The UK’s approach for defining the “active ingredient” in an SPC
17
Dec
2024
High Court weighs in on the application of Forsgren to Halozyme’s Herceptin Hylecta® and MabThera® GB SPCs

We have been following the journey of two SPC families covering the marketed products Herceptin Hylecta® and MabThera® for some time. This journey took a new turn in the UK this week, where the judge agreed with the UKIPO’s decision to refuse both GB SPC applications. The fate of both sets of SPCs turns on whether recombinant human hyaluronidase is an “active ingredient” within the meaning of Article 1(b) of the SPC Regulation. A complication here is that hyaluronidase is characterised as an excipient in the regulatory documents, so the SPC applicant Halozyme is having to rely on evidence outside of the regulatory documents in support of hyaluronidase being an “active ingredient”.

The leading case here is the Court of Justice of the European Union’s (CJEU) decision in Forsgren (C-631/13) and, as reported previously, there has been divergence between the national courts when applying this decision to Halozyme’s SPC applications. As we reported in our previous article , this divergence led the Czech Supreme Administrative Court to refer questions on Article 1(b) to the CJEU in an effort to clarify the scope of Forsgren in the EU. The referral has been allocated case number C-456/24.

In the UK, which is no longer an EU Member State and thus no longer bound by the CJEU’s judgments, we reported earlier this year that the UKIPO had refused both of Halozyme’s GB SPCs for Herceptin Hylecta® and MabThera®. Halozyme appealed to the High Court. However, in a judgment handed down on 16th December 2024, Meade J dismissed Halozyme’s appeal ([2024] EWHC 3202 (Pat)). Disappointingly for stakeholders, the judgment does not provide any general guidance regarding how the active ingredient should be assessed by the UK IPO.

Background – the importance of the “active ingredient” and the “product”?

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 previously been 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. The key question in these circumstances is what counts as an “active ingredient”?

The most relevant judgment from the CJEU on this point is Forsgren (C- 631/13). Here, the CJEU held that an “active ingredient” is a substance which produces “a pharmacological, immunological or metabolic action of its own which is covered by the therapeutic indications of the marketing authorisation”. The assessment of whether these criteria are met should be determined “in the light of all the facts of the dispute”.

Halozyme’s Herceptin Hylecta® and MabThera® SPC families

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.

Separate marketing authorisations had been granted for trastuzumab and rituximab as monotherapies many years before either of the two patents mentioned above were filed. Subsequent authorisations for Herceptin Hylecta® and MabThera® were then granted, which now also included the hyaluronidase. However, it is important to note that, in both Herceptin Hylecta® and MabThera®, hyaluronidase was listed in the regulatory documents not as an active ingredient but as an excipient. The later date of these Herceptin Hylecta® and MabThera® authorisations meant that they could serve as basis for SPCs with meaningful term.

However, Article 3(d) of the SPC Regulation requires that the marketing authorisation supporting the SPC application is the first authorisation to place the product on the market. In view of the monotherapy approvals, Halozyme had to argue that the “product” authorised in the later authorisations was the combination of trastuzumab or rituximab with hyaluronidase, i.e., that the hyaluronidase is also an “active ingredient” notwithstanding the statements in the regulatory documents that it is merely an excipient. To make these arguments, Halozyme argued that the Forsgren criteria were met by relying on evidence and data which were not included in the regulatory documents. A key issue in these SPCs is the question of whether or not these data may be relied on to support Halozyme’s case.

Herceptin Hylecta® and MabThera® SPCs in the UK

In March 2024, the UKIPO refused both the Herceptin Hylecta® and MabThera® SPC applications in one decision (IPO decision BL O/0257/24). In the decision, the Hearing Officer concluded that it was possible for evidence outside of the marketing authorisation to be considered when assessing whether a substance was an active ingredient, but that to be convincing, the evidence had to be relevant to the specifically approved therapeutic indication. Analysing the various evidence filed by Halozyme, the Hearing Officer noted that “while these references indicate that hyaluronidase has properties that show it has potential to be used to treat cancer in general and that it is worth investigating further, it does not provide information on how hyaluronidase acts in the treatment of the specific cancers of interest, e.g., HER2 breast cancer or NHL, the specific treatments referred to by the respective MAs.” Failure to provide such specific evidence led, in part, to the refusal.

However, in a further blow to Halozyme, and indeed to SPC applicants more generally, the Hearing Officer held that “in order for a substance to be considered an active ingredient, 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” [emphasis added]. To meet this requirement, an SPC applicant would seemingly have to point to something positive in the marketing authorisation documents supporting that the component in question is an “active ingredient”. This is difficult to align with Forsgren, where the CJEU held that the assessment for whether a component is an “active ingredient” must be made “in the light of all the facts of the dispute”. Taking the Hearing Officer’s reasoning forward, an SPC application would seemingly be refused if there was no indication that the Forsgren criteria were met in the marketing authorisation, even if there was compelling evidence outside of the marketing authorisation.

The High Court’s judgment

In his judgment, Meade J noted that the two key issues in the case were:

  1. The general 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”.

Focussing on the second issue, the judgment noted the Hearing Officer’s finding that, even if Halozyme’s evidence from outside of the regulatory documents were taken into consideration, hyaluronidase did not satisfy the Forsgren criteria meaning that it is not an “active ingredient”. So, unless Halozyme was able to show the Court that the Hearing Officer was wrong on the facts, it was not necessary to consider the first issue.

Meade J pointed out that, as he was reviewing a finding of fact from the Hearing Officer, “I am not to ask myself whether I would have reached the same decision, but rather whether the decision was one that was reasonably open to the Hearing Officer or, or the other hand, whether he made an unsupportable decision because, for example, he failed to take something relevant into account, or reached an irrational conclusion.” Applying this standard to the evidence relied on by Halozyme, the Court found that the Hearing Officer’s finding was one that was reasonably open to him, and so Halozyme’s appeal was dismissed.

The case was dealt with without the Court opining on the correctness of the first issue discussed above (the correctness of the “SmPC/EPAR-led approach”). The UKIPO did ask the Court to issue guidance on this, however Meade J took the view that it would be better to consider this point at a later date once the outcome of C-456/24 from the Czech Supreme Administrative Court is known (even though CJEU case law is no longer binding in the UK). In particular, Meade J found that, in this particular case: “I was uncomfortable that I did not have the full picture about the effect on an unsuccessful SPC applicant’s right to appeal if the regulator’s decision on the active ingredient/excipient characterisation led to an automatic rejection by the UKIPO, and I was not at all confident that I knew whether the regulator asks the same question as the Forsgren test requires when it considers what is an excipient.

Analysis

As well as being disappointing for Halozyme, this judgment is likely to be disappointing for stakeholders hoping that the High Court would issue guidance on how the Forsgren criteria should be applied in the UK. However, the judgment does serve as a useful reminder for practitioners that, for UK SPCs, it is challenging to have findings of fact overturned when appealing refusals from the UKIPO. This is especially pertinent for practitioners used to the EPO’s Boards of Appeal, where findings of fact from first instance tribunals are often overturned.

Also of interest are Meade J’s comments on the pending CJEU referral from the Czech courts (C-456/24). Followers of SPCs will be aware that, in the UK, the question of applicability of CJEU case law following Brexit is a hot issue which is currently being considered by the Court of Appeal in Merck Serono. However, one could argue that, at least in the view of Meade J, CJEU case law should be, at the very least, persuasive authority in the UK.