Following widespread litigation over Halozyme’s two SPC families for Herceptin Hylecta® and MabThera®, inconsistent decisions across Europe led to a much-needed referral in 2024 to Europe’s highest court, the CJEU. The key issue for the CJEU to grapple with is whether recombinant human hyaluronidase can be considered an “active ingredient” within the meaning of Article 1(b) of the SPC Regulation, despite its characterisation as an excipient in the marketing authorisation (MA) documents for the marketed medicinal products.
Today, a significant step was taken with the publication of a legal opinion by Advocate General Emiliou (available here). The Advocate General (AG) proposes that the “active ingredient” of a medicinal product should be determined by reference to the classification of substances set out in the MA relied upon in support of the SPC application. Hence, a substance which is expressly designated as an excipient in the MA cannot be regarded as an active ingredient.
Background
Article 3(d) of the SPC Regulation requires that SPCs are granted based on the first authorisation to place the “product” on the market. The term “product” is defined in Article 1(b) as an “active ingredient” or a “combination of active ingredients”, but the term “active ingredient” is not further defined in the SPC Regulation.
In many cases, it is clear how to define the “active ingredient(s)” in a medicine. However, every so often, a situation arises which raises questions. In the case of Herceptin Hylecta® and MabThera®, which combine previously approved trastuzumab or rituximab, respectively, with recombinant human hyaluronidase, a question arose during the course of examination of Halozyme’s SPC applications for these combinations as to whether recombinant human hyaluronidase qualifies as an “active ingredient” under Article 1(b) of the SPC Regulation. In the MAs for Herceptin Hylecta® and MabThera®, recombinant human hyaluronidase is listed as an excipient. However, Halozyme has relied on evidence outside of the regulatory documents to support its position that recombinant human hyaluronidase should be considered an active ingredient in its own right.
If recombinant human hyaluronidase is found not to be an “active ingredient”, Halozyme’s SPC applications would be unallowable under Article 3(d) in view of earlier MAs for the antibody monotherapies, trastuzumab and rituximab.
On the basis of the existing case law regarding the meaning of “active ingredient”, the Czech Supreme Administrative Court was unable to resolve whether Halozyme’s Czech SPC applications should be granted and so referred questions to the CJEU (see our previous articles here and here). The central question referred is whether Article 1(b) should be interpreted as precluding a substance expressly designated as an excipient in the MA for a medicinal product from being regarded as an “active ingredient”. If this is not the case, the CJEU was asked to clarify which documents can be considered when determining whether a given substance can be considered an “active ingredient”. The CJEU was also asked subsidiary questions about how to assess whether a combination product is protected under Article 3(a) of the SPC Regulation.
The AG Opinion
Today’s publication of AG Emiliou’s opinion is a major milestone in this case. An AG is usually asked by the CJEU’s judges to prepare an advisory opinion about the legal issues at stake before those judges reach a decision. While non-binding, AG opinions are often influential on the CJEU’s decision as well as in future cases.
AG Emiliou has proposed that the qualification of a substance as an “active ingredient” within the meaning of Article 1(b) of the SPC Regulation is to be determined by reference to the classification of that substance as an active substance or an excipient by the competent regulatory authority (e.g. the European Medicines Agency) in the MA, in particular the summary of product characteristics, relied upon in support of the SPC application. This means that a substance which is expressly designated as an excipient in the relevant MA cannot be regarded as an “active ingredient” for the purpose of Article 1(b) of the SPC Regulation.
In coming to this conclusion, the AG emphasised the importance of legal certainty and the inextricable link between the SPC Regulation and the regulatory framework for pharmaceuticals. In particular, he confirms that “active substance” in the Medicinal Products Directive and “active ingredient” in the SPC Regulation should be applied uniformly and consistently across both legal frameworks, and on this basis, “excipients” and “active substances” must be distinct and mutually exclusive categories in both contexts.
The AG also explained that a substance cannot be subsequently reclassified as an active ingredient during the SPC procedure in order for it to qualify as a “product” eligible for SPC protection. The complex, technical assessment of what constitutes the active substance in a medicinal product is carried out by the competent regulatory authority and that assessment must not be replaced or disregarded during the SPC procedure. Reassessment by national patent offices and courts would be at odds with the objective of simplicity and efficiency pursued by the SPC Regulation, whilst at the same time undermining legal certainty. The task of national patent offices is instead confined to a formal verification of the classification attributed to that substance in the MA. Indeed, the AG’s view is that the classification in the MA remains determinative, even if research from after the grant of the MA indicates that a substance not classified as an active ingredient in the MA nonetheless performs a function comparable to that of an active ingredient.
Having answered the first referred question relating to Article 1(b) in a way that resolves the underlying dispute such that recombinant human hyaluronidase is not an active ingredient, the AG did not consider it necessary to propose an answer to the other questions relating to Article 1(b). He also did not propose answers to the questions concerning Article 3(a), having been asked not to do so by the CJEU, but AG Emiliou comments that the issues raised in those questions have already been resolved by the CJEU’s judgment in joined cases C-119/22 and C-149/22 Merck (see our article).
Conclusion
The AG’s proposed, strict approach that the classification in the MA is determinative and may not be departed from will likely be welcomed by some as improving certainty and simplicity in certain cases. It is also interesting to note that this proposed approach was supported by the European Commission and all national governments that submitted observations in the Halozyme case. There will, however, be voices that argue that the AG’s approach fails to address technical nuances, and that it risks leading to an undue denial of SPC protection in cases involving significant and valuable research and innovation.
While the AG opinion offers some guidance at this stage, it is ultimately non-binding and we will have to wait for the CJEU’s eagerly anticipated decision to provide definitive answers.