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In a boost for generic pharma companies, a U-turn by the EU’s highest court removed protection for repurposed active substances, as Robert Stephen and Gareth Morgan of CMS Cameron McKenna Nabarro Olswang explain.
The July 9 Santen decision (C-673/18) from the Court of Justice of the European Union (CJEU) resolves the issues that arose from the earlier Neurim decision (C-130/11) issued by the same court. Essentially, and unusually, the CJEU reversed its own earlier decision.
Active substances that are repurposed for new uses will no longer be eligible for a supplementary protection certificate (SPC) under the Neurim approach. Repurposed actives that are protected only by such Neurim-type SPCs are now vulnerable to immediate generic competition.
Article 3 of the SPC Regulation 469/2009 requires that, for an SPC to be granted:
(a) The product is protected by a basic patent in force;
(b) A valid authorisation to place the product on the market as a medicinal product has been granted in accordance with directive (2001/83) or directive (2001/82), as appropriate;
(c) The product has not already been the subject of an SPC; and
(d) The authorisation referred to in point (b) is the first authorisation to place the product on the market as a medicinal product (emphasis added).
Article 3(d) is the real focus of Santen and Neurim. The “product” and related “medicinal product” are defined in article 1 as follows:
- A medicinal product means any substance or combination of substances presented for treating or preventing disease in human beings or animals and any substance or combination of substances which may be administered to human beings or animals with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in humans or in animals.
- A product means the active ingredient or combination of active ingredients of a medicinal product.
The earlier CJEU decisions in Yissum (C-202/05), MIT (C-431/04) and Pharmacia (C-31/03) had indicated that the definition of the product did not include any aspect of the therapeutic use of the active ingredient.
Therefore, given that the first marketing authorisation (MA) of article 3(d) is the first MA for the product, and given that the product has no limitation by indicated use (nor whether those approved indications were for veterinary or human medicinal uses), in the run up to the Neurim decision of 2012, the first article 3(d) MA was understood to be the first authorisation for the product as a medicinal product irrespective of its use. The Neurim decision changed this position.
Neurim discovered that appropriate formulations of melatonin could be used as a medicine for insomnia in humans and applied for an SPC, basing its application on the MA obtained to market its product Circadin and a patent protecting the new use of the active ingredient.
The UK Intellectual Property Office (UKIPO) refused to grant the SPC. It had identified an earlier MA, dating from 2001, for melatonin for use in sheep and sold as the branded medicine, Regulin. Regulin was used as a method of regulating the seasonal breeding activity of sheep. The UKIPO’s refusal was thus based on the fact that, contrary to the requirement of article 3(d) of the SPC Regulation, the Circadin MA was not the first MA relating to melatonin.
A referral to the CJEU followed, and in essence the referral asked whether the provisions of article 3 of the SPC Regulation were to be interpreted as meaning that the existence of an earlier MA for a veterinary medicinal product was sufficient to preclude the grant of an SPC for the product application which obtained the other, later, MA.
The referring UK court had in particular the incentives for the pharmaceutical industry in mind in its referral, with Lord Justice Jacob stating: “We consider that Neurim’s arguments are not only tenable: in our view they are right. Many kinds of valuable pharmaceutical research will not get the encouragement or reward they deserve if they are not.
“Pharmaceutical research is not confined to looking for new active compounds. New formulations of old active substances are often sought. Most are unpatentable but from time to time a real invention is made and patented. Moreover, there is much endeavour to find new uses for known active ingredients.
“The European Patent Convention 2000 has indeed made the patenting of inventions in this area clearer. Its effect is that a patent for a known substance or composition for use in a method of treatment is not to be regarded as old (and hence unpatentable) unless use for that method is known. It would be most unfortunate if second medical use patents could not get the benefit of an SPC.”
The UK appeal court concluded that that if Neurim was wrong then the SPC Regulation “will not have achieved its key objects for large areas of pharmaceutical research: it will not be fit for purpose”.
The CJEU decision in Neurim specifically noted that the fundamental objective of the SPC Regulation is to ensure sufficient protection to encourage pharmaceutical research, which plays a decisive role in the continuing improvement in public health.
The decision concluded—no doubt with the objective of the SPC Regulation in mind—that only the MA of the first medicinal product, comprising the product (the active ingredient) and authorised for a therapeutic use corresponding to that protected by the patent relied upon for the purposes of the application for the SPC, may be considered to be the first MA of ‘that product’ as a medicinal product exploiting that new use within the meaning of article 3(d) of the SPC Regulation.
Therefore, the “mere existence of an earlier MA obtained for a veterinary medicinal product does not preclude the grant of an SPC for a different application of the same product for which an MA has been granted, provided that the application is within the limits of the protection conferred by the basic patent relied upon for the purposes of the application for the SPC”.
The SPC based on the patent covering Neurim’s new use could rely only upon the first MA for that new use, creating a link between, on the one hand, the MA referred to in article 3(b) and (d) of the SPC Regulation, and on the other, the claim scope of the basic patent referred to in article 3(a) of that regulation.
“The writing was certainly on the wall after Abraxis, where the AG’s opinion commented on the rationale of Neurim in a negative way.”
As a result, Neurim could rely on its own MA and had its SPC.
Patent offices, however, struggled to know how to apply the principles of Neurim. Most applied a narrow interpretation. The CJEU itself in subsequent decisions such as Abraxis, relating to a reformulation of an old active, also pointed out that article 3(d) should not be interpreted permissively with respect to other types of improvements made to existing medicinal products.
In effect the CJEU seemed set on maintaining the Neurim case as an isolated exception from that narrow interpretation of article 3(d).
The writing was certainly on the wall after Abraxis, where the AG’s opinion commented on the rationale of Neurim in a negative way, choosing to highlight the inconsistency of that decision with other lines of case law (including those identified above) on other provisions of the SPC Regulation.
Santen had a European patent protecting an ophthalmic emulsion in which the active ingredient was ciclosporin, and obtained a MA for the corresponding medicinal product, marketed under the name Ikervis, used to treat severe keratitis in adult patients with dry eye disease.
An SPC was refused because an MA had been granted for a medicinal product, marketed under the name Sandimmun, that also had ciclosporin as its active ingredient. That medicinal product was presented in the form of an oral solution and was indicated for preventing the rejection of solid organ and bone marrow grafts and for other therapeutic indications, including the treatment of endogenous uveitis, an inflammation of all or part of the uvea, the middle part of the eyeball. Therefore, Santen argued, there was a different formulation and different uses.
Santen argued that the concept of “different (therapeutic) application” within the meaning of the judgment in Neurim, must be interpreted broadly, including not only therapeutic indications and uses for different diseases, but also different formulations, posologies and/or means of administration.
The CJEU in Santen went back to basics and once again considered articles 1(b) and article 3(d).
Article 1(b) was—(just as in earlier decisions)—concluded to include no use limitation to the active.
Crucially, in the light of the strict definition of the term “product” within the meaning of article 1(b), the CJEU concluded that the wording of article 3(d) must therefore be read narrowly (C-673/18, paragraph 51):
“The first MA for the product as a medicinal product means the first MA for a medicinal product incorporating the active ingredient or the combination of active ingredients at issue irrespective of the therapeutic application of that active ingredient, or of that combination of active ingredients, in respect of which that MA was obtained.”
Moreover, the Neurim principle was overturned (C-673/18, paragraph 53):
“Contrary to what the court held in paragraph 27 of the judgment in Neurim, to define the concept of ‘first (MA for the product) as a medicinal product’ for the purpose of article 3(d) of Regulation 469/2009, there is no need to take into account the limits of the protection of the basic patent.”
In terms of the public policy point, the court justified its position by noting that the purpose of the SPC Regulation was never to provide protection for all research (C-673/18, paragraph 55):
“As is apparent from paragraph 11 of the Explanatory Memorandum referred to in paragraph 45 above, the EU 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” (emphasis added).
Moreover, the court considered that its interpretation of the regulation to exclude Neurim-type second use inventions was the right balance (C-673/18, paragraph 57):
“That interpretation also enables a fair balance to be struck between, on the one hand, the objective of the SPC regime, as it is made apparent from recitals 3 to 5 and 9 of Regulation 469/2009, of compensating for the inadequacy of protection conferred by a patent for the purpose of covering the investment put into research concerning new active ingredients or combinations of active ingredients and, therefore, of encouraging such research and, on the other hand, the EU legislature’s intention, as set out in recital 10 of that Regulation, to achieve that objective in a manner that takes into account all the interests at stake, including those of public health, in a sector as complex and sensitive as the pharmaceutical sector.”
Neurim-type SPCs are dead, but that is not to say all SPCs based on second, or further, medical uses are dead.
Article 3(d) can still be satisfied where the MA serving as a basis for the SPC application covers a product (active) which was already known before the “new use” patent was granted but which had never given rise to an MA as a medicinal product.
In that scenario a medical use patent claim would be needed, but the MA that would be relied upon is the first MA for the active such as was the case with Reminyl (galantamine), owned by Shire. However, this will be a minority of cases (and it should be acknowledged that the Reminyl SPC was found invalid for other reasons).
The CJEU decision clarifies the position under article 3(d) but the position is now that there is no equivalent incentive for those who repurpose known actives that have already been authorised in medicinal products. The UK referring court in Neurim considered that the SPC Regulation would not be fit for purpose if it did not somehow make SPCs available for such inventions.
The conclusion of the CJEU is essentially that the SPC Regulation was not intended to cover Neurim-type SPCs, and indeed this strikes the right public policy balance in any event. It will be for companies who repurpose known actives to argue the case for such an incentive to be provided.
There is an ongoing review of the SPC legislation within the EU. Santen may therefore lead to a re-examination of the right balance on incentives, in legislation which is nearly 30 years old. One variable to consider will be the extent to which second medical use products contribute now to the pool of commercially available drugs, and the extent to which they are expected to contribute in future.
Fundamentally, there seems no sound policy rationale for discouraging companies to invest in research into active substances known to be safe and already in use as medicinal products. Given the established use and known safety profile, the timeline for bringing such products to market for new uses might be shorter and expose fewer patients to clinical trials.
Whether the EU legislature considers that those advantages of potentially truncated and cheaper product development should be sufficient benefit for those companies to continue to invest in such research could well form part of the balancing exercise the European Commission undertakes in its current consultation on the EU’s IP action plan.
Finally, repurposed actives which are protected only by such Neurim-type SPCs are vulnerable to immediate generic competition.
Robert Stephen is a patent attorney and co-chair of life sciences and healthcare at CMS Cameron McKenna Nabarro Olswang. He can be contacted at: firstname.lastname@example.org
Gareth Morgan is a partner and head of patent litigation at CMS Cameron McKenna Nabarro Olswang. He can be contacted at: email@example.com
Santen, SPCs, generic, CJEU, Neurim, European patent, medicinal product, UKIPO, Regulin, active ingredient, therapeutic application, clinical trials