Michel De Puydt, Auteur à Droit & Technologies

Propriété intellectuelle

Publié le 28/12/2005

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

Rédige un résumé fluide et bien structuré de l’article suivant, d’une longueur comprise entre 220 et 250 mots : 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: 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 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: 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? 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? 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 .

Propriété industrielle

Publié le 18/11/2005

The bird flu: the provision and commercialization of Tamiflu under EC and international law

Rédige un résumé fluide et bien structuré de l’article suivant, d’une longueur comprise entre 220 et 250 mots : At this moment, several sources report the fast growing and international spreading of the bird flu (avian influenza). Recent news has in particular confirmed that this virus has reached the frontiers of the European Community, and even has penetrated within this territory via the UK. It is well known that Tamiflu is the medication that can treat people infected with bird flu. Tamiflu is not a vaccine, as it does not prevent from getting the disease. It is used when the patient becomes infected. Hereafter we will examine some relevant aspects of the legal framework pertaining to the provision and commercialization of Tamiflu or similar medicines. Firstly we will address the issue of compulsory licensing under patent law, being a mechanism allowing the overriding of existing patent rights on a medicine. Secondly we also discuss the relevant issue of the selling Tamiflu or similar medicines over the internet. 1. Aspects of patent law The Suisse pharmaceutical company Roche Holding AG owns the monopoly over production and marketing of the Tamiflu drug. The patent on this highly sought after bird flu drug is owned by the US biotech firm Gilead Sciences Inc. These exclusive rights of Roche and Gilead Sciences are now increasingly challenged, as governments all over the world are confronted with the mounting lack of production capacity by Roche to produce Tamiflu. Indeed, with fears of a global bird flu pandemic increasing, countries around the world have been advised to stockpile the drug, with the result that Roche is said not to be able to fulfill orders for the quantities necessary. Due to the urgent demand of Tamiflu, comparisons have been drawn with the availability of anti-AIDS drugs in poor countries. This is important under (international) patent law, as the Aids-crises led to new rules in the World Trade Organisation (WTO) that allow governments to cope with a public health emergency by waiving the patent rights of a private company and allowing the export of the drugs to encounter these public health problems. Indeed, on 30 August 2003, the WTO members agreed to open up a loophole in the TRIPs Agreement by giving some countries compulsory licensing rights for patented medicines in order to protect the public health within their territory ( for the content of this decision). All WTO member countries are eligible to import patented medicines under this decision, but 23 developed countries announced voluntarily that they will not use this system to import. A number of other countries announced separately that if they use the system it would only be for emergencies or extremely urgent situations. They are: Hong Kong China, Israel, Korea, Kuwait, Macao China, Mexico, Qatar, Singapore, Chinese Taipei, Turkey and United Arab Emirates. This means that in principle any WTO member, other than those who have renounced to use the system, may apply for a compulsory license on a patented drug that will help to face a disease threatening the public health of its population. In this regard, one can note that it has already been frequently suggested that the bird flu, and in particular the medicine Tamiflu, falls within the scope of this new agreement. Therefore, a WTO member would be allowed to apply for a compulsory licensing on the patent of Tamiflu in order to cope with a (possible) human flu pandemic. Under these new rules, any WTO member seeking to produce an anti-flu drug must first try to reach an agreement with the licence holder. It is reported that Roche said it had received only one request to produce Tamiflu so far, from Taiwan. Indian drugs maker Cipla, which is also involved in the production of cheaper generic copies of HIV/AIDS drugs under the WTO rules, reportedly has also shown an interest in producing copies of anti-flu drugs. However, despite the existence of the Agreement since August 2003, WTO members are still discussing on how to implement this political decision in the TRIPs Agreement. Discussion are in particular held with regard to the need to proceed this implementation via a new article, a footnote or otherwise. Divergent point of views also exists pertaining to the statute of the WTO Presidency declaration preceding the adoption of the August 2003 Agreement (which has a restrictive effect on the August 2003 system). One can hope that the current WTO negotiations on farm issues will result in a favorable climate to find an agreement in this domain of patent law. In the meanwhile, the European institutions currently discuss a draft regulation that envisages a uniform implementation of the August 2003 Agreement in national legislation of the EC Member States ( for the content of this draft). It is foreseen that the European Council will soon be able to reach an agreement in this regard. Taking into consideration the current lack of transposition of the WTO political agreement of August 2003 into the TRIPS Agreement and into the national legislations of the WTO members, one can wander into which extent this Agreement is enforceable by countries willing to apply for a compulsory license. It would not be so surprising if also this enforceability will depend on a certain degree of political willingness by some industrialized members… 2. The commercialization of Tamiflu over the internet In this context, the issue of the selling over the internet of bird flue medicines has to be addressed as well. It is indeed a fact that Tamiflu, as well as other, new or generic bird flue medicines, are currently being sold over the internet and that there are several advertising actions in this regard. When considering the legal framework of this practice, one may refer to the Deutscher Apothekerverband case of the European Court of Justice (E.C.J., 11 December 2003, Case C-322/01), from which the following can be derived: With regard to medicines that are only available on prescription, the Court of Justice took the view that allowing such medicines to be supplied on receipt of a prescription and without any other control could increase the risk of prescriptions being abused or incorrectly used. Furthermore, the fact that the labeling of a medicinal product may be in a different language can have more harmful consequences in the case of prescription medicines. Consequently, according to the Court, a national prohibition on mail order sales of medicinal products available only on prescription can be justified. In the case of non-prescription medicines, such a prohibition is not justified, since it would be possible that adequate advice and information may be provided. Internet buying may even have certain advantages, such as giving consumers time to think about any questions they may wish to ask the pharmacist from home. As the Tamiflu medicine is, according to our knowledge, in most cases only available on prescription, one has to conclude that the EC Member States concerned will be entitled to enjoin the selling of this medicine over the internet in the event this is done without a prescription. EC Member States sometimes prohibit the advertising to the general public of medicinal products, which are available on medical prescription only. In this regard, the Court stated that is not precluded a national prohibition on advertising the sale by mail order of medicinal products which may be supplied only in pharmacies in the Member State concerned, in so far as the prohibition covers medicinal products which are subject to prescription. In the present context, this court ruling means that the national courts of the EC- Member States will in principle be permitted to apply a law that forbids the advertising over the internet of the Tamiflu that merely can be supplied by pharmacies. With regard to the commercialization over the internet of new or generic bird flu medicines, one has further to take into account article 6 of Directive 2001/83/EC of on the Community code relating to medicinal products. This article states that no medicinal product may be placed on the market of a Member State unless a marketing authorization has been issued by the competent authorities of that Member State or an authorization has been granted in accordance with Regulation No 2309/93 (i.e. the Community Authorization Procedure). This obligation exists in all the EC Member States and is considered as being necessary to ascertain the safety, quality and efficiency of the medicinal products concerned. According to Article 18 of this Directive, an authorization granted by a Member State can nevertheless be recognized by another Member State of the European Union, but the latter is not compelled to proceed as such. Therefore, when an internet seller located and obtained an authorization in a particular EC Member State has not registered the medicinal product concerned in another EC Member State, a procedure of mutual recognition can be applied. Regarding imports of medicinal products by mail order by pharmacies authorized in other Member States in response to individual orders placed over the internet, the Court of Justice stated in the above mentioned case that, in relation to medicinal products which have not been authorized in a Member State, a general prohibition to commercialize these imported products in the latter is in conformity with the EC law and therefore applicable. However, as regards medicinal products, which have been authorized for sale on the market of a Member State, the Court points out that a national prohibition on the sale of medicinal products by mail order is not in conformity with the European Community law and is therefore not allowed. Considering this case law, one is permitted to sell a new or generic bird flu medicine over the internet when this product has been authorized. However, the selling will not be allowed the case when this product is sold over the internet into the EC Member State where no authorization has been granted for that product. EC Member States, or their courts, are therefore entitled to enjoin the internet sales of said medicinal products without an authorization, this depending on their domestic public health policies. In general, differences in policies indeed exist: for instance, The Netherlands have a more permissive attitude towards the commercialization of medicinal products via the internet, whereas France has a more restrictive approach. 3. Conclusion It is reported that health professionals are becoming concerned at the H5N1 bird flu strain’s emerging resistance to Tamiflu. Therefore, this and similar drugs might be less useful than anticipated if resistant-strains of the bird flu virus become more prevalent and the virus gains the ability to pass easily from person to person. One can therefore hope that the above said regulations will not hamper the necessary flexibility to face this new complication in combating this virus.

Michel De Puydt

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