Supplementary Protection Certificates
This article was originally published in SRA
Executive Summary
AG interprets meaning of ‘combination of active ingredients’
AG interprets meaning of ‘combination of active ingredients’
A combination product containing an active ingredient and an excipient that enhances the effectiveness of that ingredient can be eligible for an EU supplementary protection certificate (SPC), according to Advocate General Philippe Léger of the European Court of Justice1.
The advocate general was replying to a question posed by the German federal court of justice (Bundesgerichtshof) relating to Article 1(b) of Regulation No 1768/92. The regulation states that an SPC can be awarded to a product that is protected by a patent and has a marketing authorisation, and defines ‘product’ as an active ingredient or a combination of active ingredients2. The federal court wanted to know whether this definition should be interpreted as including a combination of two substances where only one has pharmacological properties but the other is necessary for that substance's efficacy.
The case before the German court involved Gliadel, an implantable wafer combining the anticancer, carmustine, with a polymeric biodegradable excipient, polifeprosan. Gliadel is marketed for malignant brain tumours by Guilford Pharmaceuticals (now part of MGI Pharma) under licence from the Massachusetts Institute of Technology (MIT).
MIT had applied to the German patent and trademark office for an SPC for Gliadel. But in 2001 the office rejected the application, saying that polifeprosan could not be considered an active ingredient within the meaning of the SPC regulation. The combination of carmustine and polifeprosan in Gliadel, it said, was therefore not a ‘combination of active ingredients’ as required by the regulation and did not qualify for an SPC.
MIT appealed to the German federal patent court, which dismissed the appeal, saying that both of the constituents had to be active ingredients, each with its own therapeutic effect. MIT subsequently took its case to the federal court of justice, claiming that polifeprosan was not an excipient but an essential component of Gliadel that enhanced the efficacy of carmustine. Without polifeprosan, the controlled release of the highly toxic carmustine would not be possible.
Definition of active ingredient
The federal court of justice noted that there was no definition of the terms ‘active ingredient’ or ‘combination of active ingredients’ either in the regulation or in the court's case law. In its view, it could be assumed that the combination of a new excipient with a known active substance would be eligible for an SPC if it resulted in a new medicinal product in which the therapeutic effects of the active substance were defined and controlled by the excipient. It noted that this interpretation had been adopted by some member states, in so far as France and the UK had already awarded SPCs for Gliadel.
The advocate general went along with this interpretation. ‘Whilst Article 1(b) of Regulation No 1768/92, as it is worded, means in principle, a combination of two or more active substances, I do not think that a purely literal interpretation of that provision allows a combination comprising an active ingredient and an excipient to be disqualified from classification as a ‘product’ within the meaning of the regulation in the specific case where the excipient is necessary for the therapeutic efficacy of the active ingredient.’
Moreover, he said, this interpretation was line with the regulation's aim of improving public health in the EU by rewarding therapeutic advances. Gliadel was an example of such an advance, as it allowed the efficacy of carmustine to be improved and its side-effects reduced. He said it clearly would not be appropriate to grant an SPC whenever the characteristics of a medicinal combination were changed slightly. However, in the case of Gliadel, the product involved was a major innovation resulting from long and costly research and was precisely the kind of advance that the regulation sought to protect. Disqualifying such products from qualifying for an SPC might discourage investment in the development of such products in the EU. Such research, he declared, was essential to progress in medical treatment and to the competitiveness of the pharmaceutical industry in the EU.
The advocate general said that the determining factor in ascertaining whether a combination of two substances was covered by ‘combination of active ingredients’ should be ‘the necessity of the excipient for ensuring the therapeutic efficacy of the active ingredient’. The French government had expressed concern about the difficulties that would be faced by national bodies responsible for granting SPCs in applying such a criterion, and the possibility that different practices might emerge in the various member states, the advocate general noted. But he did not see a problem with that. The national bodies, he said, had access to the necessary information in the basic patent and the marketing authorisation, the latter having to contain highly precise data on the characteristics of the product and its constituents, and on its pharmaceutical qualities and efficacy. Moreover, he said, while there was a risk of different assessments being adopted by national bodies in applying the criterion, this risk was inherent in the SPC procedure itself, as the award of an SPC remained a national procedure.
The opinion is seen as an additional incentive to the development and patenting of new formulations of existing products, provided these new formulations represent a significant advance over existing treatments.
References
1. Opinion of advocate general Léger, 24 November 2005, Case C-431/04, reference for a preliminary ruling from the Bundesgerichtshof, Germany, http://europa.eu.int/jurisp/cgi-bin/form.pl?lang=en&Submit=Submit&alldocs=alldocs&doc =docj&docop=docop&docor =docor&docjo=docjo&numaff=C-431%2F04&datefs=&datefe=&nomusuel= &domaine= &mots=&resmax=100
2. Council Regulation EEC No 1768/92 of 18 June 1992 concerning the creation of a supplementary protection certificate for medicinal products, http://pharmacos.eudra.org/F2/eudralex/vol-1/REG_1992_1768/REG_1992_1768_EN.pdf