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.

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