England and Wales High Court (Patents Court) Decisions

IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT

		Royal Courts of Justice Strand, London, WC2A 2LL
		12/07/2010

Mr Justice Lewison:

1. Yeda Research and Development Co Ltd ("Yeda") appeals from the decision of Dr Lawrence Cullen, the Hearing Officer acting on behalf of the Comptroller General of Patents, dated 23 February 2010. The Hearing Officer refused two applications for supplementary protection certificates (an "SPC") relating to EP 0 667 165 B1 ("the patent").
2. The patent was filed in September 1989 and granted in 2002. It has now expired. The invention disclosed by the patent relates to the treatment of cancer. It explains [0011] that the primary goal in treating tumours is to kill the cells of the tumour. Two forms of agent are used. One is cytotoxic (i.e. it kills the cancer cells); the other is cytostatic (i.e. it stops them from replicating but does not kill them). Monoclonal antibodies are among the latter, and were known in the art. The problem with cytotoxic agents is that they are toxic to the patient (i.e. they kill healthy cells as well). What the patentee discovered [0018] was that:

"the combined treatment of one of the novel monoclonal antibodies with anti-neoplastic drugs … provides a more efficient treatment for inhibiting the growth of human cancer cells that express human EGF receptors and are mitogenically stimulated by human EGF than the use of the novel monoclonal antibody of the anti-neoplastic agent by itself. The combined treatment is advantageous because it combines two anti-cancer agents, each operating via different mechanisms of action to yield a cytotoxic effect to human tumor cells."

3. In effect the combination of the two agents means that patients can be treated with lower doses of cytotoxic agents. The patent specification contains information both about the relevant antibodies and about their uses in combination with anti-neoplastic agents. The relevant claims reflect the disclosure in the specification. Claim 1 claims:

"A therapeutic composition comprising:

(a) a monoclonal antibody which inhibits the growth of human tumour cells by said antibody binding to the extra-cellular domain of the human EGF receptors of said tumor cells in an antigen-antibody complex, said tumor cells being characterized by their expression of human EGF receptors and mitogenic stimulation by human EGF; and

(b) an anti-neoplastic agent

wherein the antibody is not antibody 108 produced by hybridoma cell line ATCC HB 9764 or antibody 96 produced by hybridoma cell line ATCC HB 9763."

4. It is clear from this claim that the invention resides in the combination of the two agents. Claim 2 claims:

"The therapeutic composition of claim 1 for separate administration of the components."

5. Thus it is clear that the components of the combination may be separately administered. The only other claim I need mention is claim 6 which claims:

"Use of (a) a monoclonal antibody and (b) an anti-neoplastic agent, as defined in any one of claims 1 to 5, for the preparation of a therapeutic composition for treating cancer."

6. The chosen monoclonal antibody (which has been approved for medical use) is cetuximab (known as Erbitux). The chosen anti-neoplastic agent is irinotecan. Following the usual clinical trials the appropriate regulatory authorities have approved the treatment. Precisely what they have approved is one of the issues on this appeal. The first approval came from the Swiss authorities. In December 2003 they issued a decision recording that:

"The application … for marketing authorisation of the preparation Erbitux, infusion solution, is approved.

The preparation Erbitux is approved for the indication/possible use in combination with Irinotecan for the treatment of patients with EGFR-expressing metastising colorectal carcinoma, when a cytotoxic therapy including Irinotecan has failed."

7. A marketing authorisation granted by the Swiss regulators is, so I was told, recognised in Liechtenstein although not in other member states of the European Union. This authorisation enabled Erbitux to be placed on the market in Liechtenstein, subject to the limitations of the approval. In order to be able to market more widely in the EU a further approval was necessary. This was granted by the European Commission on 26 June 2004 following an evaluation by the European Agency for the Evaluation of Medicinal Products. The Commission decision begins by saying that it is "granting marketing authorisation for the medicinal product for human use "Erbitux – cetuximab". The decision recites that "the medicinal product Erbitux – cetuximab complies" with certain regulatory requirements. Article 1 states:

"The marketing authorization … is hereby granted in respect of the medicinal product, "Erbitux – cetuximab" whose characteristics are summarized in Annex 1 hereto. This medicinal product shall be entered in the Community Register of Medicinal Products under the numbers:

EU/1/04/281/001 Erbitux-2 mg/ml-Solution for infusion-Intravenous use-Vial (glass) 50 ml-1 vial"

8. Annex 1 names the medicinal product as "Erbitux-2 mg/ml-solution for infusion". It said that each ml contained 2 mg of cetuximab and that cetuximab was a chimeric monoclonal antibody produced by recombinant DNA technology. It went on to say that Erbitux was a colourless solution that might contain particles. Under clinical particulars it said:

"Erbitux in combination with irinotecan is indicated for the treatment of patients with epidermal growth factor (EGFR) expressing metastatic colorectal cancer after failure of irinotecan including cytotoxic therapy."

9. It went on to describe the dosage of Erbitux and said that:

"For the dosage of concomitant irinotecan, refer to the product information for this medicinal product. … However, recommendations for dose modifications of irinotecan according to the product information for this medicinal product must be followed."

10. Section 5 of Annex 1 contains details of the pharmacological properties of cetuximab. Although it says that cetuximab was investigated in combination with irinotecan in two clinical studies, it says nothing else about irinotecan.
11. Based on this marketing authorisation and the patent, the patentee applied for SPCs. Jacob J explained the background to SPCs in Draco's Application [1996] RPC 417, 436:

"I now turn to the supplementary protection certificate (SPC) scheme under which the appeal arises. Because of the drug regulatory scheme it was recognised by the Member States of the European Community that research in the drug field was not getting its proper reward. Although the term of a patent is 20 years, it was taking so long to get through the necessary procedures leading to authorisation to sell a drug that the practical period of protection was often too short. So Council Regulation No. 1768/92 concerning the creation of an SPC scheme for medicinal products was enacted. The basic idea is that where a patentee of a medicine has lost time in obtaining his authorisation, he may gain a further period of protection by the grant of an SPC. The period (subject to a maximum of 5 years) of an SPC is the time between grant of the basic patent and first authorisation to sell ("place the product on the market") less five years."

12. The recitals to the regulation further explain its purpose. Among the recitals, recital (10 ) is significant:

"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."

13. Article 1 of the regulation contains the following relevant definitions:

"For the purposes of this Regulation:

(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 defined in (b) 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;

(d) "certificate" means the supplementary protection certificate."

14. Article 3 sets out the conditions that must be fulfilled in order to obtain an SPC:

"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 point (b) is the first authorisation to place the product on the market as a medicinal product."

15. Article 4 deals with the scope of protection and says:

"Within the limits of the protection conferred by the basic patent, the protection conferred by a certificate shall extend only to the product covered by the authorisation to place the corresponding medicinal product on the market and for any use of the product as a medicinal product that has been authorized before the expiry of the certificate."

16. The period of protection is governed by article 13 which says:

"1. The certificate shall take effect at the end of the lawful term of the basic patent for a period equal to the period which elapsed between the date on which the application for a basic patent was lodged and the date of the first authorisation to place the product on the market in the Community reduced by a period of five years.

2. Notwithstanding paragraph 1, the duration of the certificate may not exceed five years from the date on which it takes effect."

17. The patentee applied for two SPCs. The first (referred to as "037") specified the product to be protected as "cetuximab in combination with irinotecan". The Hearing Officer refused to grant the certificate on the ground that the marketing authorisation upon which the application was based was an authorisation for cetuximab alone. Accordingly, that application did not comply with article 3 (b). The second (referred to as "038") specified the product to be protected as "cetuximab". The Hearing Officer refused to grant the certificate on the ground that cetuximab (as opposed to the combination of cetuximab and irinotecan) was not protected by the patent. Accordingly, that application did not comply with article 3 (a). Thus the patentee fell between two stools, and was not entitled to any SPC. It is from those two decisions that the patentee now appeals.
18. Mr Powell, who argued the appellants' case, said in effect that it was all very difficult and that the right course was to refer a series of questions to the Court of Justice, particularly in the light of the fact that the Court of Appeal has recently referred a series of questions relating to article 3: Medeva BV v Comptroller General of Patents [2010] EWCA Civ 700. Mr Mitcheson, on the other hand, arguing the case for the Comptroller, said that it was all very simple and that there was nothing worthy of referral.
19. To my mind it is clear from recital (10) and from the case law that what constitutes a "product" is to be strictly construed: Generics (UK) Ltd v Daiichi Pharmaceutical Co Ltd [2009] EWCA Civ 646. In deciding what is a "product" one must focus, as the Hearing Officer put it, "on what the product is, rather than what it does". As the ECJ said in Case C-202/05 Yissum Research and Development Co v Comptroller-General (§ 18):

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

20. Jacob J made the same point in Takeda Chemical Industries Ltd's SPC Applications No 3 [2004] RPC 3, § 13. Moreover, it is only the active ingredients of the product that count. This is clear from the decision of the ECJ in Case C-431/04 Re Massachusetts Institute of Technology [2006] RPC 34 in which they said (§ 25):

"… 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"."

21. Whether the Hearing Officer was right to refuse the SPC on the 037 application depends on the correct interpretation of the marketing authorisation. More specifically, the question is: what "product" did it authorise to be placed on the market? Was it cetuximab alone (as the Hearing Officer decided); or was it the combination of cetuximab and irinotecan (as Mr Powell argued)?
22. The procedures by which a Community marketing authorisation is granted are governed by Regulation 726/04. This lays down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishes a European Medicines Agency ("the Medicinal Products Regulation"). Article 3 says that no medicinal product appearing in the annex (which includes products for treating cancer) may be placed on the market in the Community unless a marketing authorisation has been granted in accordance with the regulation. Article 6 governs the form of the application for marketing authorisation. Among other things the application must comply with article 8 (3) of Directive 2001/83/EC ("the Medicinal Products Directive"). Article 8(3) of the Medicinal Products Directive requires the application to state (among other things): the name of the medicinal product; qualitative and quantitative particulars of all the constituents of the medicinal product; therapeutic indications, contraindications and adverse reactions; and posology, pharmaceutical form, method and route of administration and expected shelf life.
23. The Hearing Officer analysed the marketing authorisation as follows (§ 33):

"If, as Mr Powell asked me to do, I consider the MA as it was when the SPC application was filed, i.e., in decision C(2004)2509, the attached SmPC makes clear that the medicinal product that is the subject of the authorisation is Erbitux and that it contains cetuximab as the active ingredient. The title of the decision refers to "Erbitux – cetuximab" alone and not to a combination of Erbitux and Irinotecan. The medicinal product is clearly identified as Erbitux, the active ingredient is cetuximab, the physical form is a solution for infusion – see Sections 1, 2 & 3 of the SmPC. This data does not change and defines clearly what is the medicinal product and the active substance which is the subject of the MA. This is in my view distinguishable from how this medicinal product is used. This can change on the basis of further clinical evidence and experience and this will happen over the life of an MA. It is only those parts of the MA that deal with the use of Erbitux in patients that mention Irinotecan. The MA is otherwise silent on Irinotecan, its use, constituents, safety, etc. In those parts of the MA that define the medicinal product in terms of quality or safety, e.g. describing how it is prepared and what are its components, there is no mention of Irinotecan…. Section 6 of the SmPC, entitled "Pharmaceutical Particulars" does not make any mention of Irinotecan as being a component of this medicinal product. Thus, Irinotecan is not present in any way in the medicinal product that has been approved by this MA."

24. The Hearing Officer made further points (§ 40):

"In my view, the MA filed in support of this SPC application only comprises complete information regarding the quality, safety and efficacy of one medicinal product or substance – Erbitux – and one product or active ingredient in that substance – cetuximab. It is clear from the original MA for Erbitux that the other medicinal product – Irinotecan – is the subject of a different MA and the reader is directed to consult that MA for details. Thus, despite the view put forward by Mr Powell, I consider that the passages he referred me to in the SmPC, and the assessment report, do not tell the full story. They describe conditions under which Erbitux may be used clinically. I have to concern myself with determining what exactly is the medicinal product that has been approved and not just with its use or uses. Furthermore, such a focus on what the product is, rather than what it does, is consistent with the fact that what it does can change in the life of the MA but the product itself does not. In my view the MA for Erbitux is not one for a medicinal product that is a combination of substances rather it is one for a single substance. Thus the corresponding product which is approved in terms of Article 1(b) of the Regulation is a single active ingredient, cetuximab. The MA for "Erbitux" allows the holder to place this medicinal product on the market and so is the first for the active ingredient "cetuximab". It is not one for the combination of "cetuximab in combination with Irinotecan"."

25. Mr Powell had two points in rebuttal of this compelling analysis. The first point was that data about irinotecan were incorporated by reference into the marketing authorisation with the consequence that, on its true interpretation, it authorised the combination of cetuximab and irinotecan. The second point is that the Swiss authorities, acting on the same information that had been provided to the Community regulator, had approved Erbitux for the indication/possible use in combination with irinotecan. Thus the Community marketing authorisation should be construed as authorising the same combination. I am not persuaded by either point.
26. So far as the first point is concerned, article 1 of the decision plainly identifies the medicinal product, "Erbitux – cetuximab" as the subject-matter of the authorisation. No other medicinal product is identified. The direction to enter that product in the Community Register of Medicinal Products is to the same effect. Article 3 specifies the form of the labelling and package leaflet. The outer packaging makes no mention of irinotecan at all. The package leaflet contains two brief mentions of irinotecan in explaining how cetuximab is used. The summary of the product characteristics likewise contains brief mentions of irinotecan in explaining how cetuximab is used. But as the case law shows, how a medicinal product is used does not form part of the identification of the product itself. In my judgment the brief references to irinotecan in explaining how cetuximab is used are wholly insufficient to amount to a marketing authorisation of a product consisting of both cetuximab and irinotecan. In short, I agree with the Hearing Officer for the reasons that he gave.
27. So far as the second point is concerned, in the first place I am not convinced that the Swiss authorities gave a marketing authorisation for a combined product, as opposed to a combined use (or, to put the point another way, they attached a condition about use to their approval of cetuximab as a product). In the second place what is important for present purposes is not what the Swiss regulators have authorised but what the Community regulators have authorised. If they have authorised different things, so be it. Third, it may well have been open to the patentee to frame its application to the Community regulator for marketing authorisation in such a way as would have resulted in an authorisation for a combination of cetuximab and irinotecan. But it did not. I agree, therefore, with the Hearing Officer that there was a mismatch between the 037 application and the marketing authorisation. He was right to refuse the SPC. Consequently the appeal against his determination on the 037 application must be dismissed.
28. The 038 application sought an SPC for cetuximab alone. Cetuximab alone was the subject of the marketing authorisation. So far, so good. The question that arose in the 038 application was whether cetuximab alone was "protected by a basic patent in force". There has been some debate about what the quoted phrase means. The two rival meanings are (a) the active ingredients of the product authorised by the marketing authorisation are disclosed and claimed by the basic patent in force and (b) the manufacture or supply of the product authorised by the marketing authorisation would infringe the basic patent in force. The current state of the law favours the first, and narrower, test. It was this debate that led the Court of Appeal in Medeva BV v Comptroller General of Patents to refer a number of questions to the Court of Justice. Of the two rival meanings, the second is more favourable to the patentee. Mr Mitcheson said that even on that test the Hearing Officer in the present case was right.
29. It is, in my judgment, plain that claim 1 of the patent claims only the combination of the monoclonal antibody (i.e. cetuximab) and an anti-neoplastic agent (i.e. irinotecan). Thus the manufacture or supply of cetuximab alone would not infringe that claim; or, indeed, claim 2 which claims the same combination although administered separately. The Hearing Officer dealt with this as follows (§ 67):

"Thus, it is clear whether administered together or separately, the use of both components together is more effective than the use of either component on its own. The innovation that the patent has been granted for is thus the preparation and therapeutic use of an antibody, such as cetuximab, which binds specifically to EGF receptors in human cells, with an anti-neoplastic agent, such as irinotecan. There is nothing, in my view, in the disclosure of the patent to indicate that it was envisaged to use the antibody on its own. Indeed it is clear that the antibody on its own is not effective in reducing tumour growth only in halting it (see para [0012]). As a consequence, I agree with the assessment of the examiner that this patent is not suitable as the basic patent in support of SPC application SPC/GB 04/038 which specifies cetuximab only as the product. However, as indicated above, it is suitable as the basic patent in support of SPC application SPC/GB 04/037, which specifies cetuximab and irinotecan as the product."

30. In my judgment this analysis is entirely correct. I did not understand Mr Powell to disagree, on the assumption that the Hearing Officer applied the correct legal test (i.e. the narrower of the two tests). But he put forward a different argument on the assumption that the infringement test was the correct test. What he said was that claim 6 (the medical use claim) is to the use of the monoclonal antibody (e.g. cetuximab) and an anti-neoplastic agent (e.g. irinotecan) for the preparation of a therapeutic composition for treating cancer. Claim 6 may be dependent on claim 2, in which case the monoclonal antibody may be supplied and administered separately to the anti-neoplastic agent. Claim 6 may thus be regarded as a claim to an application of the monoclonal antibody: its use with separately administered irinotecan in the treatment of cancer. In so far as a combination of the two is required to make up the "therapeutic composition" claimed by claim 6, the combination will take place inside the patient's bloodstream. Accordingly if someone supplied cetuximab with the intention that it would be administered to a patient that supply would be a supply of a means, relating to an essential element of the invention, for putting the invention into effect. Since the marketing authorisation said that cetuximab was to be used in conjunction with irinotecan, it would be obvious to the supplier of the cetuximab that it was intended to put the invention into effect. This would amount to secondary infringement under section 60 (2) of the Patents Act 1977. In Case C-392/97 Farmitalia Carlo Erbas Srl's Supplementary Protection Certificate Application [2000] RPC 580 the ECJ said that whether a product was protected by a basic patent in force was a question of national law. Since the national law of the United Kingdom includes secondary infringement, cetuximab is protected by the basic patent in force.
31. Mr Mitcheson had two answers to this submission on the assumption that the infringement test is the right test. First, he said, the notion of secondary infringement is not relevant to ascertaining what is protected by the basic patent in force. In support of this submission he relied on the decision of the German Federal Supreme Court in Case X ZB 1/08 in which that court held that if the basic patent protects an agent combination then an SPC cannot be issued if the marketing authorisation relates to a separate agent only. The court said that the scope of protection was to be determined simply by construing the claims. Secondary infringement was not directly addressed, but was implicitly rejected. Second, he said, the therapeutic composition must be one which exists outside the patient's body (albeit that the component parts of the composition may exist in separate containers or as separate tablets). The manufacture or supply of cetuximab alone does not infringe the patent. After all, the patent acknowledges that monoclonal antibodies (such as cetuximab) are part of the state of the art. It is only the treatment following prescription by a medical practitioner which can amount to putting the invention into effect in the sense of producing the therapeutic composition within the patient's body. If the patentee is forced to rely on the making of the therapeutic composition inside the body of the patient during the course of treatment then what the patentee is claiming is a method of treatment which cannot be a patentable invention: Patents Act 1977 s 4A (1).
32. If (and it is quite a big "if") the infringement test is the right test, then in my judgment Mr Powell's point about secondary infringement is a tenable argument in the light of the Farmitalia decision that the scope of protection is a matter of national law. Nevertheless I would reject it. Secondary infringement is, so to speak, an "add-on" to the claims of the patent. Given the restrictive interpretation of "product" which is firmly entrenched in the case-law (and the reference in article 1 (c) of the regulation to the protection of a product "as such") it seems to me that to incorporate the notion of secondary infringement into the SPC regime would be an illegitimate extension. However, I would not regard my rejection of this argument as acte claire. Since the questions referred by the Court of Appeal invite, in part at least, the Court of Justice to revisit its ruling in the Farmitalia case that might have persuaded me to stay the appeal and refer another question to the Court of Justice. However, Mr Mitcheson's second point is a question of national rather than European law. In my judgment it is a good one, for the reasons that he gave.
33. After I had circulated my draft judgment Mr Powell said that I had not dealt with his secondary infringement argument based on claims 1 and 2. On re-reading his two skeleton arguments prepared for the appeal and my notes of the hearing, it seems to me to be clear that the secondary infringement argument was based on claim 6 alone on the basis that it was (or could be) dependent on claim 2. Claim 1 did not feature in this argument at all; and claim 2 featured only because it paved the way for the argument about claim 6. That is also what I understood at the time. The purpose of circulating a draft judgment is not to allow parties the opportunity to re-argue their case. I do not consider that it would be right to allow the appeal to be re-opened at this stage.
34. In those circumstances I consider that the appeal in the 038 application must likewise be dismissed.