What is a ʽProductʼ and an ‘Active ingredient’?

The definition of ʽproductʼ in Article 1(b) Regulation No 469/20091 (̔SPC Regulationʼ) says that it is an ʽactive ingredientʼ or combination of active ingredients. The attempt to draw a line around what is an active ingredient, and therefore a product, for the purpose of the SPC Regulation has proved difficult.

Until July 2012, CJEU authority on the meaning of ‘active ingredient’ in Article 1(b) had appeared to take a strict approach, as exemplified by the decision in Massachusetts Institute of Technology (MIT)2 . In MIT, an SPC was not permitted for a combination of the cytotoxic agent carmustine and the polymeric matrix polifeprosan, in circumstances where there was a marketing authorisation for carmustine alone before the authorisation for the combination. This decision was because polifeprosan was not regarded as an active ingredient – it is a substance that does not have a therapeutic effect on the human or animal body of its own, but merely provides a pharmaceutical form for the active ingredient to work. The combination could not, therefore, be a new combination of active ingredients.

Furthermore, in Yissum Research3, the CJEU ruled that ‘Product’ in Article 1(b), must be interpreted strictly to mean the active ingredient and could not include the therapeutic use of an active ingredient protected by the basic patent. In summary, these two decisions were authority that a product is an active ingredient, per se, not an excipient or other non-therapeutic substance, and not a second medical use.

Teleological approach – second indications

This approach then came into question in July 2012 with the ruling in Neurim Pharmaceuticals4. This case actually addresses article 3(d) of the SPC Regulation, rather than Article 1(b), but because Article 3(d) also relies on the definition of product, it is difficult to reconcile it with the strict approach by the CJEU, as explained below.

In Neurim, under Article 3(d), the CJEU ruled that melatonin, specifically for the treatment of insomnia in humans, could be subject to an SPC on the basis of a marketing authorisation granted for this purpose in 2007. This was despite the fact that melatonin for a different purpose – regulating the seasonal breeding of sheep – had already been the subject of a marketing authorisation granted in 2001. At first instance, Arnold J decided that the strict approach taken in MIT, Yissum and other authorities meant an SPC could not be granted; melatonin, as an ʽactive ingredient’, had already been the subject of a first marketing authorisation.

But, on referral, the CJEU did not agree. It held that SPC protection for a second and subsequent use of a known active ingredient is permissible. In doing so, it appeared to follow the Advocate General’s Opinion by adopting a ‘teleological’ approach to the meaning of ‘product’ rather than a strict one. In essence, this means the court should look to the purpose of the SPC Regulation, which is, very broadly, to provide sufficient protection for the investment made in the research and development of medicinal products.

In short, Neurim allows a product to extend not just to an active ingredient, but to a new use for an active ingredient. Not surprisingly, the investment-based, teleological, approach of the CJEU that resulted in this decision has since been relied on by applicants in SPC applications for a number of products that would probably not fall within the strict approach, as follows:

Adjuvants

Are adjuvants active ingredients? GlaxoSmithKline Biologicals5 concerned applications for an SPC on both an adjuvant (called ‘AS03’) combined with an antigen (an influenza virus component), and on the adjuvant alone. Specifically, the applicant argued that an ‘active ingredient’ includes the AS03 adjuvant in its own right.

At first instance in the English Patents Court, the expert evidence established that the adjuvant had no therapeutic effect of its own, but merely enhanced the therapeutic effect of the antigen when combined with it. But, the applicant argued that the strict authority of MIT did not apply in this case because it only excludes from SPC protection minor variants of a product such as new doses, different salts and esters, and different formulations, which have no physiological effect on the body. Instead, it was argued, AS03 has the physiological effect of enhancing the therapeutic action of the antigen. The applicant also relied upon the argument in Neurim that the SPC Regulation was intended to apply to products that are the result of innovative research.

Upon referral, the CJEU decided that an adjuvant to a vaccine, having no therapeutic effect of its own, was not an active ingredient capable of protection by an SPC, either alone or as a combination of active ingredients with a vaccine. The decision in GSK Biologicals therefore appeared to limit the application of the teleological approach to ingredients capable of their own therapeutic effect, as previously thought.

But then, a very similar issue was tested in the context of re-formulations of an active ingredient in Bayer Cropscience:

‘Safeners’

The CJEU ruling in Bayer CropScience AG6 concerned what is called a ‘safener’ – that is, a substance or preparation which is added to a plant protection product to eliminate or reduce phytotoxic effects of the product on certain plants. But safeners are not, themselves, active pesticides and on the facts, the referring court held that they could at most only be said to have an indirect effect on plants. Could these be the subject of an SPC, under the plant protection products SPC Regulation 1610/96? This Regulation is drafted in closely similar terms to the SPC Regulation and the Bundespatentgericht referred to the CJEU the question whether the terms ‘product’ and ‘active substance’, which are parallel to the definitions in the SPC Regulation, could be interpreted as including a safener.

In this case, the CJEU ruled that ‘product’ and ‘active substance’ may include a substance intended to be used as a safener, where that substance has a toxic, phytotoxic or plant protection action of its own. Importantly, the ruling suggests that this action does not need to be limited to action directly on harmful organisms as a protective substance, but may also include its protective action indirectly with the plant protection product. In this respect, if one compares the action of a safener with an adjuvant, which could also be said to have an indirect effect, the two cases appear inconsistent.

Conjugated carrier protein

Then there was another referral to the CJEU in Arne Forsgren7 , concerning a conjugated carrier protein, Protein D.

An application was made to the Austrian authorities for an SPC on Protein D. Protein D is present in a pneumococcal vaccine for paediatric use, called ‘Synflorix’, which is subject to a marketing authorisation. This is the marketing authorisation that the SPC applicant relied on. In Synflorix, protein D is a carrier protein conjugated by covalent bonds to several pneumococcal polysaccharide serotypes and adsorbed on aluminium phosphate. While Protein D does not contribute to the activity of Synflorix, the applicants argued that it does have active properties of its own, albeit that these are against Haemophilus influenzae and not covered by the Synflorix marketing authorisation.

Could an SPC be granted on the basis of an active ingredient that is covalently bound to other active ingredients in a medicinal product? The CJEU ruled that it is possible for an active ingredient to give rise to the grant of an SPC where it is covalently bound to other active ingredients in the authorised medicinal product. However, the SPC is not permitted, as in this case, for an active ingredient whose effect does not fall within the therapeutic indications covered by the marketing authorisation.

The CJEU was also asked the slightly different question of whether, as a carrier protein conjugated to pneumococcal polysaccharides used in synflorix, Protein D could be regarded as an active ingredient of the pneumococcal vaccine. In particular, relying on the ruling in Bayer CropScience, the applicant argued that Protein D contributes to the induction of a specific immune response to the pneumococcal polysaccharides to which is it conjugated. However, the CJEU was apparently unwilling to make a comparison with Bayer CropScience, and left it for the national court to determine whether these claimed effects amounted to a pharmacological immunological or metabolic action of their own. So it is now unclear where the Bayer authority stands.

Re-formulation

There is one more referral to the CJEU on this subject area, which was made in 2017. This is Abraxis Bioscience8, which addresses the apparent inconsistency between Article 1(b) and 3(d).

Abraxis markets nab-paclitaxel, as Abraxane. This comprises paclitaxel formulated as albumin bound nanoparticles. According to Abraxis, nab-paclitaxel, rather than paclitaxel, is the active ingredient of Abraxane, due to the tight association of paclitaxel to albumin.

The UK Intellectual Property Office refused Abraxis’ application for an SPC on the basis that paclitaxel is the active ingredient of nab-paclitaxel, and paclitaxel is the subject of an earlier marketing authorisation. In light of the authorities (in particular MIT, GSK Biologicals and Forsgren) Arnold J, in the English Patents Court, concluded that Article 1(b) must be interpreted narrowly and that an active ingredient is a substance which produces a pharmacological, immunological or metabolic effect of its own. The role of albumin did not change that paclitaxel was the active ingredient of nab-paclitaxel and case law on Article 1(b) was considered sufficiently clear on this that no reference was required to the CJEU.

However, Arnold J then dealt with the related issue of Article 3(d). Under this provision, Abraxis argued that, in light of Neurim, Article 3(d) of the SPC Regulation was capable of protecting a new formulation of an old active ingredient. The judge observes that the CJEU’s reasoning in Neurim does not make clear how its decision on the meaning of a product under Article 3(d) can be reconciled with previous case law on Article 1(b). Due to this uncertainty, the judge has referred the question to the CJEU which, in essence, asks if Article 3(d) is to be interpreted as permitting the grant of an SPC for a new formulation of an old, and previously authorised, active ingredient?

But, the judge has expressed his own view that it is inconsistent with a strict interpretation of Article 1(b) to interpret Article 3(d) in this way.

Drug-device combinations

There is one more case to mention on the subject of products, but this one does not actually concern Article 1(b) or 3(d). Instead it is about Article 2, which states that any medicinal product protected by a patent and subject to a marketing authorisation is capable of SPC protection. Rather than a simple medicinal product, however, the case relates to Boston Scientific’s application for an SPC on a stent having Paclitaxel as an integral part. The German Federal Patent Court has referred to the CJEU the controversial question whether the SPC Regulation applies to combinations of pharmaceuticals and medical devices9 . In particular, the German Court has asked the CJEU if an authorisation granted for a drug-device combination pursuant to Article 1(4) of the Medical Devices Directive 93/42 has to be considered equivalent to a marketing authorisation according to Medicinal Products Directive 2001/83 EC, if the drug component has been examined for quality, safety and usefulness by a member state authority for medicinal products in a procedure comparable to that in the Medicinal Products Directive.

The German Court thinks there should be equivalence. It argues that the wording of Article 2 SPC Regulation only excludes the grant of SPCs for pure medical devices, and not drug-device combinations. In its view, what matters is whether the authorisation in question meets the procedural and substantive requirements for an authorisation of the Medicinal Products Directive.

What next?

It will be interesting to see what the CJEU decides about this and it is notable that one of the arguments being relied on is again that a broad interpretation to include such SPCs would be consistent with the sense and meaning of the SPC Regulation as incentivising further pharmaceutical research and development activities. This is the thread that runs through all these cases, from Neurim onwards. And although it has no doubt resulted in a broader approach to the products that can be protected in some respects, such as second medical use, there do seem to be limits. Although, as described, these may not all be consistent.