Fixed-dose combination of active substances

A fixed-dose combination is a medicinal product that combines several active substances in a single pharmaceutical form and at set doses. Where those substances are already used in authorised medicinal products but have not yet been combined for therapeutic purposes, Article 10b of Directive 2001/83/EC requires the results of new pre-clinical tests or clinical trials relating to the combination, without requiring scientific references for each individual substance. Fixed-dose combinations are a common life-cycle management tool for medicinal products.

The regulatory regime

The applicant must justify the rationale for the combination, for example a benefit in efficacy, safety or compliance, compared with separate administration of the substances. A generic of the combination must refer to the authorised combination and demonstrate bioequivalence with it.

Fixed-dose combinations and the supplementary protection certificate

Regulation (EC) No 469/2009 defines the product as the active ingredient or combination of active ingredients of a medicinal product, which makes it possible to apply for a supplementary protection certificate for a combination. The combination must, however, be protected by the basic patent. The Court of Justice of the European Union requires that the combination necessarily fall, from the point of view of the person skilled in the art, under the invention covered by the patent, read in light of the description, and that each of the active ingredients be specifically identifiable. A certificate sought for a combination including an active ingredient already covered by an earlier certificate also raises questions that have given rise to successive references for a preliminary ruling.

Fixed-dose combinations in patent law

In patent law, a combination of known substances is in principle inventive only if it produces a technical effect of its own that goes beyond the sum of the effects of each substance. Inventive step is assessed in light of this effect, and case law distinguishes a true combination invention, whose elements cooperate towards a common result, from a mere juxtaposition of known means. In launch litigation, a generic of the combination may infringe both the patent on the combination and the patents still in force on each substance.

Key points

A fixed-dose combination is both a stand-alone regulatory product and the subject of patents and certificates whose validity is often disputed. For each combination, the specific regulatory protection, the basic patent capable of supporting a certificate and the status of the rights covering each substance should be checked. For a generic manufacturer, the expiry of the rights on the individual components is not enough to clear the combination.

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This glossary entry is general in scope and does not constitute legal advice.

Dhenne Avocats acts in pharmaceutical patent disputes and on the medicines regulatory questions that accompany them, from the marketing authorisation to the supplementary protection certificate.

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