Excipient or active ingredient? Look to the marketing authorisation…

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 “no” to the question of whether a substance designated as an “excipient” in the marketing authorisation (MA) for a medicinal product can nonetheless be considered an “active ingredient” 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.

Background

The case in question centres around Halozyme’s 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.  The MA for Herceptin SC lists trastuzumab as an active ingredient, and rHuPH20 as an excipient.  However, Halozyme’s 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.

In the EU medicinal products SPC Regulation, Article 1(b) defines the “product” as  “the active ingredient or combination of active ingredients of a medicinal product”.  Identifying the “product” for which an SPC is sought is important because other provisions in the Regulation – including the requirements for grant in Article 3 – are defined with reference to it.  However, “active ingredient” is not defined in the SPC Regulation.

In the Halozyme case, if rHuPH20 could not be considered an active ingredient, the “product” would be trastuzumab alone.  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.

Halozyme had filed SPC applications across Europe, with divergent outcomes as national offices reached different conclusions.  Ultimately, the Czech court made a request for clarification by the CJEU.  Of the six questions referred to the CJEU, Q1-4 dealt with the “active ingredient” issue (Q5 & 6 related to Article 3(a) and are not addressed in the Opinion).  Q1 asked:

Is Article 1(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?

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.

The Advocate General Opinion

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.  Moreover, his comments do not appear to be limited to excipients alone, but suggest that determining whether “a substance” qualifies as an active ingredient should rely exclusively on the classification of the substance in the MA.

A key factor in the Advocate General’s 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.  He points, for example, to provisions in the SPC Regulation which tie the SPC “product” to the language in the MA – for example “the product covered by the MA” in Article 4.  He also notes that in his view, the terms “active substance” as used in the Directive and “active ingredient” as used in the SPC Regulation are conceptually synonymous and should be applied in a consistent way, in line with the CJEU’s previous decisions in MIT (C-431/04) and GSK (C-210/13).  He notes that the Directive clearly distinguishes between active substances and excipients – in his view this same distinction should also be followed in the SPC procedure.

In the Opinion, the Advocate General repeatedly stresses that the relevant regulatory authorities have the necessary expertise to assess substances for “active ingredient” status – and that any attempt at reassessment of this status by national patent offices (who are not similarly equipped) would not be appropriate.  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.  Conversely, revisiting the issue at a national patent office – with potential reclassification of an excipient in the MA as an active ingredient – would be contrary to the SPC Regulation’s objectives, as the excipient would not have been subject to the same degree of scrutiny as an active substance during the regulatory process.

Halozyme’s 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.  In the Advocate General’s 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’s 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.

Next steps and practice points

The Advocate General Opinion is ultimately non-binding on the court, and therefore we await the final CJEU judgement with interest.

If the court follows the strict approach in the Opinion, this would provide clarity in the system, but would also appear to largely close the door to attempts to overcome Article 3(d) restrictions by asserting that active ingredients formulated with specific excipients represent combinations of actives. What does seem clear is the need for close cooperation and communication between regulatory teams and patent attorneys to ensure that regulatory and SPC strategy are consistent, as the Advocate General clearly favours alignment of the two for SPC purposes.

More broadly, MA classification and differences between regulatory frameworks are also important factors in two other pending referrals at the CJEU (Boehringer Ingelheim C-15/26 and Stada C-794/25).  It will be interesting to see whether the approach in the Opinion might also have implications for the outcome in those referrals.

This article was prepared by Patent Director Karen Russell.