In recent years, we have been following the journey of two SPC families covering the marketed products Herceptin Hylecta® and MabThera®. Crucial to the fate of these SPC applications 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 regulatory documents. After widespread litigation, the SPC applicant Halozyme has been left with inconsistent decisions across Europe.
Since our 2024 article, two significant developments have occurred: (i) a much-needed CJEU referral by the Czech courts on Halozyme’s SPC application for Herceptin SC (also referred to as Herceptin Hylecta®), and (ii) the judgment of the England and Wales High Court to dismiss Halozyme’s appeal against the UKIPO’s refusal of both of their GB SPC applications. These developments are discussed in more detail in this article, along with a background to the litigation.
Background
SPCs are granted based on the first marketing authorisation for a “product”. The “product” is defined in Article 1(b) as an “active ingredient” or “combination of active ingredients”, neither of which is defined in the SPC Regulation. This means that a combination of “active ingredients” that has not previously been approved together is treated as a new “product”, even if each component has been previously authorised separately. Therefore, when an applicant is seeking an SPC to a new product containing an “active ingredient” that has previously been authorised, establishing that there is a second “active ingredient” present in the new product can open the door to new SPC protection for the combination. A key question in these circumstances is what counts as an “active ingredient”?
Herceptin Hylecta® contains trastuzumab in combination with recombinant human hyaluronidase, and its SPCs are based on EP‑B‑2,163,643. MabThera® contains rituximab also in combination with hyaluronidase, and its SPCs are based on EP‑B‑2,405,015. Trastuzumab and rituximab were authorised as monotherapies many years before these basic patents were filed.
Given the prior authorisations for trastuzumab and rituximab, Halozyme needs recombinant human hyaluronidase to be considered an “active ingredient” to obtain SPCs for Herceptin Hylecta® and MabThera®. This is required for the combination of trastuzumab or rituximab with hyaluronidase to be considered a new “product”. Halozyme needs this to be the case for at least two reasons:
1. To satisfy Article 3(d), Halozyme needs the marketing authorisations of the combination products supporting the SPC application to be the first authorisation to place each product on the market (otherwise, the prior approval of trastuzumab/rituximab would be considered the first authorisation).
2. Halozyme needs the later dates of the combination product authorisations to be the relevant marketing authorisation dates for the purposes of calculating SPC term. Only the authorisation dates of the combination products would yield positive SPC term (SPCs based on the monotherapy approvals would have no positive term).
Article 1(b)
As noted above, Article 1(b) of the SPC Regulation defines a “product” as “the active ingredient or combination of active ingredients of a medicinal product”. The CJEU has already spent quite some time considering the interpretation of “active ingredient” in the context of Article 1(b).
In MIT (C-431/04), the CJEU held that an “active ingredient” in the context of Article 1(b) must provide an effect of its own on the human or animal body. Therefore, an excipient that provided no effects was not an “active ingredient”. In GSK (C-210/13), the CJEU held analogously than an adjuvant which provides no therapeutic effects of its own is not an “active ingredient”.
A seminal case on the interpretation of Article 1(b) is Forsgren (C-631/13). In this case, the CJEU held that an ”active ingredient“ “produces a pharmacological, immunological or metabolic action of its own which is covered by the therapeutic indications of the marketing authorisation…in light of all the facts of the dispute”. This reference to “all the facts” in the Forsgren decision is relevant to the Halozyme cases because it arguably permits applicants to refer to literature outside the regulatory documents to show that a component of the medicinal product is an active ingredient.
CJEU referral
When grappling with Halozyme’s Herceptin SC product, the Czech Supreme Administrative Court considered the law sufficiently unclear that a CJEU referral was needed. The referral has been allocated case number C-456/24.
During examination of the Czech SPC application, Halozyme argued that hyaluronidase was an “active ingredient” in its own right and that the “product” was the combination of trastuzumab and hyaluronidase. Halozyme referred to scientific literature and other evidence outside of the regulatory documents to support its arguments.
The Czech Patent Office disagreed and held that, because hyaluronidase was classified as an excipient, the only “product” within the meaning of Article 1(b) to which the SPC application could relate was trastuzumab per se. The SPC application was therefore refused, inter alia, under Article 3(d) (because Herceptin SC was not the first approval of trastuzumab). The case made its way to the Czech Supreme Administrative Court, which in turn referred questions to the CJEU.
The first four questions of the referral relate to Article 1(b) and specifically to the interpretation of “active ingredient”, is as follows:
1. Is Article 1(b) of Regulation (EC) No 469/2009 of the European Parliament and of the Council concerning the supplementary protection certificate for medicinal products 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?
2. If the answer to question 1 is in the negative, is Article 1(b) of Regulation No 469/2009 to be interpreted, in the light of Article 8(1) and Article 10(1) to (3) of that regulation, as meaning that a substance must be deemed to constitute an active ingredient if it has a therapeutic effect of its own which is included in the therapeutic indications of the marketing authorisation and which is also demonstrably identifiable from the basic patent and the documents mandatorily presented with the application for a certificate?
3. If the answers to questions 1 and 2 are negative, is Article 1(b) of Regulation No 469/2009 to be interpreted as meaning that a substance must be deemed to constitute an active ingredient if it has a therapeutic effect of its own which is included in the therapeutic indications of the marketing authorisation and that a person skilled in the art would identify as documented as of the date of the basic patent application or the date of priority of that patent?
4. Is Article 1(b) of Regulation No 469/2009 to be interpreted as meaning that, inter alia, an excipient must be deemed to constitute an active ingredient with a therapeutic effect of its own which is included in the therapeutic indications in the authorisation of a medicinal product for treating breast cancer, if it breaks down another substance that occurs naturally in the human body, thereby facilitating the effects of the product’s main active ingredient on cancerous cells in breast cancer, if, according to certain studies and scientific articles, that excipient or a substance related thereto has resulted, in and of itself, in vitro or in animal models, in arresting the growth of tumours of the same as well as another type, or to the shrinkage thereof, and if other scientific articles confirm its potentially similar effect in humans?
The first question asks whether a substance being classified as an excipient in regulatory documents precludes it from being an active ingredient – the Czech referring court considers the answer to this question should be “yes”, following GSK. If the CJEU considers that an excipient can be an “active ingredient”, the second and third questions seek to establish which documents can be considered when determining whether the Forsgren criteria are met, i.e. whether a given component can be considered an “active ingredient”. The referring court considers that examination of an SPC application should be a “formal procedure” without complex factual reassessments needing to be undertaken patent offices. Therefore, the referring court opined that the assessment of whether the Forsgren criteria are met should be carried out based on “the content of the documents obligatorily attached to the application [i.e. the marketing authorisation] and the basic patent” only. The fourth question is directed towards the specific facts of the Halozyme case.
It should be noted that the Czech court also referred questions based on the interpretation of Article 3(a) (whether the combination of trastuzumab and hyaluronidase was “protected” by the basic patent). This issue is outside of the scope of this article, but it is worth noting that, since the Halozyme referral, the CJEU has issued further guidance on the application of Article 3(a) for combination products in Merck (joined cases C-119/22 and C-149/22). Given this new guidance on Article 3(a), it remains to be seen whether the CJEU will even entertain the Article 3(a) questions in this referral.
Based on current timescales, we should expect to hear from the CJEU by the middle of 2026.
UK – High Court judgment
In last year’s article, we reported that the UKIPO refused both the Herceptin Hylecta® and Mabthera® GB SPC applications in one decision (IPO decision BL O/0257/24). GB SPC applications are assessed following EU SPC law retained post-Brexit, including not only the retained SPC Regulation but also retained CJEU case law such as Forsgren.
In summary, when deciding how to apply Forsgren, the UKIPO Hearing Officer held that “it is necessary that the marketing authorisation, including the EPAR, must contain, at the very least, some indication that the substance gives rise to a pharmacological, immunological or metabolic effect of its own for the therapeutic indication covered by the MA”, which was clearly not met by hyaluronidase as it was characterised as an excipient in the regulatory documents. Further, the Hearing Officer considered that even if the evidence relied on by Halozyme from outside of the marketing authorisation was considered, it still did not establish that hyaluronidase has a therapeutic effect on the relevant authorised indications (i.e., HER2-overexpressing breast cancers or non-Hodgkin lymphoma) and therefore could not be considered an “active ingredient”.
Since last year’s article, Halozyme appealed the UKIPO decision to the High Court, and the appeal was heard by Meade J ([2024] EWHC 3202 (Pat)). Meade J noted that the two key issues in the case were:
1. The general legal question of whether the Hearing Officer was correct to find that the regulatory documents must contain “some indication that the substance gives rise to a pharmacological, immunological or metabolic effect of its own for the therapeutic indication covered by the MA” (which he referred to as the “SmPC/EPAR-led approach”), or whether any evidence may be relied on; and
2. The factual finding as to whether hyaluronidase is an active ingredient “based on the materials that it is legitimate to consider”.
Meade J noted that the legal issue need not be decided unless Halozyme could show that the Hearing Officer made a factual error in his decision. In accordance with UK precedent, as Meade J was reviewing a factual assessment from the UKIPO, the relevant test he applied was not “whether [the Court] would have reached the same decision, but rather whether the decision was one that was reasonably open to the Hearing Officer”. Meade J was satisfied that the Hearing Officer’s finding was one that was reasonably open to him, so Halozyme’s appeal was dismissed on a factual basis. Halozyme’s request to appeal further to the Court of Appeal was denied, so the refusals for both of Halozyme’s GB SPC applications are now final.
This decision feels like a missed opportunity for the UK Courts to have provided clarity on what evidence is relevant when determining what is an “active ingredient” in line with Forsgren, which is an issue that often arises when planning SPC filing strategies. A possible glimmer of clarity offered by Meade J was that he noted the pending CJEU reference from Halozyme and opined that “[t]he result of the reference will not be binding on this Court but could well be persuasive”. Therefore, even though new CJEU decisions are no longer directly binding on the UK post-Brexit, the CJEU’s decision will be eagerly awaited on both sides of the Channel.
Conclusion
Given the inconsistent approaches that have been taken across Europe with regards to Halozyme’s SPC families, it is unsurprising that a CJEU referral on Article 1(b) has occurred, and it seems that it may provide clarity both in the EU and in the UK. We look forward to seeing how the CJEU grapples with the referred questions and whether any guidance on the interpretation of the Forsgren criteria will be handed down. SPC applicants will no doubt be hoping for the CJEU to clearly endorse a holistic, fact-based approach that considers all the evidence available to the Court.
Originally published in the CIPA Journal.