal products obtained by different methods of manufacture.

LFB also argued that, in the assessment report of the European Medicines Agency (EMA) which led to the MA, the purified and concentrated C1 INH (i.e. C1 inhibitor) after pasteurization and nanofiltration is considered as the active substance.

The Cour d’appel responded that

the subject matter of this report was a marketing authorization application for Cinryse, so that, if [the report] specifies what its active ingredient is, it does not conclude that it would be a new product, the novelty of the medicinal product being different from that of its active ingredient; accordingly this does not contradict the decision of the INPI.

Moreover, the Cour d’appel noted that this latter argument was not submitted to the INPI which, therefore, could not do otherwise than decide that the MA for the drug Cinryze was not the first one for the active ingredient which is the “C1 inhibitor, human”.

It is to be noted that the latter argument was however decisive in overcoming the objection of the Dutch patent office based on Article 3(d) of the SPC regulation for the corresponding SPC application in that country (NL SPC application No. 300510), thereby securing the grant of an SPC.

It is therefore tempting to imagine that the fate of the French SPC application could have been changed for the best had the attention of the INPI examiner been drawn to the definition of the active substance in the assessment report of the EMA.

As a final note, this case reminds us of the ruling of the Paris Cour d’appel of April 12, 2016 which upheld the decision of the INPI to reject SPC application No. 08C0003 covering Cervarix®(GlaxoSmithKline Biologicals) which was discussed here.

In that case also the Cour d’appel refused to take into account the impact of the manufacturing process of biological products (production in yeast cells vs. insect cells) on their structure, sticking to the definition of the product given in the MA.

One can wonder if this literal approach, which has the advantage of simplifying examination of SPC applications, is in keeping with the fundamental objective of the SPC regulation which is to make up for the insufficiency of the period of effective protection of a medicinal product under a patent to cover the investment put into pharmaceutical research as recalled by the CJEU in C‑130/11 (Neurim).

Indeed, in the present case, it appears from the assessment report of the EMA that new clinical data was produced for the C1 inhibitor of Cynrize® in support of the MA application. This is probably because the C1 inhibitor of Cynrize® is a biological product the structure of which depends on the manufacturing process, thereby making it impossible to rely on clinical data obtained with previous C1 inhibitors.

It is generally considered that clinical trials amount for the larger part of investment in drug development. It could therefore be considered that the active ingredient of Cynrize® is a new product the development of which necessitated investment entitling it to SPC protection.

As such, when assessing conformity with Article 3(d) of the SPC regulation, perhaps the necessity to generate specific clinical data in order to obtain an MA for a biological product should be the primary criterion for determining if an MA is the first one to place the biological product on the market, rather than simply determining if the name of the active ingredient is the same one as that of a prior MA.

Thank you Lionel. Easter being about resurrection even more than about chocolate eggs, it remains to be seen whether this SPC application may come back to life on cassation appeal.

CASE REFERENCE: Cour d’appel de Paris, pôle 5 chambre 2, January 20, 2017, SA Laboratoire Français du Fractionnement et des Biotechnologies v. Directeur général de l’INPI, RG No. 16/08814.

Of yeast and insects

It is with great pleasure that I am hosting a new contribution by Lionel Vial on this blog. Today, Lionel asks the question whether the regulatory specificity of biological medicinal products has just been denied by French courts.

It is known that Supplementary Protection Certificates (SPCs) make up a particularly tricky part of patent law. So tricky that national courts regularly feel the need to refer questions of law in this respect to the Court of Justice of the European Union (CJEU); and so tricky that the answers provided by the CJEU in its preliminary rulings have a tendency to fuel yet further references from national courts.

But when it comes to biological medicinal products, things can get even thornier, especially since policymakers may have primarily had chemical medicinal products in mind when the SPC regulation was drafted.

So let Lionel now explain how the difference may come into play.

The decision we discuss today was rendered by the Cour d’Appel de Paris on April 12, 2016 and deals with the appeal lodged by the Government of the United States of America against the decision of the Director of the INPI (French patent and trademark office) to reject SPC application No.08C0003 covering Cervarix® (GlaxoSmithKline Biologicals).

As a side note, we will first remind our readers that appeals against decisions of the Director of the INPI, such as rejections of patent applications or SPCs, are to be lodged directly to the Cour d’Appel de Paris, i.e. the second instance court, and not to the first instance Tribunal de Grande Instance de Paris.

Back to the case at hand, Cervarix® is a vaccine intended for use in women and girls from nine years old to protect against cancer of the cervix (neck of the womb) and precancerous lesions (abnormal cell growth) in the genital area (cervix, vulva or vagina) caused by certain types of the human papillomavirus (HPV). Cervarix® HPV-16/18 L1 AS04 vaccine contains recombinant C-terminally truncated major capsid L1 proteins of HPV types 16 and 18 as active ingredients. The L1 proteins of HPV-16 and HPV-18 are separately produced using a recombinant Baculovirus expression system and the insect cell line Hi-5 Rix4446 derived from Trichoplusia ni.

For those not versed in the biological arts, this basically means that the antigens contained in the vaccine are shortened versions of viral proteins from two different viruses (HPV-16 and HPV-18), which proteins have been produced in vitro in insect cells.

The SPC application was filed on January 18, 2008 on the basis of European patent EP 0662132 filed on September 3, 1993 and of the Marketing Authorization (MA) No.EU/1/07/49/001 of September 20, 2007. It was rejected on March 16, 2015 by the INPI.

The decision of the INPI was essentially based on the Actavis judgment C-443/12 of December 12, 2013 by the CJEU (following a reference for a preliminary ruling from the High Court of Justice of England and Wales), and more particularly on points 40 and 42 of this judgement:

40. Bearing in mind the objective of Regulation No. 469/2009 [i.e. the SPC regulation] […] – namely, to compensate the patent holder for the delay to the commercial exploitation of his invention by providing him with an additional period of exclusivity – first, the grant of the first SPC in respect of the single active ingredient irbesartan [i.e. the drug at stake in the judgment] has already afforded the holder such compensation and, second, the objective of that regulation is not to compensate the holder fully for the delay to the marketing of his invention or to compensate for such delay in connection with the marketing of that invention in all its possible forms, including in the form of combinations based on that active ingredient. […] (emphasis added) 

42. It follows that, in such a situation, Article 3(c) of Regulation No. 469/2009 precludes a patent holder from obtaining, on the basis of one and the same basic patent, more than one SPC in connection with irbesartan, since such SPCs would in fact be connected, wholly or in part, with the same product […]”

Indeed, another SPC No.07C0020 covering Gardasil® (GlaxoSmithKline Biologicals) was granted earlier on the basis of the same patent in regard of a L1 protein from HPV16. The INPI thus considered that this previous SPC also protected the C-terminally truncated form of the L1 protein, purported to be obtained by production from insect cells, and that the product for which SPC No.08C0003 was applied for had already been the subject-matter of a certificate.

As it appears from the ruling, the main argument of the appellant against the decision of the INPI was that the HPV16 L1 protein obtained from insect cells, which forms the subject-matter of SPC No.08C0003, is a different product from the HPV16 L1 protein obtained from yeast cells, which forms the subject-matter of SPC No.07C0020, because of the differences in the glycosylation pattern and amino acid chains depending on the cell type (yeast or insect) in which the protein is produced. Accordingly, the MAs of Gardasil® and Cervarix® relate to medicinal products having different active ingredients and SPC No.07C0020 and SPC application No.08C0003 relate to different products. In addition, pursuant to Articles 4 and 5 of Regulation (EC) No 1768/92 (i.e. the previous version of the SPC regulation), an SPC may not confer a protection extending to a product which is not the one related to the marketing authorization.

"How could you possibly mistake me for a yeast?" said the beetle.
“How could you possibly mistake me for a yeast?” said the beetle.

However the Court ruled that:

As is rightly pointed by the Director of the INPI, firstly, the basic patent claims (claim 1) “an isolated HPV16 capsomer structure comprising L1 capsid protein” which is not characterized by its manufacturing process and the patent does not explain the differences between the proteins asserted by the appellant, [the patent] referring to various manufacturing processes (insect cells such as for Cervarix, yeast cells such as for Gardasil, and even mammalian cells (cf. page 20 of the patent)), secondly, the asserted differences are not mentioned either in the MAs provided with the two SPC applications which relate secondarily to the manufacturing process without drawing any conclusion regarding the protein structure, and finally, SPC application No.08C0003 initially related – before the amendments brought by the applicant in relation with the forms and production methods in response to the objections from the INPI during the examination procedure of the application – to a product defined as “L1 proteins from type 16 human papillomavirus”, this definition being precisely that mentioned in SPC application No.07C0020 filed on March 20, 2007;

Article 1 of the previously cited Regulation defines the product as “the active ingredient or combination of active ingredients of a medicinal product”, without any reference to the manufacturing process of the active ingredient;

Accordingly, the HPV16 L1 protein comprised in Cervarix and that comprised in Gardasil constitute one and the same product within the meaning of the previously cited Regulation, regardless of their possible differences regarding their forms and their manufacturing processes;

It results from Articles 4 and 5 of the Regulation that the protection and the rights conferred by an SPC are framed by the basic patent and that the MA is used to determine the product forming the subject-matter of the protection; it is thus irrelevant, for assessing the regularity of the rejection of SPC application No.08C0003, whether this application is based on an MA specially obtained for Cervarix, which, even though it aims at treating the same pathologies, is different from Gardasil, which has a different MA, since the HPV16 L1 protein comprised in the two drugs is the same;

Under these conditions, the Director [of the INPI] was right in considering that SPC No.07C0020 granted on July 23, 202 also applied to the HPV16 L1 protein comprised in Cervarix, even if obtained from insect cells, and in rejecting SCP application No.08C0003 filed on June 18, 2008 by the Government of the United States of America.

Accordingly, the decision of rejection of SPC application No.08C0003 was upheld.

This decision is interesting in that the Court decided, following the INPI, that the protection conferred by an SPC extends beyond the physical product which can be found in the marketed medicinal product to encompass all products falling within the definition of the product in the SPC or SPC application.

This construction of Articles 4 and 5 of the SPC Regulation may not give rise to too much discussion for chemical medicinal products, as in addition to C-443/12 (Actavis) it could also be considered to be an application of the previous ruling of the CJEU in C-392/97 (Farmitalia) (“where a product in the form referred to in the marketing authorisation is protected by a basic patent in force, the supplementary protection certificate is capable of covering the product, as a medicinal product, in any of the forms enjoying the protection of the basic patent”). But it may give rise to more concerns as regards biological medicinal products, as in the present case.

In fact, it can be regretted that the present decision was not taken as an opportunity to discuss – and why not to request a preliminary ruling on – the question of knowing if the same standard is to be applied to chemical and biological medicinal products when applying Articles 4 and 5 of the SPC Regulation.

Indeed, the specificity of biological medicinal products has been recognized by European Union law. By way of example, Article 10 of Directive 2001/83/EC notably provides that where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided.

Accordingly, in view of the objective of the SPC Regulation which is, as was recalled above, to compensate the patent holder for the delay to the commercial exploitation of his invention by providing him with an additional period of exclusivity, it could be questioned whether biological products obtained by different manufacturing processes could not be considered as truly different products and not merely as different forms of a same product.

As a final side note, we would like to add that the above-mentioned Actavis decision of the CJEU is only one of numerous rulings following from references from the High Court of Justice of England and Wales. It is with some sadness that the commentator in us sees the Brexit taking away the most active Case Law provider in SPC matters.

Although I share Lionel’s concern regarding Britain’s major contribution to SPC case law, maybe we should not be too sad too soon; after all there are still many unknowns as to what comes next.

CASE REFERENCE: Cour d’appel de Paris, Pôle 5 chambre 1, April 12, 2016, The Government of the United States of America v. Directeur Général de l’INPI, RG No. 15/12234.