Supplementary protection certificates: the concept of the combination of active ingredients of a medicinal product

Publié le 28/12/2005 par Paul Van den Bulck, Michel De Puydt

In case C-431/04 the European Court of Justice is being asked to consider the concept of ‘combination of active ingredients of a medicinal product’ within the meaning of Article 1(b) of Regulation No 1768/92 of 18 June 1992 concerning the creation of a supplementary protection certificate for medicinal products. In this regard, Advocate General Philippe…

In case C-431/04 the European Court of Justice is being asked to consider the concept of ‘combination of active ingredients of a medicinal product’ within the meaning of Article 1(b) of Regulation No 1768/92 of 18 June 1992 concerning the creation of a supplementary protection certificate for medicinal products.

In this regard, Advocate General Philippe Léger delivered his opinion on 24 November 2005, in which he concludes that the Court of Justice should respond in the affirmative.

Hereafter, we reflect his reasoning and arguments put forth.

I. Introduction

For reasons of protection of public health, the placing a proprietary medicinal product on the market requires an authorization to be granted by the EC Member States or Community authorities.

In Belgium, the national authorization is granted according to the Medicines Act of 25 March 1964, whereas the European community authorization is granted according to Regulation No 726/2004 of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.

Given the lengthy procedure related to this authorization, the filing of the application for a patent and the grant of authorization to place the product on the market reduces significantly the duration of the exclusive exploitation rights.

Therefore, in view of extending the duration of the rights that the patent confers on its holder, protection under a supplementary protection certificate can be sought. In Belgium, an SPC is be granted according to the Act of 29 July 1994 concerning the medicines protection certificate.

In this case, however, Regulation No 1768/92 concerning the creation of a supplementary protection certificate for medicinal products (hereafter: ‘SPC’) is at stake. This Regulation indeed introduces a SPC in completion to a previously granted national or European patent and at the request of the holder of this patent.

As to its duration, note that the SPC, according to Article 13 of the Regulation, takes effect upon the expiry of the basic patent for a period equal to the period which elapsed between the date on which the application for a patent was lodged and the date of the first authorization to place the product on the market in the Community reduced by a period of five years. This duration may not exceed five years from the date on which it takes effect.

II. History of case C-431/04

The chronology in this case goes as follows:

Massachusetts Institute of Technology (hereafter: ‘MIT’) is the holder of a European patent filed in 1987 and a German marketing authorization granted for Gliadel in 1999. Gliadel, being used to treat recurrent brain tumours in addition to surgery, is composed of an active substance, carmustine, and a polymeric, biodegradable excipient, polifeprosan.

Consequently, MIT applied to the German Patent and Trade Mark Office for a SPC, whereby it in particular requested that this SPC be granted for the combination carmustine with polifeprosan.

However, on the ground that polifeprosan cannot be considered to be an “active ingredient” within the meaning of Article 1(b) and Article 3 of Regulation No 1768/92, the German Office rejected this application.

An appeal was lodged against this decision, but rejected by the German Federal Patent Court in November 2002, as the latter now considered that the combination of carmustine and polifeprosan was not a “product” within the meaning of Article 1(b) of Regulation No 1768/92.

MIT then lodged an appeal with the German Federal Court of Justice against this latest decision.

Having doubts about the correct interpretation of Regulation No 1768/92, the German Federal Court of Justice submitted the European Court of Justice the following question:

Is there a ‘combination of active ingredients of a medicinal product’ within the meaning of Article 1(b) of Regulation No 1768/92 of 18 June 1992 concerning the creation of a supplementary protection certificate for medicinal products in the case of a medicinal combination of two substances, one of which is a known substance with pharmacological properties of its own and the other makes it possible to increase significantly the therapeutic effects of the first substance?

III. Regulation No 1768/92 as construed by the Advocate General

A. Construction of the concepts of “active ingredient” and “excipient”

Article 1 (b) of the Regulation defines a “product” as the active ingredient or combination of active ingredients of a medicinal product.

Note that the concept of ‘active ingredient’ is not defined in this Regulation. However, by referring to another Regulation No 847/2000 laying down the provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product, the Advocate General (hereafter: “A.G.”) defines an active ingredient as designating “a substance, such as a chemical compound or a natural solution, with pharmacological or physiological properties on which the therapeutic effect is based.”

The A.G. hereby distinguishes an ‘active ingredient’ from an ‘excipient’ and describes the latter as “an auxiliary substance, generally therapeutically inert, and needed for the manufacture, administration or conservation of the active ingredient. Its function is to act as a vector or carrier for the active ingredient, thereby contributing to certain properties of the product, such as its stability, its galenical form or its acceptability for the patient.”

Prolifeprosan is the excipient at issue in the present case. It has been developed in order to counter inefficiency problems related to therapies offered for the treatment of brain cancer (such as chemotherapy).

Even if prolifeprosan does not have any pharmacological properties of its own, it allows, one the one hand, to increase the intended therapeutic effect of the active ingredient and, on the other hand, to avoid the harmful side-effects associated with the intravenous administration of carmustine (which is a toxic substance causing the patient painful and harmful side effects following its intravenous administration).

B. Subject matter of case C-431/04

In the specific case where the excipient is necessary for the therapeutic efficacy of the active ingredient, the A.G. does not believe that Article 1 (b) of the Regulation precludes a combination comprising an active ingredient and an excipient from classification as a “product”.

He is indeed of the opinion that such an interpretation would be too restrictive and that it is neither consistent with ‘the broad logic’ of the Regulation, nor with ‘the objectives pursued by the Community legislature’:

Firstly, by referring to the Articles 3, 4 and 5 of the Regulation, the A.G. underlines that the SPC is closely linked to the national or European patent previously granted and to the marketing authorization granted by the competent national authorities.

Indeed, as to the conditions set forth by the Regulation, the SPC may be granted only if the product in question is both protected by a basic patent and authorized to be placed on the market. Its protection hereby extends only:

1. within the limits of the protection conferred by the patent, this to say that the holder of the certificate not only enjoys the same rights as conferred by the basic patent, but is also subject to the same limitations and the same obligations laid down by the patent; and
2. to the product covered by the marketing authorization.

For these reasons, the A.G. does not see why a medicinal combination, (i) protected by a patent and (ii) for which a marketing authorization has been granted, would be excluded from enjoying supplementary protection under Regulation No 1768/92, if that combination is also among the therapeutic innovations covered by this Regulation.

Secondly, under reference to its advantages reflected above, the A.G. highlights that the combination of the excipient prolifeprosan gives the active ingredient entirely new properties in terms of efficacy and safety of use. Accordingly, in view of the A.G., it is not really important for the grant of the SPC that the active ingredient has already been known before, since it did not have these kinds of pharmaceutical properties.

The A.G. believes it to be regrettable if this new method of therapeutic treatment were not protected in the same way as research into active ingredients alone.

As the combination of an active ingredient with a substance (even if does not have any pharmacological properties of its own) allows the biologically active substance to effectively release its therapeutic effects, he in particular takes the view that such a combination must fall within the scope of ‘combination of active ingredients of a medicinal product’ within the meaning of Article 1(b) of Regulation No 1768/92.

Within this framework, the necessity of the excipient for ensuring the therapeutic efficacy of the active ingredient must be the determining factor in ascertaining whether a combination of these two substances is indeed covered by this concept of ‘combination of active ingredients of a medicinal product’.

IV. Conclusion

In the light of the above, the A.G. concludes that “the concept of “combination of active ingredients of a medicinal product” within the meaning of Article 1(b) of the Regulation must be interpreted as meaning that it does not preclude the grant of an SPC to a combination of two substances, one of which is a known substance with pharmacological properties of its own for a specific therapeutic indication and the other is necessary for the therapeutic efficacy of the first substance, for this indication.”

One has to look now into which extent the Court of Justice will follow the A.G.’s opinion. More important is that, regardless of the outcome of this case, the Court will consider the issue and give its interpretation of Article 1 (b) of the Regulation (to be taken up by the EC Member State authorities).

Within this framework, we finally point out that not only this case C-431/04 will lead to the interpretation of what constitutes a “product” under Article 1(b). Indeed, one has to refer also to case C-202/05, in which a preliminary ruling concerning the following issues has been requested:

1. In a case in which the basic patent protects a second medical application of a therapeutic agent what is meant by “product” in Article 1 (b) of the Regulation and in particular does the application of the therapeutic agent play any part in the definition of « product » for the purpose of the Regulation?
2. Does the term « combination of active ingredients of a medicinal product » within the meaning of Article l (b) of the Regulation mean that each component of the combination must have therapeutic activity?
3. Is there a « combination of active ingredients of a medicinal product » where a combination of substances comprising two components of which one component is a substance with a therapeutic effect for a specific indication and the other component renders possible a form of the medicinal product that brings about efficacy of the medicinal product for that indication?

More info ?

Reading the opinion of the Advocate General on our website on our website .