The concept of “active ingredient”: Insights from the Halozyme referral (C-456/24)
By Natali Goginashvili at Associate, HOYNG ROKH MONEGIER, Paris
Background
The applicant, Halozyme Inc, specializes in drug delivery technologies for emerging and established therapies. Its core technology ENHANZE® is based on recombinant human hyaluronidase (“rHuPH20“), which is a drug delivery enzyme that locally breaks down human hyaluronic acid, and when co-formulated with other drugs, facilitates their subcutaneous delivery after injection. Halozyme has partnered for ENHANZE® with multiple pharmaceutical companies, including Roche who markets a combination of trastuzumab and rHuPH20 branded as Herceptin®. Trastuzumab is a known active ingredient, which is a monoclonal antibody widely used in the treatment of breast cancer. When combined with rHuPH20, it can be administered subcutaneously, while trastuzumab as such is only administered intravenously.
Halozyme holds a basic patent entitled “Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof.” The patent protects rHuPH20, but it does not specifically mention trastuzumab or a combination of trastuzumab and rHuPH20 (=Herceptin SC®). Nevertheless, the patent describes a pharmaceutical composition containing, in addition to rHuPH20, a monoclonal antibody for use in treating a tumour (claim 20).
Halozyme sought SPC protection for Herceptin SC® throughout Europe and inter alia in the Czech Republic. The Czech Industrial Property Office rejected the application as it found that the application did not meet the requirements of Article 1 and 3 of Regulation 469/2009, as trastuzumab did not appear in the patent claims or patent description (i.e. not a product protected by the patent), and, taken alone, was already subject to another approval (i.e. not the first authorisation of the product). As to rHuPH20, it was explicitly listed as an excipient in the marketing authorisation (i.e. not a combination of active ingredients, thus not a product).
The applicant was also unsuccessful before the Prague court of first instance which dismissed Halozyme’s request primarily on the grounds that rHuPH20 was not an active ingredient, as it did not clearly appear from the evidence that rHuPH20 in combination with trastuzumab had its own particular pharmacological, immunological or metabolic action in the treatment of breast cancer.
Against this background, the granting of an SPC was held to be possible only if rHuPH20 itself would constitute an “active ingredient”, which would make Herceptin SC® a combination of two active ingredients according to Article 1(b) of Regulation 469/2009. Furthermore, this combination must be covered by the basic patent.
The Supreme Administrative Court of the Czech Republic referred multiple questions to the CJEU, which aim to clarify the definition of an “active ingredient” under Regulation (EC) No 469/2009 (questions 1-4) and the necessary protection by the basic patent (questions 5 and 6).
The questions referred
The referring court holds that the labelling of a substance as an excipient in a medicinal product’s marketing authorization automatically precludes it from being considered an active ingredient and seeks the CJEU’s confirmation in this regard (question 1). If the CJEU were to take a different view, the referring court seeks to ascertain whether assessment based only on the marketing authorization documents and the basic patent (question 2) or at least based on the art available at the basic patent’s priority/application date is possible (question 3). Lastly, the referring court seeks further guidance as to what the criteria and standard of evidence for establishing the effects of an “active ingredient” are (question 4). Questions 5 and 6 shall shed further light on the question of whether rHuPH20 in its combination with trastuzumab falls under the protection of the basic patent or not.
Outlook and Implications
The referring court emphasises that SPC proceedings should be formal and confined to extending the basic patent’s term, without conducting a detailed re-examination of the substance’s nature. This approach may lead to greater uniformity across Europe on the key aspects of SPC disputes.
Although the existing case law of the CJEU allows insight into the relation between Regulation No. 469/2009 and Directive 2001/83, and especially the concept of an “active ingredient,” the Halozyme case itself shows that a uniform approach throughout Europe has not yet been achieved: SPCs were granted in Austria, Belgium, and Germany, while refusals have occurred in the Czech Republic, France, the Netherlands, Sweden, and the UK.
Also, the case law of the national courts has developed differently: Whereas the Czech referring court seems to favour a stricter, more formal approach not allowing the characterization of a substance that appears as an “excipient” in a regulatory dossier as an “active ingredient” under Regulation No. 469/2009, the German Federal Patent Court tends to assess an “active ingredient” independent of the marketing authorization (although relying on the application and regulatory documents for the necessary facts; BPatG, 26 June 2020, 14 W (pat) 5/18). The French Supreme Court favoured a balanced approach in the Halozyme case and established that “when the marketing authorization does not qualify a substance as an “active ingredient”, there is a rebuttable presumption that this substance does not produce its own pharmacological, immunological or metabolic effect” (Cour de cassation, 1 Feb. 2023, No. 21-15.221). Most recently, the High Court of England and Wales based its refusal on the factual finding that various evidence submitted by Halozyme, including those beyond the SmPC/EPAR, did not demonstrate that hyaluronidase was an active ingredient (Halozyme, Inc v The Comptroller-General of Patents, Designs and Trade Marks [2024] EWHC 3202 (Pat)(16 December 2024).
The CJEU’s answers to these questions could foster a more unified approach, thereby further harmonising SPC law across Europe.
As to the timing, the average length of the CJEU proceedings (between the referral and the ruling) being 16 months according to the CJEU’s recent statistics, the ruling can be expected by October 2025.
The concept of “active ingredient”: Insights from the Halozyme referral (C-456/24)
By Natali Goginashvili at Associate, HOYNG ROKH MONEGIER, Paris
