In his recently issued (non-binding) Opinion in the Halozyme referral to the Court of Justice of the EU (C-456\/24), the Advocate General has delivered a decisive \u201cno\u201d to the question of whether a substance designated as an \u201cexcipient\u201d in the marketing authorisation (MA) for a medicinal product can nonetheless be considered an \u201cactive ingredient\u201d for SPC eligibility purposes. In fact, the Advocate General appears to go further, suggesting that the classification of substances in the MA is decisive for determining whether the substance can be considered an active ingredient in general.<\/p>\n
Background<\/strong><\/p>\n The case in question centres around Halozyme\u2019s attempts to obtain SPC protection for the combination of trastuzumab (a monoclonal antibody) and rHuPH20 (a recombinant hyaluronidase), based on approval of the Herceptin SC product.\u00a0 The MA for Herceptin SC lists trastuzumab as an active ingredient, and rHuPH20 as an excipient.\u00a0 However, Halozyme\u2019s position (pointing to evidence outside of the MA) was that despite this classification, rHuPH20 should be regarded as an active ingredient in its own right.<\/p>\n In the EU medicinal products SPC Regulation, Article 1(b) defines the \u201cproduct\u201d as \u00a0\u201cthe active ingredient or combination of active ingredients of a medicinal product\u201d.\u00a0 Identifying the \u201cproduct\u201d for which an SPC is sought is important because other provisions in the Regulation \u2013 including the requirements for grant in Article 3 \u2013 are defined with reference to it.\u00a0 However, \u201cactive ingredient\u201d is not defined in the SPC Regulation.<\/p>\n In the Halozyme case, if rHuPH20 could not be considered an active ingredient, the \u201cproduct\u201d would be trastuzumab alone.\u00a0 Since trastuzumab had already been approved and marketed for some time, the Herceptin SC MA would not be the first approval of the product and the SPC application would not meet the requirements of Article 3(d) of the Regulation.<\/p>\n Halozyme had filed SPC applications across Europe, with divergent outcomes as national offices reached different conclusions.\u00a0 Ultimately, the Czech court made a request for clarification by the CJEU.\u00a0 Of the six questions referred to the CJEU, Q1-4 dealt with the \u201cactive ingredient\u201d issue (Q5 & 6 related to Article 3(a) and are not addressed in the Opinion).\u00a0 Q1 asked:<\/p>\n Is Article\u00a01(b) of [the SPC Regulation] to be interpreted as meaning that a substance expressly designated as an excipient, in the authorisation for a medicinal product, cannot be regarded as an active ingredient<\/em>?<\/p>\n The remaining Q2-4 sought clarification as to whether any other evidence, apart from the MA, might be relied on to determine active ingredient status.<\/p>\n The Advocate General Opinion<\/strong><\/p>\n The Advocate General has made it clear that, in his view, the classification of the relevant substance as specified in the MA is decisive, and a substance which is designated as an excipient in the MA cannot be regarded as an active ingredient for SPC purposes.\u00a0 Moreover, his comments do not appear to be limited to excipients alone, but suggest that determining whether \u201ca substance\u201d qualifies as an active ingredient should rely exclusively on the classification of the substance in the MA.<\/p>\n A key factor in the Advocate General\u2019s reasoning appears to be what he describes as an inextricable link between the SPC regime on one hand, and the EU pharmaceutical regulatory framework (in particular the EU Medicinal Products Directive) on the other.\u00a0 He points, for example, to provisions in the SPC Regulation which tie the SPC \u201cproduct\u201d to the language in the MA \u2013 for example \u201cthe product covered by the MA\u201d in Article 4.\u00a0 He also notes that in his view, the terms \u201cactive substance\u201d as used in the Directive and \u201cactive ingredient\u201d as used in the SPC Regulation are conceptually synonymous and should be applied in a consistent way, in line with the CJEU\u2019s previous decisions in MIT (C-431\/04) and GSK (C-210\/13).\u00a0 He notes that the Directive clearly distinguishes between active substances and excipients \u2013 in his view this same distinction should also be followed in the SPC procedure.<\/p>\n In the Opinion, the Advocate General repeatedly stresses that the relevant regulatory authorities have the necessary expertise to assess substances for \u201cactive ingredient\u201d status \u2013 and that any attempt at reassessment of this status by national patent offices (who are not similarly equipped) would not be appropriate.\u00a0 In that sense, he continues, reliance on the MA classification is in line with the objectives of the SPC regime which seek simplicity, transparency and uniformity.\u00a0 Conversely, revisiting the issue at a national patent office \u2013 with potential reclassification of an excipient in the MA as an active ingredient \u2013 would be contrary to the SPC Regulation\u2019s objectives, as the excipient would not have been subject to the same degree of scrutiny as an active substance during the regulatory process.<\/p>\n Halozyme\u2019s attempts to rely on evidence of therapeutic activity outside the approval documents, based in part on the CJEU ruling in the earlier Forsgren case (C-631\/13) are rejected.\u00a0 In the Advocate General\u2019s view, the Forsgren judgement should be construed more narrowly in the context of the facts in that case, where the substance at issue had not been clearly classified in the MA. Moreover, and in any case, he considers that the Forsgren ruling in fact supports his position that the MA is authoritative. Halozyme\u2019s arguments with respect to the Bayer CropScience case (C-11\/13) concerning possible SPC eligibility of safeners in plant protection products are also dismissed, partly on the basis that plant protection products are subject to a different regulatory framework.<\/p>\n