UK: CJEU AG's Opinion In Santen Referral Proposes To Abandon Neurim

CJEU’s AG in Santen referral (C-673/18) invites the Court to make a clear choice between reversing Neurim (main proposal) or extending the interpretation of the concept of 'product' in order to achieve the result sought in Neurim (alternative proposal)

On 23 January 2020, AG Giovanni Pitruzzella provided his Opinion on the interpretation of Article 3(d) of Regulation (EC) No 469/2009 of the European Parliament and of the Council of 6 May 2009 concerning the supplementary protection certificate for medicinal products (“SPC Regulation“).

In doing so, AG Pitruzzella makes two proposals to the CJEU.

His favoured proposal would significantly curtail the availability of SPCs for second medical uses of known and previously authorised compounds, as it strictly interprets the meaning of 'product' under Article 1(b) and precludes an interpretation of Neurim according to which a marketing authorisation ("MA") for a "different and new application of an old active ingredient" could be considered as the first MA of a previously authorised active ingredient.

His alternative proposal permit SPCs in a wider set of circumstances by interpreting Neurim as allowing an SPC to be granted if the new MA "covers a new therapeutic indication of said active ingredient or relates to a use of it in which this active ingredient exerts a new pharmacological, immunological or metabolic action of its own".

Business impact

Article 3(d) of the SPC Regulation provides that an SPC cannot be granted if there has been an earlier MA for the same 'product' (ie, the active ingredient or active ingredients of the medicinal product under Article 1(b) of the SPC Regulation). However, the CJEU in Neurim (Case C-130/11) held that Article 3(d) did not preclude an SPC from being granted for a different application for human use of a product that had been previously authorised for a veterinary use, provided that the SPC application is based on a patent for which that second medical use falls within the limits of its protection.

The CJEU's decision in Neurim was seen as a departure from its earlier case law (Yissum (Case C-202/05) and Pharmacia Italia (Case C-31/03)), as it did not strictly interpret Article 3(d) and indicated that SPCs were available for second medical uses of known active ingredients. This interpretation in Neurim was subsequently resumed notably in paragraph 27 of the CJEU's decision in Actavis v. Sanofi (C-443/12). This was an encouraging development for the pharmaceutical industry and was an incentive to invest significantly in researching and developing new indications for known products that improve the treatment of patients and save lives.

However, in March of last year, the CJEU held in Abraxis (Case C-443/17) that an SPC could not be obtained for new formulations of previously approved active ingredients, with this following the Opinion of AG Saugmandsgaard Øe that suggested that the "Neurim exception" was limited to the "particular, and probably exceptional, kind of situations at issue in Neurim" (see our update here). As a consequence, there is uncertainty as to the circumstances in which an SPC can be obtained for a second medical use of a known active ingredient and guidance is needed from the CJEU.

If the Grand Chamber of the CJEU follows the AG Giovanni Pitruzzella preferred proposal then this will severely limit the application of the "Neurim exception" and the availability of SPCs for second medical uses of known and previously authorised products and be a disappointing result for R&D based pharmaceutical companies.

Background

A reference was made to the CJEU by the Paris Court of Appeal following its decision of 9 October 2018. That case related to Santen's French SPC application (No. 15C0040), which is based on the European Patent, EP 1 809 237 (entitled 'Ophthalmic oil-in-water type emulsion with stable positive zeta potential') and a centralised MA for the medicinal product, IKERVIS®. IKERVIS® contains as its active ingredient 1 mg/ml cyclosporine in the form of an emulsion, which is administered as an eye drop for the treatment of severe keratitis in adult patients. Originally the SPC application was for 'cyclosporine eye drops, emulsion', but following observations from the French Patent Office this was amended to 'cyclosporine for use in the treatment of keratitis'.

Prior to the grant of the centralised MA for IKERVIS®, an MA had been granted for the medicinal product SANDIMMUN®, which contained as its active ingredient 100 mg/ml of cyclosporine in the form of an oral solution for the prevention of rejection of solid organ and bone marrow grafts, and for the treatment of endogenous uveitis (an inflammation of some or all of the uvea, which is the middle layer of the eye).

In light of the earlier authorisation for SANDIMMUN®, the French Patent Office rejected Santen's SPC Application in its decision of 6 October 2017 and held that the requirements in Neurim were not satisfied as: (i) EP 1 809 237 protected not only a new use of cyclosporine (claims 23 to 24) but also types of ophthalmic emulsions of cyclosporine (claims 1 to 21 and 25 to 26); and (ii) the medical use of IKERVIS® was not a new therapeutic use of cyclosporine within the meaning of Neurim, as the therapeutic use of SANDIMMUM® was also for the treatment of ophthalmic inflammations.

The French Patent Office argued that the grant of an SPC is designed to be an exceptional reward for innovative medicinal products, such that several conditions must be satisfied and that Neurim must be narrowly applied. Despite arguing for a narrow application of Neurim, the French Patent Office did not want to limit its application to its specific facts (ie, where a human use follows a veterinary use). The French Patent Office therefore held that an SPC can be obtained if it relates to medicinal product that has a new therapeutic scope. The new therapeutic scope arising from either a medicinal product containing a new active ingredient, or from a medicinal product containing a known active ingredient utilising a different mode of therapeutic action when compared to the earlier authorisation.

On appeal, the Paris Court of Appeal noted the disagreement between Santen and the French Patent Office on the correct interpretation of the CJEU's decision in Neurim. It also noted that “both medicinal products [in suit] relate to the treatment of inflammation of parts of the eye in humans, using the same anti-inflammatory mechanism of cyclosporine” and that both IKERVIS® and SANDIMMUM® “differ in their therapeutic indications and in their formulation, dosage and posology“, and that “it is not disputed that the [indications of both medicinal products relate to] different diseases, affecting different parts of the eye“. Given the uncertainty over the application of Neurim and when an SPC is available for a different application of a known active ingredient, the Paris Court of Appeal referred the following questions to the CJEU:

"Must the concept of a 'different application' within the meaning of the judgment of 19 July 2012, Neurim (C-130/11, EU:C:2012:489), be interpreted strictly, that is to say:

– as limited only to the situation where an application for human use follows a veterinary application;

– or as relating to an indication within a new therapeutic scope, in the sense of a new proprietary medical product, compared with the earlier marketing authorisation, or a medicinal product in which the active ingredient acts differently from how it acts in the medicinal product to which the first marketing authorisation related;

– or more generally, in the light of the objectives of Regulation (EC) No 469/2009 of establishing a balanced system taking into account all the interests at stake, including those of public health, must the concept of a "new therapeutic use" be assessed according to stricter criteria than those for assessing the patentability of the invention;

– or must it on the other hand be interpreted broadly, that is to say, as including not only different therapeutic indications and diseases, but also different formulations, posologies and/or means of administration?

Does the expression "[application] within the limits of the protection conferred by the basic patent" within the meaning of the judgment [of the Court of Justice] of 19 July 2012, Neurim (C-130/11, [EU:C:2012:489]), mean that the scope of the basic patent must be the same as that of the marketing authorisation relied upon and, therefore, be limited to the new medical use corresponding to the therapeutic indication of that marketing authorisation?"

Analysis

In his Opinion for the Grand Chamber of the CJEU, AG Giovanni Pitruzzella highlights that the CJEU's decision in Neurim was out of line with its earlier case-law on the meaning of 'product' in Article 1(b) of the SPC Regulation. He emphasises that the use in Neurim of the undefined expressions "new therapeutic application", "new use", "different application" or "other therapeutic indication" rises several possible interpretations of this decision.

In light of this, AG Giovanni Pitruzzella considers the implications of the conclusions of Neurim, its departure from the CJEU's earlier case-law and the subsequent case-law of the CJEU.

Considering the earlier case law, AG Giovanni Pitruzzella highlights the CJEU's decision in Yissum where the CJEU held that "the concept of ‘product’ cannot include the therapeutic use of an active ingredient protected by a basic patent". In his view, the CJEU's decision in Neurim "dissociated" the concept of a 'first MA' from the concept of a 'product' under Article 1(b) of the SPC Regulation in order for it to be linked to the concept of 'basic patent' under Article 1(c) of the SPC Regulation. The cases following Neurim, then reaffirmed a strict definition of 'product', whilst at the same time acknowledging that Neurim permitted SPCs for new therapeutic indications of an old active ingredient (see GSK (Case C-210/13) and Georgetown (Case C-484/12)). This was the position until the recent decision of the CJEU in Abraxis, which in AG Giovanni Pitruzzella's view, upheld a "different and inconstant interpretation of Article 3(d)" compared to Neurim, whilst not reversing that earlier decision. To resolve this position, AG Giovanni Pitruzzella's recommendation to the CJEU is that it should not limit Neurim to a narrow exception on its facts, but that it should make a clear and definitive choice between either reversing Neurim or departing from a strict definition of the meaning of 'product' under Article1(b) of the SPC Regulation.

AG Giovanni Pitruzzella's preference is for the CJEU to maintain a strict definition of 'product' and for the CJEU to reverse its decision in Neurim, as electing any criterion other than a chronological one for determining the first MA would be contrary to the clear drafting of Article 3(d). In the alternative, to permit SPCs for second medical uses of previously authorised products under Article 3(d) would require that the CJEU adopt a broader, less strict interpretation of 'product' under Article 1(b).

Over several pages of his Opinion, AG Giovanni Pitruzzella considers the need for the CJEU to define "which type of research is encouraged" by the SPC Regulation and the current ambiguity that exists on this topic. In his Opinion, the reward of an SPC was not created for any kind of research, but he recognises the inconsistencies of the CJEU's statements in Neurim and Abraxis. In doing so, he quotes and appears to endorse the CJEU's statement in Abraxis that "the legislature intended, in establishing the SPC regime, to protect not all pharmaceutical research giving rise to the grant of a patent and the marketing of a new medicinal product, but to protect research leading to the first placing on the market of an active ingredient or a combination of active ingredients as a medicinal product". AG Giovanni Pitruzzella therefore concludes that the SPC system should be consistent, easy and transparent, such that it achieves the correct balance of interests between the various stakeholders, and that this was not achieved in Neurim which "altered this balance in favour of pharmaceutical companies". This, in his view, supports his preferred recommendation to the CJEU to reverse the decision in Neurim and maintain a strict definition of 'product'.

Should the CJEU not agree with this conclusion, in the alternative, AG Giovanni Pitruzzella proposes that the correct balance needs to be found between strictly limiting the availability of SPCs to situations where a human use would follow a veterinary use and permitting SPCs for any subsequently authorised products that included the same active ingredient, such as new formulations, posologies or modes of administration. In his view, the correct balance is found if the MA on which the SPC is based "covers a new therapeutic indication of said active ingredient or relates to a use of it in which this active ingredient exerts a new pharmacological, immunological or metabolic action of its own."

A translation of the conclusion of AG Giovanni Pitruzzella's Opinion, which is not currently available in English, is:

"In light of all of the foregoing considerations, I suggest that the Court, mainly, respond to the Paris Court of Appeal (France) as follows:

Article 3(d) [...] read in conjunction with Article 1(b) [...] must be interpreted as meaning that the marketing authorization referred to in Article 3(b) of that regulation, relied upon in a supplementary protection certificate application relating to a different and new application of an old active ingredient, cannot be considered to be the first marketing authorization for the product in suit as a medicinal product when this active ingredient has already been the subject of such an authorization per se.

In the alternative, in the event that the Court decides to proceed to the interpretation of the Neurim decision, I propose that the Court answer the questions referred by the Paris Court of Appeal as follows:

1) Article 3 [...] must be interpreted as meaning that the grant of a supplementary protection certificate for a different application of an active ingredient for which a previous marketing authorization has been granted in the Member State concerned, within the meaning of the decision of 19 July 2012, Neurim Pharmaceuticals (1991), (C-130/11, EU: C2012: 489), requires that the marketing authorization relied upon to apply for a supplementary protection certificate covers a new therapeutic indication of said active ingredient or relates to a use of it in which this active ingredient exerts a new pharmacological, immunological or metabolic action of its own.

2) Article 4 [...] must be interpreted as meaning that, in the case where the supplementary protection certificate relates to a different application of an old active ingredient, the concept of ‘product’, in the meaning of this provision, designates only said application and does not extend to the active ingredient as such or to other applications thereof."

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