Europe’s highest court has been asked new questions to clarify which components of a medicinal product are SPC-eligible active ingredients. The answers from the CJEU may illuminate how Europe’s other pharmaceutical regulations impact SPC law.

After several diverging decisions from national courts, the Supreme Administrative Court in the Czech Republic has referred Halozyme’s SPC application for Herceptin SC (also referred to as Herceptin Hylecta®) to the CJEU. A key question in this case is whether recombinant human hyaluronidase can be an “active ingredient” within the meaning of Article 1(b) of the SPC Regulation notwithstanding the fact that it is characterised as an excipient in the regulatory documents. The case also concerns the now-familiar issue of how Article 3(a) should be applied to combination products.

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. A 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 this criterion is met should be determined by the referring court “in the light of all the facts of the dispute”. Also of relevance is GSK (C-210/13) where the CJEU held that an adjuvant which has no therapeutic effect of its own cannot be an active ingredient.

Article 3(a) and combination products

Article 3(a) requires that the “product” be “protected by a basic patent” for an SPC to be available. For combination products, a key case from the CJEU is Teva (C-121/17), which held that:

“even if the combination of active ingredients is not expressly mentioned in the claims of the basic patent, those claims relate necessarily and specifically to that combination. For that purpose, from the point of view of a person skilled in the art and on the basis of the prior art at the filing date or priority date of the basic patent:

• the combination of those active ingredients must necessarily, in the light of the description and drawings of that patent, fall under the invention covered by that patent, and
• each of those active ingredients must be specifically identifiable, in the light of all the information disclosed by that patent.”

The recently issued Advocate General’s opinion on joint cases Teva II and MSD (C-119/22 and C-149/22, respectively) suggested that this test be interpreted strictly in a manner which, if adopted by the CJEU, would likely make combination SPCs much more difficult to obtain. The CJEU’s judgment is expected before the end of 2024.

Halozyme’s Herceptin SC SPC family

The SPC at issue here is based on EP-B-2,163,643 (“EP’643”) and relates to the Herceptin SC product, which is indicated for the treatment of certain types of breast cancer, and which contains the monoclonal antibody trastuzumab in combination with recombinant human hyaluronidase. EP’643 is entitled “Soluble Hyaluronidase Glycoprotein”, and the relevant claims are reproduced below:

12. “ A pharmaceutical composition, comprising the substantially  purified hyaluronidase polypeptide of any of claims 1-4.

…

18. The pharmaceutical composition of claim 12 for use in treating atumour, wherein the composition further comprises an anti-cancer agent selected from … an antibody…

19. The pharmaceutical composition of claim 18 for use in treating a tumour wherein the anti-cancer agent is an antibody.

20. The pharmaceutical composition of claim 19 for use in treating a tumour, wherein the antibody is a monoclonal antibody.

21. The pharmaceutical composition of any of claims 19 or 20 for use in treating a tumour, wherein the tumour is a cancer of the breast.”

An earlier marketing authorisation had been granted for trastuzumab monotherapy before EP’643’s filing date. Following this initial authorisation, a subsequent authorisation for Herceptin SC was granted which now included hyaluronidase. The later date of the subsequent authorisation means SPCs based on EP’643 and the subsequent authorisation would have meaningful term.

In the SPC applications, Halozyme argued that the “product” was the combination of trastuzumab and hyaluronidase, i.e., that the hyaluronidase is an “active ingredient” (even though it is listed as an excipient, rather than as an active ingredient, in the regulatory documents). To support its position that hyaluronidase was an active ingredient which meets the Forsgren criteria, Halozyme relied on evidence outside of the regulatory documents for Herceptin SC.

However, the Czech patent office held that, as hyaluronidase was listed as an excipient, the only “product” within the meaning of Article 1(b) to which the SPC application could relate was trastuzumab per se. However, this had been approved prior to Herceptin SC, and so the application was refused for failing to comply with Article 3(d) because Herceptin SC was not the first approval of trastuzumab. The Czech patent office also held that the application failed to comply with Article 3(a) because trastuzumab was not mentioned in the claims of EP’643 and did not appear in its description either.

The Czech court’s judgment

The Czech Supreme Administrative Court found that the issues in this case were not acte clair and referred questions to the CJEU concerning the application of Articles 1(b) and 3(a). These questions are given in full at the end of this article.

Article 1(b)

In the court’s opinion, the fact that a substance is described in the regulatory documents as an excipient should preclude it from being an “active ingredient” within the meaning of Article 1(b). The court, relying on GSK (C-210/13), held that to find otherwise would be to carry out a “reassessment of the nature of [the substance described as an excipient] in the SPC application procedure”. The court took the view that the examination of an SPC application should be a “formal procedure” only which should not “lead to a factual reassessment of the marketing authorisation process … on the basis of extensive evidence” (see question 1 below.)

However, should the CJEU find that a substance listed as an excipient can be an “active ingredient”, the 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. Again, the court justified this by pointing to its belief that the SPC examination should be formal in nature meaning that only the patent and the documents that the applicant is legally obliged to provide with the application should be considered (see question 2 below).

Further, should the CJEU find that an excipient can be an “active ingredient”, and that evidence other than the patent and marketing authorisation may be relied on to show that the Forsgren criteria are met, the court expressed uncertainty as to the type of evidence that may be relied on (see question 3 below). In particular, the court seemed unsure as to whether the date on which the substance (hyaluronidase in this case) was shown to have “a pharmacological, immunological or metabolic action of its own which is covered by the therapeutic indications of the marketing authorisation” is of relevance to Article 1(b). The court pointed out, on the one hand, that if the therapeutic effect of a substance is held to be an objective fact, the time at which that fact was demonstrated should not be relevant. However, the court also noted that this was potentially inconsistent with the purpose of the SPC Regulation. This uncertainty led to question 3 below. A fourth question was also included in the event that questions 1-3 were answered in the negative.

Article 3(a)

The court chose also to refer questions on Article 3(a) and its application to combination products (see referred questions 5 and 6), despite the CJEU’s judgment in joint cases Teva II and MSD (C-119/22 and C-149/22, respectively) being expected in a matter of months following the recent issuance of the Advocate General’s opinion.

The referring decision does not mention Teva II and MSD once. The Czech court appears to advocate for a different and potentially more lenient approach to assessing Article 3(a), compared to the test put forward by the Advocate General in Teva II and MSD. In particular, the court suggested that, to comply with the two-part test in Teva, it would need to be established that:

• according to the skilled person, it follows from the patent that the invention consisted not only in the discovery of hyaluronidase but also in the discovery of a method of its use, together with monoclonal antibodies, for the treatment of breast cancer, and
• the skilled person could specifically identify at the filing date of EP’643 that trastuzumab was a monoclonal antibody for use in the treatment of breast cancer.

Conclusion

This referral of questions to the CJEU on Article 1(b) is unsurprising given that this provision has seemingly been applied inconsistently across Europe in situations where the applicant for the SPC wishes to recategorize components as active ingredients. There appears to be a contrast between countries such as France and Spain, which have taken a more pro-applicant position, and, for example, Sweden which has been less applicant friendly in this scenario.

The Czech court’s decision to refer questions on Article 3(a) is surprising, and it remains to be seen whether the CJEU will deem it necessary to answer the questions on this point once the decision in Teva II and MSD has been issued.

Referred questions:

(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?

(5) Is Article 3(a) of Regulation No 469/2009, in conjunction with Article 1(b) thereof, to be interpreted as meaning that a product protected by a basic patent must also be deemed to include a combination of two active ingredients, if the subject of the invention to which the basic patent applies is only one of the two ingredients and the patent claims include its potential combination with other alternatively specified categories of active ingredients, one of which may include the other active ingredient, according to the opinion of a person skilled in the art based on the state of knowledge as at the date of the basic patent application or the priority date of that same patent?

(6) If the answer to question five is negative, is Article 3(a) of Regulation No 469/2009, in conjunction with Article 1(b) of that regulation, to be interpreted as meaning that a product protected by the basic patent may be considered as including a combination of two active ingredients, if the subject of the invention to which the basic patent applies is only one of the two substances and the patent claims include its potential combination with other alternatively specified categories of active ingredients, one of which included the only active ingredient that was the subject of the authorisation for the medicinal product, regardless of whether there were, as at that date, other substances falling into that same category?