Can an SPC be based on an adjuvant?

The UK Intellectual Property Office (UK IPO) has recently issued two decisions rejecting supplementary protection certificate (SPC) applications, one filed by GlaxoSmithKline Biologicals SA (GSK) and the other by Genzyme Corporation, to try to extend the term of protection for their authorised medicines. GSK had two applications rejected which related to adjuvant systems used with their Prepandrix® influenza vaccine. Genzyme’s rejected SPC application related to additional salt forms of sevelamer, an ion-exchange resin-type polymer which is an active ingredient in Renvela®, a medicine for controlling hyperphosphataemia.

These UK IPO decisions reinforce the reality that it is difficult for pharmaceutical companies to obtain SPCs in the United Kingdom which relate to new adjuvants or adjuvant/antigen combinations and alternative salt forms of a drug, rather than an active drug per se. 

However, GSK appealed its decision to the High Court and, very recently, succeeded in persuading Mr Justice Arnold to refer a further question to the European Court of Justice (ECJ) on the subject. The specific question (or even questions) has yet to be finalised. Nonetheless, it is understood that the referral will concern the question of whether an agent which potentiates the action of an active ingredient (in particular, an adjuvant) can be the subject of an SPC.

Background
The purpose of SPCs is to compensate patent holders for the amount of time taken to obtain marketing authorisation for a medicine which is covered by a patent. Once a patent has expired, an SPC can extend the term of protection for the authorised medicinal product for a period equal to that between the filing date of the patent and the date of the first marketing authorisation to place the product on the market in the European Community, up to a maximum of five years. For the purposes of the EU SPC Regulation (469/2009), the "product" is regarded as the active ingredient or combination of active ingredients of a medicinal product (Article 1(b) of the regulation). The regulation states that the product must not have already been the subject of an SPC (Article 3(c)) and the marketing authorisation must be the first one for that product (Article 3(d)). Thus, the grant of an SPC can depend on what precise components of a medicine are considered to be the "product".

GSK’s adjuvant system SPC applications – was the adjuvant an “active ingredient”?
GSK applied for two SPCs relating to novel adjuvant systems which were based on the marketing authorisation for Prepandrix. Prepandrix is a pre-pandemic influenza vaccine consisting of an influenza virus antigen, adjuvanted by a combination of substances (squalene, alpha tocopherol and polysorbate 80) referred to as AS03. The first SPC related to the adjuvant composition, whereas the second SPC related to the combination of adjuvant and antigen. Each SPC was based on a separate patent.

The examiner had objected that the AS03 adjuvant was not an active ingredient for the purposes of Article 1(b) of the SPC Regulation, based on the European Court of Justice’s (ECJ) judgment in Massachusetts Institute of Technology (MIT) (C-431/04), which concerned a combination of an active ingredient and a polymeric excipient. In MIT the excipient was not considered to be covered by the concept of "active ingredient" since it had no therapeutic effect of its own. 

The case at hand was heard as BL O/506/12. GSK argued that MIT did not apply because adjuvants are fundamentally different from excipients, because the adjuvant has a physiological effect when administered alone and because the adjuvant has a therapeutic effect within the medicinal product. However, the hearing officer decided that MIT could apply and went on to consider whether the AS03 adjuvant was an active ingredient. The key question in view of MIT was whether the adjuvant was “a substance that has no therapeutic effect of its own but renders the medicinal product in a pharmaceutical form that is efficacious”. Taking into account evidence from an expert witness, the hearing officer concluded that AS03 had no therapeutic effect on its own. Although its effects were necessary to ensure the efficacy of Prepandrix, they were general and non-specific. It was the antigen which had a therapeutic effect of its own. Thus, the hearing officer held that neither the adjuvant nor the adjuvant-antigen combination constituted an active ingredient or a combination of active ingredients as required by Article 1(b) of the SPC Regulation, so neither SPC should be granted. However, GSK was informed that it could amend either or both of the product definitions in the two SPC applications to try to get at least one of them to grant on the basis that the antigen alone would prima facie qualify as a "product".

Genzyme’s salt form SPC application
Genzyme’s SPC application related to sevelamer, an ion-exchange resin-type polymer which is the active ingredient in the approved medicinal product Renvela. In particular, Genzyme’s SPC related to sevelamer carbonate or bicarbonate as the active ingredient. However, Genzyme had an earlier SPC relating to sevelamer which was based on the same basic patent and on the marketing authorisation for Renagel®, a related product also for controlling hyperphosphataemia, in which the active ingredient is sevelamer hydrochloride.

The application had been rejected by the examiner on the basis that:

• The "product" which was the subject of the new SPC application was already protected by the earlier SPC, contravening Article 3(c) of the SPC Regulation.
• The marketing authorisation was not the first marketing authorisation to place the product on the market in the European Community, contravening Article 3(d). 

The applicant argued that the products which were the subject of the two applications were different because, although the same cationic polymer was used (sevelamer), the anions, and hence the active ingredients, were different. It also pointed out that Renagel was approved for a narrower patient group than Renvela and the European Medicines Agency had distinguished the two products on that basis, issuing two separate marketing authorisations. Genzyme’s case was heard as BL O/495/12. The hearing officer considered whether the active ingredients of the two products could be regarded as different, which would make it possible to distinguish the earlier sevelamer hydrochloride SPC and marketing authorisation from the subsequent sevelamer carbonate or bicarbonate SPC and marketing authorisation.

In making his decision, the hearing officer referred to Farmitalia (C-392/97), in which the ECJ had made it clear that SPCs are not necessarily restricted to a specific salt or ester that has been approved in a marketing authorisation. This point was supported by the intended purpose underlying Article 3(c) of the SPC Regulation. The rationale of this approach was to avoid a situation where an SPC could be evaded simply by marketing a different salt or pharmaceutical presentation of an active which is nonetheless therapeutically equivalent. The hearing officer also referred to the Patents Court’s decision in Draco (1996, RPC47), where reformulation of a product from aerosol to additive-free agglomerated particles did not change the active ingredient or result in a different product for the purposes of the SPC Regulation, despite differences in efficacies of the two formulations.

Based on the evidence presented, the hearing officer decided that the difference between the two medicinal products lay only in the respective anions used, which do not in themselves act to treat the indication. Both would be presented as identical polymers at the intestinal lumen. The change of anion was considered only to mitigate the potential for metabolic acidosis (a side effect), making Renvela more suitable for the broader patient group. It did not help Genzyme’s case that the summary of product characteristics for Renvela emphasised that the active was the same as in sevelamer hydrochloride and the safety data relied in part on data obtained for sevelamer hydrochloride. The active ingredients of Genzyme’s Renagel and Renvela-related SPCs and marketing authorisations were therefore considered to be the same (ie, sevelamer, irrespective of the anion).  Therefore, Genzyme’s later SPC for sevelamer carbonate or bicarbonate was rejected for failure to comply with Articles 3(c) and 3(d) of the SPC Regulation.

Comment

Genzyme’s decision does not appear to have been appealed and so the UK IPO’s reluctance to allow SPCs directed to alternative salt forms of an active ingredient in such situations will remain unchallenged. Nonetheless, this decision endorses the view that an SPC covering the active ingredient may, in view of Farmitalia, already cover alternative forms of that active. 

In a case showing parallels with the GSK decision, the German Federal Patent Court recently referred questions to the ECJ regarding the definitions of "product" and "active ingredient" in view of the MIT decision. The German court's referral (C-11/13) concerns "Isoxadifen and the salts and esters thereof".  Isoxadifen is a "safener" – a substance which prevents the harmful action of herbicides in plants.  

Since Mr Justice Arnold's reluctance to refer questions when considering Neurim (C-130/11) back in 2010, he seems to have become increasingly frustrated with the lack of clarity provided by the ECJ when opining on SPC matters. For example, when referring further questions asking how Article 3(a) of the regulation should be interpreted in Actavis Group PTC EHF v Sanofi Pharma Bristol-Myers Squibb SNC, he noted that the ECJ has failed to provide a clear test clarifying Article 3(a), despite numerous references being made. When referring further questions up to the ECJ on a different SPC issue, in Astrazeneca AB v Comptroller-General of Patents, Designs and Trade Marks, he also obliquely criticised the ECJ when pointing out that he failed to see how the court’s judgment in Neurim could be reconciled with the same court’s decisions in Synthon (C-195/09) and Generics (C-427/09). There is a sense that he sees almost any SPC matter that now comes before him as a potential candidate for referral. In general, the SPC community seems to sympathise with his frustration; the question is often asked – is this regulation fit for purpose?