Glaxosmithkline Biologicals SA v Comptroller-General of Patents, Designs and Trade Marks

On 10 October 2008 the Appellant (“GSK”) filed application SPC/GB08/046 for a supplementary protection certificate for “an oil in water emulsion comprising squalene, DL-α-tocopherol and polysorbate 80”, an adjuvant known as AS03 which is protected by European Patent (UK) No 0 868 918.

On 18 August 2011 GSK filed application SPC/GB11/043 for a supplementary protection certificate for “an adjuvanted influenza vaccine comprising an influenza virus component which is an influenza virus antigen from an influenza virus strain that is associated with a pandemic outbreak or has the potential to be associated with a pandemic outbreak, wherein the adjuvant is an oil in water emulsion comprising squalene, DL-α-tocopherol and polysorbate 80”, a vaccine comprising an antigen and AS03 which is protected by European Patent (UK) No 1 618 889.

In both applications GSK relied upon marketing authorisation EU/1/08/453/001 for a pre-pandemic influenza vaccine against the H5N1 subtype of influenza A virus marketed by GSK under the trade mark Prepandrix.

By a decision dated 19 December 2012 (BL O/506/12), Dr C.L. Davies, the Deputy Director of the UK Intellectual Property Office, acting on behalf of the Comptroller, decided that neither application was allowable as it stood since AS03 was not an “active ingredient” of Prepandrix, although she was prepared to give GSK an opportunity to amend the applications. GSK has appealed against this decision. It is common ground that the resolution of the appeal depends on an issue of interpretation of Article 1(b) of European Parliament and Council Regulation 469/2009/EC of 6 May 2009 concerning the supplementary protection certificate for medicinal products (codified version) (“the SPC Regulation”) upon which a preliminary ruling from the Court of Justice of the European Union is required.

The SPC Regulation includes the following recitals:

“(3)

Medicinal products, especially those that are the result of long, costly research will not continue to be developed in the Community and in Europe unless they are covered by favourable rules that provide for sufficient protection to encourage such research.

(4)

At the moment, the period that elapses between the filing of an application for a patent for a new medicinal product and authorisation to place the medicinal product on the market makes the period of effective protection under the patent insufficient to cover the investment put into the research.

(5)

This situation leads to a lack of protection which penalises pharmaceutical research.

(6)

There exists a risk of research centres situated in the Member States relocating to countries that offer greater protection.

(7)

A uniform solution at Community level should be provided for, thereby preventing the heterogeneous development of national laws leading to further disparities which would be likely to create obstacles to the free movement of medicinal products within the Community and thus directly affect the establishment and the functioning of the internal market.

(8)

Therefore, the creation of a supplementary protection certificate granted, under the same conditions, by each of the Member States at the request of the holder of a national or European patent relating to a medicinal product for which marketing authorisation has been granted is necessary. A regulation is therefore the most appropriate legal instrument.

(9)

The duration of the protection granted by the certificate should be such as to provide adequate effective protection. For this purpose, the holder of both a patent and a certificate should be able to enjoy an overall maximum of 15 years of exclusivity from the time the medicinal product in question first obtains authorisation to be placed on the market in the Community.

(10)

All the interests at stake, including those of public health, in a sector as complex and sensitive as the pharmaceutical sector should nevertheless be taken into account. For this purpose, the certificate cannot be granted for a period exceeding five years. The protection granted should furthermore be strictly confined to the product which obtained authorisation to be placed on the market as a medicinal product.”

Articles 1, 2 and 3 of the SPC Regulation provide:

“Article 1

Definitions

For the purposes of this Regulation, the following definitions shall apply:

(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;

(b)

‘product’ means the active ingredient or combination of active ingredients of a medicinal product;

(c)

‘basic patent’ means a patent which protects a product as such, a process to obtain a product or an application of a product, and which is designated by its holder for the purpose of the procedure for grant of a certificate;

…

Article 2

Scope

Any product protected by a patent in the territory of a Member State and subject, prior to being placed on the market as a medicinal product, to an administrative authorisation procedure as laid down in Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use or Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products may, under the terms and conditions provided for in this Regulation, be the subject of a certificate.

Article 3

Conditions for obtaining a certificate

A certificate shall be granted if, in the Member State in which the application referred to in Article 7 is submitted and at the date of that application:

(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/EC or Directive 2001/82/EC, as appropriate;

(c)

the product has not already been the subject of a certificate;

(d)

the authorization referred to in (b) is the first authorization to place the product on the market as a medicinal product.”

The following account is based upon evidence given by Professor Geert Leroux-Roels in an expert report submitted by GSK prior to the hearing before the Deputy Director and upon scientific literature which he exhibited to that report. Professor Leroux-Roels is an experienced and distinguished scientist in the field of immunology. Having held a number of positions at Ghent University between 1983 and 1995, he has been Director of CEVAC – The Centre for Vaccinology – Ghent University Hospital since 1995. He is an author of over 250 publications in the field. His evidence was not tested in cross-examination, but there is no reason to think that it is not technically accurate. Any inaccuracies in the following summary will be attributable to me.

Immunity is the general term used to describe the body’s ability to resist infection by a particular pathogen (a microorganism that typically causes a disease upon infection or in the context of failing immunity). There are, broadly speaking, two main types of immunity: innate immunity and adaptive immunity.

Innate immunity describes the various resistance mechanisms that are first encountered by a pathogen upon infection. These are general and non-specific responses which are present in all individuals at all times and are not affected (nor enhanced) by repeated exposure to a particular pathogen. Aspects of the innate immune response include, for example, anatomical barriers to infection, the “complement system” (the coating of a pathogen by proteins which facilitates its removal by phagocytes, which engulf the coated pathogen) and the responses that are triggered by recognition of a pathogen-associated molecular pattern (PAMP). PAMPs are molecules that are specifically associated with groups of pathogens. They are recognised by receptors, such as Toll-like receptors (TLRs), expressed extra- or intracellularly in antigen-presenting cells (APCs) of the innate immune system. APCs are cells (such as dendritic cells, monocytes and macrophages) that display foreign antigen complexes with major histocompatibility complex (MHC) on their surface. Recognition of PAMPs by TLRs triggers signals, including the secretion of cytokines, which help initiate immune responses.

Adaptive immunity occurs after the innate response and describes the response of antigen-specific lymphocytes to a particular antigen, including the development of immunological memory. Unlike innate immunity, adaptive immunity can be boosted by repeated exposure to a particular antigen. It involves both humoral responses and cellular responses.

The adaptive immune system comprises B and T cells. B and T cells are antigen-specific lymphocytes which are named according to their sites of development in the Bone marrow and Thymus respectively.

B cells recognise antigens via B cell receptors or BCRs, and respond by proliferating and producing and secreting antibodies. B cells are divided into two main classes: conventional B cells (which have highly diverse antigen receptors and are generated in bone-marrow) and B-1 cells (which have less diverse antigen receptors and are self-renewing in peritoneal and pleural cavities).

T cells have highly variable receptors (T cell receptors or TCRs), which recognise complexes consisting of antigens bound to MHC molecules, for example on the surface of APCs of the innate immune system. Facilitator (CD4⁺) or “helper” T cells (e.g. Th1, Th2 and Tfh cells) primarily act by secreting cytokines which stimulate other parts of the immune system, such as macrophages to clear the pathogen. Adaptive effector (CD8⁺) or “killer” T cells secrete cytokines and cytotoxic factors to kill cells infected with pathogens.

Both B and T cells have so-called “memory” cells, which mediate immunological memory and are more sensitive and therefore respond more rapidly upon re-exposure to a particular antigen.

Adaptive immunity is an important aspect of vaccination as it is responsible for long-term immunity to particular pathogens. Over the last two decades an increased understanding of both innate and adaptive immunity and how they interact has led to significant advances in both vaccinology and adjuvant technology.

Vaccination has been one of the most important contributions to public health in the past century. Its immediate aim is the protection of an individual by the generation of a long lasting (ideally permanent) and protective immunity. Its ultimate aim is the eradication of particular diseases. Eradication (or near eradication) has been achieved for several human diseases, most famously for smallpox. Examples of well known diseases for which there are vaccines include rabies, diphtheria, pertussis (whooping cough), tetanus, polio, measles, mumps and rubella.

Vaccines are designed to produce an immune response which, when established as part of an individual’s adaptive immunity, recognises a particular pathogen (or parts thereof) and protects that individual against future infection by that pathogen. Accordingly, vaccination involves striking a balance between inducing a protective immune response whilst at the same time ensuring that no disease or other adverse side effects occur as a result of vaccination.

Generally speaking, vaccines contain three main components:

In classical vaccination the antigen tends to be well established and characterised and remains unchanged, for example the diphtheria and tetanus toxoid vaccines, which have been in use for over 40 years. Such vaccinations take place at predictable time points, for example, during infant years, adolescence or prior to travel, and therefore supply of these vaccines can be managed to meet what is a predictable demand.

By contrast to the well-established and stable nature of the antigens mentioned above, certain viruses, for example influenza, are prone to variation. In the case of the influenza virus, mutations in the original virus strain can result in the appearance of a variant strain. Different influenza virus strains are named according to their type (e.g. influenza A or B), the species from which the virus was isolated (omitted if human), location of isolate, the number of the isolate, year of isolation, and, in the case of influenza A viruses, the haemagglutinin (H1 to H16)) and neuraminidase (N1 to N9) subtypes. For example the 220^th isolate of an H5N1 subtype influenza A virus in Hong Kong in 1997 is designated: influenza A/chicken/Hong Kong/220/1997 (H5N1). A “clade” (or subclade) describes a group (or subgroup) of related viruses descendent from a common ancestor.

In the case of diseases like influenza, vaccines can be developed in the pre-pandemic phase in order to “prime” the population for an eventual pandemic outbreak. Priming not only achieves initial immune protection, but can also result in a better response to subsequent booster vaccinations.

In the case of influenza, the virus in the eventual pandemic outbreak may be a variant of the virus originally identified in the pre-pandemic phase because of the highly variable nature of the influenza virus. Therefore, ideally, an influenza vaccine developed in the pre-pandemic phase should be able to induce the broadest protection possible. Cross-reactivity (an adaptive immune response that is able to recognise not only the vaccine antigen, but also related variants of the antigen) is therefore a valuable property of such a vaccine.

If a pandemic outbreak occurs, typically large amounts of vaccine product must be readily available within a short period of time to satisfy the global demand. This can be achieved by a vaccine that induces the necessary immune protection with the lowest amount of vaccine possible. So-called “antigen sparing” is therefore another important factor in the context of pandemic vaccines.

Vaccine antigens are selected so that when an immune response is produced against the antigen, it will protect the individual against future infection by particular pathogens.

Many vaccines contain whole pathogens (e.g. viruses or bacteria), which is feasible when suitable versions can be administered to induce the necessary immune response without leading to disease or side effects. The administration of the whole pathogen tends to be more immunogenic and stimulates both innate and adaptive immune responses. This has the advantages of eliciting stronger and potentially broader immune responses and can produce longer lasting protection. However, whole pathogen vaccines have the disadvantages that they can have poor safety profiles and produce adverse side effects.

Where whole pathogen vaccines are not feasible, other approaches are needed and vaccines may comprise inactive split parts or sub-units of pathogens or recombinantly derived antigens. In recent decades there have been significant advances in peptide (and carbohydrate) engineering and recombinant technology that have enabled the large-scale manufacture of highly specific, safe, tolerable and highly purified antigens. However, one of the main challenges to modern vaccines that comprise such antigens is that the antigens may not be sufficiently immunogenic or potent and may induce only a weak immune response.

The concept that the immune response to antigens can be improved by the addition of certain compounds into the vaccine formulation was demonstrated approximately 100 years ago when aluminium salts were first used in vaccine formulations. Such compounds are referred to as “adjuvants” (derived from the Latin word “adjuvare” which means “to help or aid”).

The last few decades have seen extensive research and development in the field of adjuvants. There has been a surge in adjuvant technology which has been assisted by a greater understanding of innate and adaptive immunity and their close interaction at the molecular level in the response to a pathogen.

It is important to be clear as to exactly what an adjuvant does and what it does not do. It is something which aids the process of generating an antigen-specific antibody response, but it does not generate antibodies itself. The main way in which an adjuvant works is to amplify the immune response.

What an adjuvant does is to provide a quantitative change in the immune response which in turn leads to a qualitative change in the immune response. The first thing the adjuvant can do is to stimulate cytokine production, a general immune response that is not specific to any antigen. The second thing the adjuvant can do is to stimulate the antigen presentation of APCs. This leads to stimulation of the adaptive immune response, which leads to a greater generation of antigen-specific antibodies.

These quantitative effects are of value in themselves since they enable antigen-sparing. In addition, however, they lead to a qualitative effect which is greater cross-reactivity. When the body is exposed to an antigen, it normally produces what is described as a polyclonal response. That is to say, it does not just generate one antibody to the antigen, rather it generates a group of different antibodies which will be specific to different parts (epitopes) of the antigen. Within that polyclonal group, a small proportion will bind not only to that antigen, but also to related antigens. That is referred to as cross-reactivity. Because adjuvants cause more antibodies to be produced, this can result in increased cross-reactivity.

Developing a new adjuvant involves considerable research and development. An adjuvant must interact with the immune system to elicit an improved response to the antigen, but equally it must be safe.

AS03 has the following main components:

AS03 is an oil-in-water (o/w) emulsion adjuvant system, distinguished from other o/w emulsions by the presence of α-tocopherol. By comparing AS03 with an adjuvant formulation in which α-tocopherol was replaced by an equal volume of squalene, α-tocopherol has been shown to significantly and positively influence the kinetics and the magnitude of the cytokine responses in vitro and in vivo, the antigen loading in monocytes, the granulocyte recruitment to the draining lymph nodes, and the magnitude of the antibody response to the model antigen HBsAg. Thus AS03 is superior to previous o/w emulsion adjuvants.

There is good evidence that the presence of AS03 in a pre-pandemic influenza vaccine, namely Prepandrix, has three benefits:

These benefits are not expected to be specific to the use of AS03 in a pre-pandemic influenza vaccine, but they are of particular advantage in that context.

This vaccine comprises an antigen known as A/Indonesia/05/2005 (H5N1) like strain used (PR8-IBCDC-RG2) together with AS03. Studies have demonstrated that the presence of the AS03 is an important factor in ensuring that the vaccine satisfies the criteria for licensing by the United States Food and Drug Administration and the European Medicines Authority.

The issue arising on this appeal involves consideration of a number of decisions of the CJEU, which I shall take in chronological order.

In Case C-31/03 Pharmacia Italia SpA [2004] ECR I-10001 an SPC application had been made in Germany for the active ingredient cabergoline, which was protected by a basic patent filed in 1981. The application was based on a marketing authorisation for cabergoline granted for the human medicinal product Dostinex in Germany in June 1994. By virtue of the transitional provision contained in Article 19(1) of Regulation 1768/92/EEC (the predecessor of the SPC Regulation), an SPC could only be granted for a product if, on the date the Regulation entered into force, it was protected by a basic patent and “the first authorization to place it on the market as a medicinal product in the Community was obtained after” 1 January 1988. The first authorisation for Dostinex in the Community had been granted in the Netherlands in October 1992, but there had been an earlier authorisation for cabergoline as the active ingredient of a veterinary medicinal product called Galastop granted in Italy in January 1987. In these circumstances the Bundesgerichtshof (Federal Court of Justice) referred the following question to the Court of Justice:

“Is the grant of a supplementary protection certificate in a Member State of the Community on the basis of a medicinal product for human beings authorised in that Member State precluded by an authorisation to place the same product on the market as a veterinary medicinal product granted in another Member State of the Community before the date specified in Article 19(1) of the Protection Certificate Regulation, or is the sole determining factor the date on which the product was authorised in the Community as a medicinal product for human beings?”

The applicant argued that it was the date of first authorisation to place the product on the market for human use which was relevant, whereas the Commission and the United Kingdom contended that the relevant date was that of the first authorisation to place the product on the market for either human or veterinary use. Advocate General Jacobs advised the Court of Justice to adopt the latter interpretation. In his Opinion he considered Article 3(d) as well as Article 19(1), saying (footnote omitted):

“48.

Finally the applicant invokes the scheme of the Regulation and in particular the effect of Articles 3(c) and (d).

49.

In my view however the scheme of the Regulation also supports the view that the system of supplementary protection certificates which it establishes does not distinguish between medicinal products for, on the one hand, human use and, on the other hand, veterinary use, whether generally or for the specific purpose of Article 19.

50.

In particular, the interpretation which I am suggesting appears consistent with Article 3(c) and (d). Article 3(c) includes as a condition for obtaining a certificate that the product has not already been the subject of a certificate and thus precludes the grant of more than one certificate for a product in a Member State even if it has been authorised as a medicinal product more than once. Article 3(d) includes a further condition that the marketing authorisation covering the product in respect of which a certificate is sought is the first authorisation to place that product on the market as a medicinal product and thus precludes the grant of a certificate on the basis of a second marketing authorisation even if an application for a certificate has not been made on the basis of the first marketing authorisation. Those provisions highlight the significance for the system put in place by the Regulation of the notion of one certificate per product without distinction depending on the number of authorisations.  Although the authorisation referred to in Article 3(b) and (d) is the first authorisation in the Member State in which the application for the certificate is made whereas that at issue in Article 19 and the question referred is the first Community authorisation, to my mind the principle underlying Article 3 equally suggests that no distinction should be drawn for the purpose of Article 19 depending on whether the relevant authorisation was for human or veterinary use.”

In its judgment the Court of Justice followed the Advocate General’s advice, holding:

“20.

It follows, first, that the decisive factor for the grant of the certificate is not the intended use of the medicinal product and, second, that the purpose of the protection conferred by the certificate relates to any use of the product as a medicinal product without any distinction between use of the product as a medicinal product for human use and as a veterinary medicinal product.

21.

Whilst noting that the term ‘first marketing authorisation in the Community’ must be interpreted in the same way in each of the provisions of the regulation in which it is used, it should be pointed out that, according to the sixth recital in its preamble, that regulation seeks to provide a uniform solution at Community level to the problem of inadequate patent protection, thereby preventing the heterogeneous development of national laws leading to further disparities which would be likely to create obstacles to the free movement of medicinal products within the Community. However, an interpretation such as that proposed by Pharmacia would prevent the realisation of that objective. Under Pharmacia’s interpretation, the duration of the protection conferred by the certificate, calculated in accordance with Article 13 of the regulation, might be different for the same product.

22.

Lastly, and for the reasons set out in points 41 to 43 and 48 to 50 of the Advocate General’s Opinion, it must be found that neither the purpose of Article 19 nor the broad logic of the regulation militate in favour of the interpretation put forward by Pharmacia.”

In Case C-431/04 Massachusetts Institute of Technology [2006] ECR I-4089 the applicant had applied in Germany for an SPC for the product carmustine, either in combination with a polymeric biodegradable matrix called polifeprosan or alternatively on its own. The applicant relied on a marketing authorisation for the medicinal product Gliadel, which was used for the treatment of human brain tumours. Gliadel comprised carmustine as its active ingredient and polifeprosan as an excipient. Carmustine was a highly cytotoxic substance which was already covered by an earlier marketing authorisation for the treatment of brain tumours with inert excipients. Polifeprosan was a new excipient that enabled the slow release of carmustine from a disc implanted in the cranium after surgical removal of the tumor, thereby permitting the delivery of a higher but constant dose of carmustine. Accordingly to the applicant, the combined use of carmustine and polifeprosan extended the life expectancy of patients by several months. Polifeprosan was the subject of a patent which the applicant relied on as the basic patent for the application.

The application was refused by the Deutches Patent- under Markenamt (German Patent and Trade Mark Office) on the basis that (i) no SPC could be granted for the combination of carmustine and prolifeprosan since that was not a combination of active ingredients within the meaning of Article 1(b); and (ii) no SPC could be granted for carmustine on its own since the marketing authorization relied on was not the first authorization to market carmustine contrary to Article 3(d). As I understand it, the applicant appealed against holding (i), but not holding (ii). In these circumstances the Bundesgerichtshof referred the following questions to the Court of Justice:

“1.

Does the concept of ‘combination of active ingredients of a medicinal product’ within the meaning of Article 1(b) of Regulation [1768/92/EEC] mean that the components of the combination must all be active ingredients with a therapeutic effect?

2.

Is there a ‘combination of active ingredients of a medicinal product’ also where a combination of substances comprises two components of which one component is a known substance with a therapeutic effect for a specific indication and the other component renders possible a pharmaceutical form of the medicinal product that brings about a changed efficacy of the medicinal product for this indication (in vivo implantation with controlled release of the active ingredient to avoid toxic effects)?”

Advocate General Léger advised the Court of Justice to rule that Article 1(b) should be interpreted as including a combination of an active ingredient (such as carmustine) with an excipient which is necessary for the therapeutic efficacy of the active ingredient (such as polifeprosan). He did so on the basis of the kind of teleological approach to interpretation contended for by GSK in the present case, saying that this was just the kind of costly innovation that the Regulation was designed to protect. Nevertheless the Court of Justice declined to follow that advice, and ruled that such a combination was not within the scope of Article 1(b) on its proper interpretation.

The following passages in the Court’s judgment are particularly relevant to the present issue:

“17.

In the absence of any definition of the concept of ‘active ingredient’ in Regulation No 1768/92, the meaning and scope of those terms must be determined by considering the general context in which they are used and their usual meaning in everyday language (see, inter alia, Case 349/85 Denmark v Commission [1988] ECR 169, paragraph 9, and Case C-164/98 P DIR International Film and Others v Commission [2000] ECR I-447, paragraph 26).

18.

In this case, it is important to note that it is common ground, as the file in this case shows, that the expression ‘active ingredient’ is generally accepted in pharmacology not to include substances forming part of a medicinal product which do not have an effect of their own on the human or animal body.

19.

In that regard, attention must be drawn to the fact that in point 11 of the Explanatory Memorandum to the Proposal for a Council Regulation (EEC), of 11 April 1990, concerning the creation of a supplementary protection certificate for medicinal products (COM(90) 101 final), to which the French Government referred in its oral observations, it is specified that ‘[t]he proposal for a Regulation therefore concerns only new medicinal products. It does not involve granting a [SPC] for all medicinal products that are authorised to be placed on the market. Only one [SPC] may be granted for any one product, a product being understood to mean an active substance in the strict sense. Minor changes to the medicinal product such as a new dose, the use of a different salt or ester or a different pharmaceutical form will not lead to the issue of a new [SPC].’

20.

Therefore, the definition of ‘product’ in Article 1(b) of Regulation No 1768/92 does not in any way conflict with that referred to by the Commission in point 11 of that explanatory memorandum.

21.

In fact, it is apparent from that memorandum that the pharmaceutical form of the medicinal product, to which an excipient may contribute, as noted by the Advocate General in point 11 of his Opinion and the French Government at the hearing, does not form part of the definition of ‘product’, which is understood to mean an ‘active substance’ or ‘active ingredient’ in the strict sense.

… 

25.

In the light of the foregoing, the inevitable conclusion is that a substance which does not have any therapeutic effect of its own and which is used to obtain a certain pharmaceutical form of the medicinal product is not covered by the concept of ‘active ingredient’, which in turn is used to define the term ‘product’.

26.

Therefore, the alliance of such a substance with a substance which does have therapeutic effects of its own cannot give rise to a ‘combination of active ingredients’ within the meaning of Article 1(b) of Regulation No 1768/92.

27.

The fact that the substance without any therapeutic effect of its own renders possible a pharmaceutical form of the medicinal product necessary for the therapeutic efficacy of the substance which does have therapeutic effects cannot invalidate that interpretation.

28.

As shown by paragraphs 6 and 7 of this judgment, carmustine is an active ingredient which must be combined with other substances, in particular inert excipients, to be therapeutically effective. More generally, as observed by the Advocate General in point 11 of his Opinion and by the French and Netherlands Governments, it is apparently not unusual for substances which render possible a certain pharmaceutical form of the medicinal product to influence the therapeutic efficacy of the active ingredient contained in it.

29.

Thus, a definition of ‘combination of active ingredients of a medicinal product’ which includes a combination of two substances, only one of which has therapeutic effects of its own for a specific indication, the other rendering possible a pharmaceutical form of the medicinal product which is necessary for the therapeutic efficacy of the first substance for that indication, might, on any view, create legal uncertainty in the application of Regulation No 1768/92, as the French Government pointed out at the hearing. Whether a substance without any therapeutic effect of its own is necessary for the therapeutic efficacy of the active ingredient cannot, in this case, be regarded as a sufficiently precise test.

30.

Moreover, such a definition is liable to prevent the attainment of the objective referred to in the sixth recital in the preamble to Regulation No 1768/92, in the words of which a uniform solution at Community level should be provided for, thereby preventing the heterogeneous development of national laws leading to further disparities which would be likely to create obstacles to the free movement of medicinal products within the Community and thus directly affect the establishment and the functioning of the internal market.

31.

In those circumstances, the answer to the questions referred must be that Article 1(b) of Regulation No 1768/92 must be interpreted so as not to include in the concept of ‘combination of active ingredients of a medicinal product’ a combination of two substances, only one of which has therapeutic effects of its own for a specific indication, the other rendering possible a pharmaceutical form of the medicinal product which is necessary for the therapeutic efficacy of the first substance for that indication.”

The Court of Justice’s reasoning in these passages can be summarised as follows:

Although the Court did not refer to its earlier judgment in Pharmacia, and Pharmacia did not dictate the decision in MIT, the Court’s decision in MIT was consistent with the earlier decision.

In Case C-202/05 Yissum Research and Development Company of the Hebrew University of Jerusalem v Comptroller-General of Patents [2007] ECR I-2839 the applicant applied for an SPC for the product calcitriol either alone or in combination with an ointment base. The applicant relied upon (i) a second medical use patent, the claims of which were directed to the use of calcitriol in topical treatment of skin disorders including psoriasis, and (ii) a marketing authorization for Silkis ointment, which comprised calcitriol as the active ingredient with various carriers and was authorised for the topical treatment of psoriasis. The application was refused by the Comptroller because there were two earlier marketing authorisations for medicinal products containing calcitriol as the active ingredient, namely Calcijex and Rocaltrol. Calcijex was authorised for the management of hypocalcaemia in patients undergoing dialysis for chronic renal failure. Rocaltrol was authorised for administration to patients with chronic renal failure or post-menopausal osteoporosis.

On the applicant’s appeal, I referred three questions to the Court of Justice ([2004] EWHC 2880 (Pat)]). Two of those were subsequently withdrawn in the light of the Court’s judgment in MIT. The remaining question was as follows:

“In a case in which the basic patent protects a second medical application of a therapeutic agent what is meant by ‘product’ in Article 1(b) of the Regulation and in particular does the application of the therapeutic agent play any part in the definition of ‘product’ for the purpose of the Regulation?”

The Court of Justice gave its answer to that question by reasoned order on the basis that the answer to it could be clearly deduced from the existing case law, and in particular Pharmacia and MIT. In its order the Court held:

“16.

As laid down in Article 1(b) of Regulation No 1768/92, ‘product’ means the active ingredient or combination of active ingredients of a medicinal product.

17.

It is clear from Massachusetts Institute of Technology, and, in particular, from paragraphs 19, 21, 23 and 24 of that judgment, that the concept of ‘product’ referred to in Article 1(b) of Regulation No 1768/92 must be interpreted strictly to mean ‘active substance’ or ‘active ingredient’.

18.

It follows that the concept of ‘product’ cannot include the therapeutic use of an active ingredient protected by a basic patent.

19.

Moreover, the same interpretation can be inferred from paragraph 20 of the judgment in Case C-31/03 Pharmacia Italia [2004] ECR I-10001, in which the Court held that ‘the decisive factor for the grant of the certificate is not the intended use of the medicinal product and … the purpose of the protection conferred by the certificate relates to any use of the product as a medicinal product without any distinction between use of the product as a medicinal product for human use and as a veterinary medicinal product’.

20.

Consequently, the answer to the question referred must be that Article 1(b) of Regulation No 1768/92 is to be interpreted as meaning that in a case where a basic patent protects a second medical use of an active ingredient, that use does not form an integral part of the definition of the product.”

It can be seen from this that the Court of Justice confirmed that the concept of “product” in Article 1(b) of the Regulation was to be interpreted strictly and could not include the therapeutic use of the active ingredient or even whether the medicinal product was for human use or for veterinary use.

In Case C-130/11 Neurim Pharmaceuticals (1991) Ltd v Comptroller-General of Patents [2012] ECR I-0000 melatonin, a naturally occurring hormone, had been marketed by Hoechst under the trade mark Regulin for regulating the seasonal breeding activity of sheep pursuant to a patent applied for in 1987 and a marketing authorisation granted in 2001 (“the Regulin MA”). Neurim marketed melatonin under the trade mark Circadin for the treatment of insomnia in humans pursuant to a patent applied for in 1992 and a marketing authorisation granted on 28 June 2007 (“the Circadin MA”). Neurim applied to the UK Intellectual Property Office for an SPC in respect of Circadin. The IPO refused the application on the ground that it did not comply with Article 3(d) of the SPC Regulation since the Circadin MA was not the first authorisation to place melatonin on the market, the Regulin MA was. I dismissed Neurim’s appeal ([2010] RPC 22, [2010] RPC 22), but the Court of Appeal referred five questions to the Court of Justice ([2011] EWCA Civ 228, [2011] RPC 19).

The Court interpreted the first and third questions as asking, in essence, whether Articles 3 and 4 of the SPC Regulation were to be interpreted as meaning that the existence of an earlier marketing authorisation for a veterinary medicinal product precluded the grant of an SPC for a different use of the same product. It answered those questions as follows:

“23.

The reason given for the adoption of the SPC Regulation is the fact that the period of effective protection under the patent is insufficient to cover the investment put into pharmaceutical research and the regulation thus sought to make up for that insufficiency by creating an SPC for medicinal products (see Medeva, paragraph 31, and Georgetown University and Others, paragraph 25).

24.

It is apparent from paragraph 29 of the explanatory memorandum to the proposal for a Council Regulation (EEC) of 11 April 1990, concerning the creation of a supplementary protection certificate for medicinal products (COM(90) 101 final), that, like a patent protecting a ‘product’ or a patent protecting a process by which a ‘product’ is obtained, a patent protecting a new application of a new or known product, such as that at issue in the main proceedings, may, in accordance with Article 2 of the SPC Regulation, enable an SPC to be granted and, in that case, in accordance with Article 5 of the regulation, the SPC confers the same rights as conferred by the basic patent as regards the new use of that product, within the limits laid down by Article 4 of that regulation (see, by analogy, Medeva, paragraph 32, and order of 25 November 2011 in Case C-630/10 University of Queensland and CSL, ECR I-0000, paragraph 38).

25.

Therefore, if a patent protects a therapeutic application of a known active ingredient which has already been marketed as a medicinal product, for veterinary or human use, for other therapeutic indications, whether or not protected by an earlier patent, the placement on the market of a new medicinal product commercially exploiting the new therapeutic application of the same active ingredient, as protected by the new patent, may enable its proprietor to obtain an SPC, the scope of which, in any event, could cover, not the active ingredient, but only the new use of that product.

26.

In such a situation, only the MA of the first medicinal product, comprising the product 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.

27.

In the light of all the above considerations, the answer to the first and third questions is that Articles 3 and 4 of the SPC Regulation are to be interpreted as meaning that, in a case such as that in the main proceedings, 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.”

As I observed in AstraZeneca AB v Comptroller-General of Patents, Trade Marks and Designs [2012] EWHC 2840 (Pat) at [52]-[53], the Court’s judgment in Neurim is problematic for two reasons.

First, it appears that the Court was intending to depart from its earlier judgments and order in Pharmacia, MIT and Yissum. This is not clear, however, since it did not refer to those decisions. Thus one does not know if those decisions are to be regarded as having been overruled, or as qualified in some unspecified manner.

Secondly, it does not appear that the Court was intending to depart from its earlier judgments in Case C-195/09 Synthon BV v Merz Pharma GmbH & Co KGaA [2011] ECR I-0000, [2012] RPC 3 and Case C-427/09 Generics (UK) Ltd v Synaptech Inc [2011] ECR I-0000, [2012] RPC4, since it cited Synthon at [20]. It is not clear to me, however, how Neurim is to be reconciled with those decisions. The reasoning which the Court relied on in Neurim, namely that the research required to obtain a patent and marketing authorisation for a second medical use of an active ingredient justifies the grant of an SPC for the second medical use despite the fact that the same active ingredient has already been lawfully marketed as a medicinal product, seems to me to be equally applicable to Generics and Synthon.

Case C-11/13 Bayer CropScience is a recent reference from the German Bundespatentgericht (Federal Patent Court) to the CJEU. In this case Bayer applied for an SPC for isoxadifen. Isoxadifen is a so-called “safener”, a substance which is added to herbicides and other plant protection products to eliminate or reduce their phytotoxic effects on certain plants. The safener works in combination with the herbicide to allow beneficial application of the herbicide. Without the safener, in many cases the herbicide would destroy the crop in addition to the weed or pest. The question referred is whether a safener is an “active substance” within the meaning of Article 1(3) and 1(8) of European Parliament and Council Regulation 1610/96/EC of 23 July 1996 concerning the creation of a supplementary protection certificate for plant protection products (“the Plant SPC Regulation”), and hence eligible for an SPC as a product under Article 3(1).

The Federal Patent Court has set out a number of competing considerations in its reference, while indicating its own provisional view in favour of refusing the application.

First, the language of the Plant SPC Regulation supports the view that a safener is an active substance. In particular, “active substances” are defined under Article 1(3) of the Plant SPC Regulation as “substances or microorganisms including viruses, having general or specific action”. Furthermore, “plant protection products” are broadly defined in Article 1(1) as products intended inter alia to protect plants against all harmful organisms or to influence the life processes of plants (other than as a nutrient).

Secondly, however, MIT decided that a substance that is used to obtain a pharmaceutical form of a medicinal product is not covered by the concept of an “active ingredient” under the SPC Regulation, even if it renders possible the therapeutic efficacy of the substance in the medicinal product which does have therapeutic effects. This supports a strict interpretation of “active substance” which is limited to substances which have a direct therapeutic effect or plant protection action of their own. It also indicates that merely because the safener is an integral part of the plant protection product, it does not thereby necessarily constitute an active substance.

The Bundespatentgericht recognises, however, that a factual distinction can be drawn between MIT and the facts before it, since the mechanism of action of a safener is different from that of a biodegradable matrix. In particular, a safener appears to have a more complex mechanism of action which is of more direct effect.

Furthermore, by contrast, in Case C-420/10 Söll [2012] ECR I-0000 the CJEU ruled that the concept of “biocidal products” under Article 2(1)(a) of European Parliament and Council Directive 98/8/EC of 16 February 1998 concerning the placing of biocidal products on the market (“the Biocidal Directive”) follows from the concept of “active substance” as defined in Article 2(1)(d) of that Directive and includes indirect action.

Thirdly, European Parliament and Council Regulation 1107/2009/EC of 21 October 2009 concerning the placing of plant protection products on the market, which replaces Directive 91/414/EEC, clearly distinguishes between the terms “active substance” and “safener”. It indicates that active substances have general action against harmful organisms or on plants, whereas safeners are added to the plant protection product to influence its effects.

It is reasonable to consider that “active substance” should have the same meaning under the Plant SPC Regulation. In particular:

Fourthly, the substantive requirements for an authorisation of a safener are largely the same as those for an active substance. It would be consistent with the objectives of the Plant SPC Regulation to grant a certificate to compensate for the delay (and resulting reduced period of patent protection) caused by such authorisation requirements.

Finally, the lack of searchability of safeners, which do not appear on any databases of active substances, suggests that they are not intended to be treated in the same way.

The Deputy Director decided that, applying the reasoning of the Court of Justice in MIT, AS03 was not an “active ingredient” within the meaning of Article 1(b) of the SPC Regulation whether in its own right or in combination with the antigen contained in Prepandrix because AS03 did not have a therapeutic effect on its own. AS03 did not itself confer any immunity, whether against influenza or any other condition. The fact that AS03 enhanced the therapeutic effect of the antigen, irrespective of the actual antigen involved and the immunological protection sought, was not sufficient.

GSK contends that the Deputy Director’s decision was wrong. Counsel for GSK argued in summary as follows.

First, he relied upon various paragraphs of the Explanatory Memorandum to the Commission’s Proposal for Regulation 1768/92/EEC, and in particular paragraph 11, as showing that it was intended to apply to all new products which were the subject of innovative research save only for minor variants such as a new dose, the use of a different salt or ester or a different pharmaceutical formulation.

Secondly, he relied upon the primary purpose of the SPC Regulation, which was described by the Court of Justice in Case C-482/07 AHP Manufacturing BV v Bureau voor de Industriële Eigendom [2009] ECR I-7295 at [30] as follows:

“Regarding the objectives of Regulation No 1768/92, firstly, it must be noted that the fundamental objective of the Regulation, as set out in the first and second recitals in the preamble thereto, is to ensure sufficient protection to encourage pharmaceutical research, which plays a decisive role in the continuing improvement in public health (Case C-392/97 Farmitalia [1999] ECR I-5553, paragraph 19). In that regard, the third and fourth recitals in the preamble give as a reason for the adoption of the Regulation the fact that the period of effective protection under the patent is insufficient to cover the investment put into the pharmaceutical research. Regulation No 1768/92 thus seeks to make up for that insufficiency by creating an SPC for medicinal products. It seeks, in addition, to confer supplementary protection on the holders of national or European patents, without instituting any preferential ranking amongst them (Biogen, paragraphs 26 and 27).”

In this regard, counsel for GSK argued that giving effect to this purpose had been key to the Court’s reasoning in Neurim and that that decision showed that Article 1(b) should not be narrowly interpreted.

Thirdly, he argued that the present case was to be distinguished from MIT. In this regard, he argued that MIT was concerned with an excipient which had no physiological effect on the body, whereas the present case was concerned with an adjuvant which did have physiological effects on the body and which thereby enhanced the therapeutic effect of the antigen.

The Comptroller supports the Deputy Director’s decision. Counsel for the Comptroller argued in summary as follows.

First, she relied on the language of the SPC Regulation. In this regard she argued that the SPC Regulation makes a clear distinction between a “medicinal product” and a “product” (compare Article 1(a) with Article 1(b)). The former may have an effect on a physiological function, but it is only the latter which can be the subject of an SPC. As a consequence, although an adjuvant may fall within the definition of “medicinal product”, it does not mean that that the adjuvant is an “active ingredient” or “product” within the meaning of the SPC Regulation. If a substance with general and indirect physiological effects - which could be positive or negative or might or might not be related to the indication which was the subject of the marketing authorisation - also fell within the concept of “active ingredient”, then it would result in a definition which is too broad and uncertain, leading to divergent results in different Member States.

Secondly, she relied on the Court of Justice’s decision in MIT. In this regard, she disputed that the present case could be distinguished from MIT. She pointed out that the Court’s judgment made barely any reference to excipients, and that neither the ruling nor the reasoning was confined to excipients. She argued that the ruling and the reasoning were directly applicable to the present case. She also pointed out that in that case the Court had been considering a situation in which the presence of the polifeprosan was necessary to the therapeutic efficacy of the medicinal product. She argued that, if inventive merit was the only consideration, the Court would have reached the opposite conclusion.

Thirdly, she relied on European Parliament and Council Directive 2001/83/EEC of 6 November 2001 on the Community Code relating to medicinal products. In this regard, she pointed out Directive 2001/83/EEC draws a clear distinction between “active substances” on the one hand and “excipients” on the other. “Active substance” is defined in Article 1(3a) as:

“Any substance or mixture of substances intended to be used in the manufacture of a medicinal product and that, when used in its production, becomes an active ingredient of that product intended to exert a pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying physiological functions or to make a medical diagnosis.”

“Excipient” is defined in Article 1(3b) as:

“Any constituent of a medicinal product other than the active substance and the packaging material.”

Furthermore, the Directive expressly treats an adjuvant as a type of excipient. Thus Annex 1, Part I, Module 3 to the Directive provides at section 3.2.2.1 as follows (emphasis added):

“Description and composition of the finished medicinal product

A description of the finished medicinal product and its composition shall be provided. The information shall include the description of the pharmaceutical form and composition with all the constituents of the finished medicinal product, their amount on a per-unit basis, the function of the constituents of:

— the active substance(s),

— the constituent(s) of the excipients, whatever their nature or the quantity used, including colouring matter, preservatives, adjuvants, stabilisers, thickeners, emulsifiers, flavouring and aromatic substances, etc.,

— the constituents, intended to be ingested or otherwise administered to the patient, of the outer covering of the medicinal products (hard capsules, soft capsules, rectal capsules, coated tablets, films-coated tablets, etc.),

— these particulars shall be supplemented by any relevant data concerning the type of container and, where appropriate, its manner of closure, together with details of devices with which the medicinal product will be used or administered and which will be delivered with the medicinal product.”

Counsel for the Comptroller argued that it is reasonable to consider that “active ingredient” should have the same meaning in the SPC Regulation, for at least the following reasons:

In addition, counsel for the Comptroller pointed out that the then European Agency for the Evaluation of Medicinal Products’ Note for Guidance on Requirements for the Evaluation of New Adjuvants in Vaccines dated 25 April 2002 stated that “because the adjuvant is not the active ingredient, it is an individual vaccine/adjuvant combination which will be licensed”.

Fourthly, she relied upon the other purposes of the SPC Regulation, reflected in recitals (7)-(10), which the Court of Justice described in AHP as follows:

“35.

Second, Regulation No 1768/92, which was adopted on the basis of Article 100a of the EEC Treaty (subsequently Article 100a of the EC Treaty, and now, after amendment, Article 95 EC), establishes, as is apparent from the sixth and seventh recitals in the preamble thereto, a uniform solution at Community level by creating an SPC which may be obtained by the holder of a national or European patent under the same conditions in each Member State. It thus aims to prevent the heterogeneous development of national laws leading to further disparities which would be likely to create obstacles to the free movement of medicinal products within the Community and thus directly affect the establishment and the functioning of the internal market (see Case C-350/92 Spain v Council [1995] ECR I-1985, paragraphs 34 and 35, and Case C-127/00 Hässle [2003] ECR I-14781, paragraph 37).

…

39.

Thirdly, apart from the objective of adequate protection to encourage research, Regulation No 1768/92 recognises, as is apparent from the ninth recital in its preamble, the necessity, in a sector as complex as the pharmaceutical sector, to take into account all the interests at stake, including those of public health (see Spain v Council, paragraph 38). For that purpose, the SPC may not be granted for a period exceeding five years. Similarly, the eighth recital in the preamble states that the holder of both a patent and an SPC should be able to enjoy an overall maximum of fifteen years of exclusivity from the time the medicinal product in question first obtains authorisation to be placed on the market in the Community.”

In this regard counsel for the Comptroller argued that in order to give effect to these purposes it was necessary to interpret Article 1(b) strictly, as the Court of Justice had done in MIT.

As noted above, the parties are agreed that this issue should be referred to the Court of Justice for a preliminary ruling. I also agree that this is necessary, for three reasons. First, in the light of the arguments summarised above, I do not consider that the answer is acte clair. Secondly, it is clear that there is a divergence of interpretation between the different national authorities on this point. Thus the patent offices in Austria, Italy, Luxembourg and Spain have granted SPCs in respect of both AS03 and the combination of the antigen and AS03 based on the 918 patent, while the Portuguese patent office has refused an SPC in respect of AS03 alone but granted one in respect of the combination and the Swedish patent office, like the Deputy Director, has refused both applications. In addition, the patent offices in Cyprus and Italy have granted SPCs for the combination based on the 889 patent. Thirdly, the present case raises a similar issue to the issue in Bayer CropScience.

Accordingly, I shall refer the following questions to the Court of Justice:

“1.

Is an adjuvant which has no therapeutic effect on its own, but which enhances the therapeutic effect of an antigen when combined with that antigen in a vaccine, an ‘active ingredient’ within the meaning of Article 1(b) of Regulation 469/2009/EC?

2.

If the answer to question 1 is no, can the combination of such an adjuvant with an antigen nevertheless be regarded as a ‘combination of active ingredients’ within the meaning of Article 1(b) of Regulation 469/2009/EC?”

In case it assists, I shall state my own view on these questions. While I acknowledge the force of counsel for GSK’s argument that the primary purpose of the SPC Regulation is to reward innovative research of the kind that led to the development of AS03 and Prepandrix, I find the arguments presented by counsel for the Comptroller more convincing. In particular, I consider that the SPC Regulation was intended to provide a simple and predictable system that could be operated by the competent authorities of the Member States, and in particular the national patent offices, in a uniform manner. To achieve those objectives, it is necessary to have bright-line rules. Article 1(b) is such a rule. In my view the Court of Justice was correct to hold in Pharmacia, MIT and Yissum that it should be strictly interpreted. The result of a strict interpretation is to deny extended protection for what may well be meritorious inventions, but the price of not adopting a strict interpretation is a level of uncertainty and inconsistency which in my opinion is unacceptable. Accordingly, I would answer both questions no.

It is worth adding that, as counsel for the Comptroller pointed out, GSK may be able to obtain an SPC for the antigen contained in Prepandrix based on the 889 patent and the marketing authorisation for Prepandrix. Thus refusal of the appeal would not necessarily leave GSK bereft of protection.

Finally, I would observe that this is the third time in six months that I have had to refer questions of interpretation of the SPC Regulation to the CJEU. I do so with considerable regret. That this should be necessary demonstrates the dysfunctional state of the SPC system at present. This is primarily due to the poor drafting of the SPC Regulation and to the failure of the European Commission, Council and Parliament to revise it to address the problems which have emerged. Matters have not been assisted, however, by the fact that the Court of Justice’s recent case law interpreting the SPC Regulation has not provided the level of clarity and consistency that is required.