In a new referral (C-262\/26), the EU\u2019s Court of Justice has been asked to decide whether a medicine which receives a marketing authorisation (MA) as a monotherapy, but labelled with instructions to take it in combination with another medicine (a so-called \u201cloose combination\u201d) is eligible for SPC protection as a combination of active ingredients in the EU.\u00a0 The decision has the potential to resolve over a decade of uncertainty in this area and to shape the pharmaceutical industry\u2019s regulatory strategy on combination products in Europe.<\/p>\n
Background \u2013 \u201cfixed\u201d and \u201cloose\u201d combinations<\/strong><\/p>\n Although much research in the pharmaceutical industry is devoted to bringing new medicines to market, considerable research is also directed at combinations of already known medicines.\u00a0 There are many well-known benefits in combining medicines.\u00a0 For example, the two medicines may have a synergistic interaction so that their combined effect is greater than the additive effect of each of them when used alone.\u00a0 Alternatively, the use of one medicine may lessen adverse effects associated with taking the other.<\/p>\n Combination medicines may take two possible forms.\u00a0 In a \u201cfixed\u201d combination, the two active ingredients (A and B) are present in the same product, in a fixed dosage ratio.\u00a0 Fixed combinations are particularly prevalent in the field of vaccines, as administering multiple vaccinations in a single dosage form minimises the number of injections required.\u00a0 When a fixed combination receives a marketing authorisation (MA), both actives A and B are recited on the MA.<\/p>\n However, the fixed combination model is not always appropriate for all medicines.\u00a0\u00a0 For example, in the oncology field, it is common for dosages of one or both active ingredients to be tapered up and down, to maximise efficacy while minimising the risk of adverse effects.\u00a0 This is more difficult to do if the two active ingredients are present in a fixed dosage ratio in the same product.<\/p>\n To take account of this, it is common for applicants to seek an MA for only one active ingredient of such a combination therapy \u2013 but with suitable wording included in the product label that the product should be taken in combination with one or more other actives. \u00a0Such a combination therapy is termed a \u201cloose combination\u201d. The wording in the label typically takes the form:<\/p>\n \u201cA is indicated in combination with B for the treatment of patients with disease C\u201d.<\/em><\/p>\n Regardless of whether the approved combination is fixed or loose, it is undisputed that long, costly research is required for a combination product to obtain an MA.<\/p>\n Furthermore, the initial grant of the MA is not the end of the story from a regulatory perspective.\u00a0 Even if a medicine is initially granted an MA as a monotherapy for treating one condition, if further research indicates the approved drug is also efficacious against another condition, either on its own or in combination with other medicines, the MA can be amended to also include the new indication and\/or combination.\u00a0 In the EU, such an amendment is known as a \u201cType II variation\u201d of the MA.<\/p>\n EU SPC legislation for combination products<\/strong><\/p>\n Supplementary Protection Certificates (SPCs) extend the term of patents in the EU for medicinal products which require an MA before they can be marketed.\u00a0 The aim of SPCs is to compensate the patent holder for the patent term lost while the medicine undergoes the efficacy and safety testing required to obtain the MA.<\/p>\n Under Article 1(b) of the EU SPC Regulation, the \u201cproduct\u201d which is the subject of the SPC is defined as \u201cthe active ingredient or combination of active ingredients of a medicinal product\u201d<\/em>.\u00a0 However, the legislation is silent regarding whether the authorised combination must be a fixed combination or can also be a loose combination.<\/p>\n Previous case law<\/strong><\/p>\n It is settled case law in the EU and UK that an SPC can be granted for a fixed combination.\u00a0 However, several previous attempts to obtain SPC protection for loose combinations have failed.\u00a0 Typically, these cases have arisen from a mismatch between the claims of the basic patent and the subject of the MA.<\/p>\n For example, in the Yeda<\/em> case, the applicant sought SPC protection for a loose combination of cetuximab and irinotecan.\u00a0 In the UK, the SPC application was refused by the UK Intellectual Property Office for non-compliance with Article 3(b) of the SPC Regulation, on the grounds the MA was for cetuximab alone \u2013 the wording of the label to combine it with irinotecan being considered relevant only for how the medicine was to be used.\u00a0 The UKIPO also refused a parallel SPC filing directed to cetuximab as monotherapy for non-compliance with Article 3(a) on the grounds the basic patent was directed to a combination. The UK Patents Court upheld the UKIPO\u2019s decision on both SPCs, and the CJEU (in decision C-518\/10) ultimately upheld the Article 3(a) refusal.<\/p>\n More recently, in the Newron<\/em> case, the UKIPO refused Newron\u2019s SPC application for a loose combination of safinamide, levodopa and PDI on similar grounds.\u00a0 Once again, the UKIPO ruled that the MA was for safinamide alone, and the combination language related to how the product should be used and was not part of the definition of the product.\u00a0 The UK Patents Court and the Court of Appeal both upheld the UKIPO\u2019s decision.<\/p>\n Some EU countries granted parallel SPCs based on the same basic patent. Other EU countries refused SPCs directed to loose combinations of safinamide, levodopa and PDI for non-compliance with Article 3(b), and some others also refused SPCs directed to safinamide as monotherapy for non-compliance with Article 3(a).\u00a0 However, the refusals of the safinamide mono-SPCs were overturned on appeal in both Portugal and Germany (although the German SPC is now the subject of nullity proceedings).<\/p>\n In other case law, the CJEU has defined the concept of \u201cproduct\u201d in a strict sense, as not including the use of the product.\u00a0 However, these cases related to attempts to obtain SPCs for new uses or new formulations of a previously authorised product \u2013 the CJEU has not previously been asked to consider whether combination language in the product label of a drug approved as monotherapy can enable a loose combination to be the subject of SPC protection.<\/p>\n Facts of the case \u2013 Genmab\u2019s SPC applications<\/strong><\/p>\n The referral originates from Genmab\u2019s attempts to obtain SPC protection for various loose combinations including daratumumab (DARZALEX\u00ae).\u00a0 The compound was originally approved by the European Medicines Agency in 2016 as a monotherapy \u2013 but afterwards, multiple Type II variations were approved by the EMA for daratumumab in loose combinations.<\/p>\n Genmab sought multiple SPCs for loose combinations including daratumumab based on the Type II variations and its basic patent EP2081595.\u00a0 In support of the SPC applications, Genmab pointed out that the effort required to obtain a MA for a loose combination was no less demanding than that required for a fixed combination.\u00a0 Based on this, Genmab argued that the SPC Regulation should be interpreted in a purpose-based (\u201cteleological\u201d) manner to allow for loose combination SPCs in situations where it is not possible to formulate the active ingredients in a fixed combination.<\/p>\n Although the Patent Offices of some EU countries granted the combination SPCs, they were refused in many EU countries, including France, Germany and the Netherlands, for non-compliance with Article 3(b) of the SPC Regulation, on the grounds that the MA relied upon was for daratumumab.\u00a0 The UKIPO also refused the loose combination SPC applications for similar reasons, citing the earlier Yeda<\/em> and Newron<\/em> decisions, and appeals against the UKIPO\u2019s decision on most of these SPCs have been withdrawn.<\/p>\n The Danish Patent Office also refused the SPC application, and its Board of Appeal upheld the decision.\u00a0 Genmab appealed the decision further to the Danish Maritime and Commercial Court. \u00a0The Court was more receptive to Genmab\u2019s arguments that the possibility of obtaining loose combinations is consistent with the objective of the SPC Regulation, and that the combination of actives could therefore represent a new \u201cproduct\u201d within the meaning of the Regulation.\u00a0 In particular, the Court noted the applicant\u2019s view that it would be inappropriate and contrary to the objective of the Regulation to draw a distinction between fixed and loose combinations, given that it is not always possible to formulate combinations in a fixed combination. It was also open to the possibility of obtaining an SPC based on a Type II variation of an existing MA.<\/p>\n Questions referred<\/strong><\/p>\n To attempt to resolve the uncertainty over whether loose combinations merit SPC protection, the Danish Court has referred the following two questions to the CJEU:<\/p>\n