Sandoz Ltd & Anor v G.D. Searle LLC & Anor

In these proceedings the Claimants challenge the validity of supplementary protection certificate SPC/GB07/038 (“the SPC”) for a product described in the SPC as “Darunavir or the pharmaceutically acceptable salt, ester or prodrug thereof”. The proprietor of the SPC is the First Defendant (“Searle”) and the exclusive licensee is the Second Defendant (“JSI”). The SPC covers a product which is marketed in Europe by companies related to JSI under the trade mark Prezista. Prezista is an anti-retroviral medication used in the treatment of human immunodeficiency virus (HIV). More specifically, it is a protease inhibitor. The Defendants contend that the product described in the SPC was protected by European Patent (UK) No. 0 810 209 (“the Patent”), of which Searle was the proprietor and JSI was the exclusive licensee. The Claimants dispute this. Accordingly, the Claimants contend that the SPC does not comply with Article 3(a) 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”).

The Claimants seek to revoke the SPC, which expires on 23 February 2019 (including a paediatric extension of six months), in order to clear the way for the marketing of a generic darunavir product. The Claimants have admitted for the purpose of these proceedings only that, if the SPC is valid, then the marketing of their product prior to the expiry of the SPC would infringe it. The Claimants have agreed to give the Defendants 30 days’ notice before launching their product. Nevertheless the Defendants have counterclaimed for an injunction to restrain (threatened) infringement.

The SPC Regulation enables the proprietor of a patent for a medicinal product to obtain an SPC which extends the duration of the patent with respect to that product so as to compensate the proprietor for the effective loss of patent term caused by the need to obtain a marketing authorisation before the product can be marketed.

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 functioning of the internal market.

[8] Therefore, the provision 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.

…

[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. … ”

Articles 1, 3, 4 and 5 of the SPC Regulation provide, so far as relevant:

“Article 1

Definitions

For the purpose 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 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 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;

…

Article 4

Subject matter of protection

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 authorised before the expiry of the certificate.

Article 5

Effects of the certificate

Subject to the provisions of Article 4, the certificate shall confer the same rights as conferred by the basic patent and shall be subject to the same limitations and the same obligations.”

I have considered the correct approach to the interpretation of the SPC Regulation in a number of judgments, including Teva UK Ltd v Gilead Sciences Inc [2017] EWHC 13 (Pat) at [30]-[31].

I considered the interpretation of Article 3(a) of the SPC Regulation at some length in Teva v Gilead at [32]-[88]. I shall take that exposition as read and will not repeat it here. For convenience, however, I shall recapitulate the key points.

First, it is clear that it is not sufficient for a product to be “protected” by a basic patent within the meaning of Article 3(a) that dealings in the product would infringe a claim of the patent applying the Infringing Act Rules (as to which, see Teva v Gilead at [36]).

Secondly, it is also clear that it is necessary that the product falls within at least one claim of the patent applying the Extent of Protection Rules (as to which, see Teva v Gilead at [35]).

Thirdly, it is not clear whether it is sufficient that the product falls within at least one claim of the patent applying the Extent of Protection Rules. It appears from the case law of the Court of Justice of the European Union that this is not sufficient, and that more is required; but it is not clear what more is required. In Case C-322/10 Medeva BV v Comptroller-General of Patents, Designs and Trade Marks [2011] ECR I-12051 the CJEU ruled that Article 3(a) precluded the grant of an SPC “relating to active ingredients which are not specified in the wording of the claims of the basic patent”. It made the same ruling in a number of other cases decided at the same time, including Case C-630/10 University of Queensland v Comptroller-General of Patents, Designs and Trade Marks [2011] ECR I-12231, except that it used the word “identified” instead of the word “specified”. In Case C-493/12 Eli Lilly & Co Ltd v Human Genome Sciences Inc [EU:C:2013:835], [2014] RPC 21 the CJEU ruled that Article 3(a) must be interpreted as meaning that it was not necessary for the active ingredient to be identified in the claim by means of a structural formula: it is sufficient for the active ingredient to be covered by a functional description provided that the claims when interpreted in accordance with the Extent of Protection Rules “relate, implicitly but necessarily and specifically, to the active ingredient”. These are unclear tests which are difficult to apply in cases involving combinations of products like Teva v Gilead, however.

Fourthly, I have suggested to the CJEU that Article 3(a) should be interpreted as meaning that the product is “protected” by the basic patent if (i) the product falls within the scope of the claim when interpreted in accordance with the Extent of Protection Rules and (ii) the product does so because it contains an active ingredient, or a combination of active ingredients, which embodies the inventive advance (or technical contribution) of the patent. The application of this test is exemplified, albeit in the context of Article 3(c) of the SPC Regulation, in my recent decision in Teva UK Ltd v Merck Sharp & Dohme Corp [2017] EWHC 539 (Pat).

Since this is a case about Markush formulae, I should explain what a Markush formula is before going any further. The following account is based on that provided by counsel for the Defendants in their skeleton argument, to which I am indebted.

Markush formulae originated in the USA with a decision of the Commissioner of Patents: Ex parte Markush, 1925 C.D. 126, 340 O.G. 839 (Comm’r Pat. 1924). They emerged as an exception to a ban on so-called “alternative claim language” (i.e. claim language that specified at least two alternatives for an integer). The applicant, Eugene Markush, had claimed a dye, an element of which was a “diazotized solution of aniline or its homologues or halogen substitutes”. This claim language was initially rejected as being “alternative” in form. The applicant’s attempts to substitute this with “mono-amine” were also rejected, on the basis that this term would cover mono-amines other than aniline. The decision in Ex parte Markush ultimately allowed the use of an artificial group in the form “material selected from the group consisting of aniline, homologues of aniline and halogen substitutes of aniline” (i.e. material selected from the group {A, B, C, …}) in a situation where there was no true generic word that embraced that group only.

The position was explained by the United States Court of Customs and Patents Appeals (the predecessor to the Court of Appeals for the Federal Circuit) in In re Driscoll 562 F.2d 1245, 195 USPQ 434 (CCPA 1977) in the following way:

“The practice of describing a class of chemical compounds in terms of a structural formula wherein the substituents thereof are defined as ‘a member selected from the group consisting of A,B,C,D’ … was sanctioned by implication in Ex parte Markush … It is generally understood that in thus describing a class of compounds an applicant is, in effect, asserting that the members of the Markush group do not fall within any recognized generic class, but are alternatively useable for the purposes of the invention, and therefore, regardless of which of the alternatives is substituted on the basic structure, the compound as a whole will exhibit the disclosed utility.”

Since Ex parte Markush, the practice has arisen of representing the class of compounds by means of a structural formula which consists of a specified backbone with substituents typically denoted by R¹, R², etc and by means of statements in the specification and/or the claims defining the kinds of substituent which R¹, R², etc may consist of. This enables large classes of compounds to be very compendiously defined by such formulae, rather than laboriously writing out long lists of compounds or groups of compounds. Such formulae are referred to as “Markush formulae” and claims containing such formulae are referred to as “Markush claims”.

The practice of permitting the use of Markush formulae in patent claims has been followed by patent offices worldwide, and in particular by the United Kingdom, European and Japanese offices. Paragraph 14.133 of the UK Intellectual Property Office’s Manual of Patent Practice includes the following commentary on Markush claims (in the context of claim clarity):

“A claim whether independent or dependent, can refer to alternatives provided that this does not make the claim obscure or difficult to construe (see also 14.164). However, such claim formulations should be avoided if, by reason of the large number of alternatives, the generality of the claim is impossible to search in its entirety. Markush claims are an example of this type of claim: such claims set out a number of alternatives (possibly using words such as ‘selected from the group consisting of …’). They are often used in chemical cases as a way of setting out various functionally-equivalent alternatives in one or more parts of the chemical compound being claimed.”

The European Patent Office takes a similar approach. Section F-V, §5 of its Guidelines for Examination discusses “Markush grouping” (in the context of the requirement for unity of invention). According to this guidance, Markush grouping can properly be used where the alternatives are of a “similar nature” i.e. have a common property or activity and a common structure (for example, a significant structural element shared by all of the alternatives).

Similar rules apply internationally under the Patent Cooperation Treaty. Paragraph (f) of Annex B to the PCT Administrative Instructions, as in force from 15 December 2016, refers to the need for a “common property or activity” in conjunction with a “significant structural element [ ] shared by all of the alternatives” (i.e. both functional and structural properties must be shared between the members of the Markush group).

The Patent is entitled “Alpha- and beta-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors”. The application was filed on 24 August 1993 with a claimed priority date of 25 August 1992. The Patent was originally registered in the name of Searle (then called G.D. Searle & Co.) and The Monsanto Company. In 2006 Monsanto changed its name to Pharmacia Corporation, and Pharmacia assigned its rights to Searle. The Patent expired on 23 August 2013. It is common ground that the Patent contains a number of typographical and other errors, but for present purposes nothing turns on these.

The specification begins by stating at [0002] that the invention relates to retroviral protease inhibitors, and in particular to “sulfonamide-containing hydroxyethylamine protease inhibitor compounds, a composition and the use thereof for preparing a medicament for inhibiting retroviral proteases such as human immunodeficiency virus (HIV) protease and for treating a retroviral infection e.g. an HIV infection”.

The specification explains at [0003] that retroviral proteases are viral enzymes used to process precursor viral proteins into mature proteins necessary for the assembly and reproduction of a retrovirus such as HIV. In particular, during the replication cycle of the virus, the gag and gag-pol gene products are translated into proteins which are then processed by the protease to form the structural proteins of the virus core and the viral enzymes necessary for replication. It follows that inhibition of the retroviral protease may inhibit viral replication.

The specification goes on at [0004] to explain that this inhibition may involve a so-called “transition-state mimetic” compound. This is a synthetic molecule which mimics the natural substrate that binds to the protease enzyme. Mimetic compounds compete with the gag and gag-pol proteins, thereby preventing the processing of these proteins. This in turn prevents the production of the virus core and the replication enzymes, and hence also inhibits reproduction itself.

After acknowledging certain prior art, the specification sets out a brief description of the invention at [0008] as follows:

“The present invention is directed to virus inhibiting compounds and compositions. More particularly, the present invention is directed to retroviral protease inhibiting compounds and compositions, to the use of such compounds for preparing medicaments for inhibiting proteases, especially for inhibiting HIV protease and for treating a retroviral infection such as HIV infection and for treating AIDS, to processes for preparing the compounds and to intermediates useful in such processes. The subject compounds are characterizued [sic] as sulfonamide-containing hydroxyethylamine inhibitor compounds.”

The detailed description of the invention starts at [0009]-[0020] with a series of consistory paragraphs corresponding to the claims. These are framed by reference to two Markush formulae, Formula I and Formula II. Formula I is shown below.

The specification lists broad ranges of substituent groups for P¹, P², R², R³ and R⁴ at [0009]. Preferred compounds of Formula I are described at [0010]-[0012], with increasing levels of specificity. 41 specific compounds are listed in [0012].

Formula II is the same as Formula I except that it omits the stereochemistry of the lefthand two carbon atoms of the backbone. The specification again lists ranges of substituent groups and preferred compounds at [0013]-[0017].

At [0018] the specification identifies a group of compounds of Formula I which are said to comprise retroviral protease inhibiting compounds according to claim 1. It is explained at paragraph [0020] that compounds of the invention can be used to prepare pharmaceutical compositions useful for treating retrovirals, in particular HIV or AIDS.

Various terms used in the Patent are defined at [0021]-[0023]. Of particular relevance are the definitions of “alkyl” (in [0021]) as being “a straight-chain or branched-chain alkyl radical containing from 1 to 10, preferably from 1 to 8, carbon atoms”; the definition of “aryl” (in [0022]) as being “a phenyl or naphthyl radical which optionally carries one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl and the like [emphasis added]”; and the definition of “cycloalkylcarbonyl” (in [0022]) as being “an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, cyclohexanecarbonyl, or adamantanecarbonyl, or from a benz-fused monocyclic cycloalkanecarboxylic acid which is optionally substituted by, for example, alkanoylamino, such as 1,2,3,4-tetrahydro-2-naphthoyl [emphasis added]” .

Procedures for preparing compounds of Formula I are then described at [0025]-[0047]. The specification explains at [0048] that, occasionally, the reactions so described may not apply to each compound included within the scope of Formula I, but states that the skilled reader will recognise which those compounds are and will be able to apply conventional modifications to perform successful reactions.

Preferred specific embodiments are described at [0049]-[0090], in the form of Examples 1 to 9. Examples 1 to 7 illustrate synthesis steps useful in the preparation of compounds of the invention. Examples 8 to 9 relate to assays used on compounds of the invention to determine their ability to inhibit HIV protease. Example 8 is an enzyme assay conducted on isolated HIV protease and reports the results in “Table 16” (except that there is no Table 16 and it appears that the intended reference is to Tables 2A and 2B) in terms of IC₅₀ values. Example 9 is a CEM cell assay conducted using live human CEM CD4+ cells and whole HIV-1 viruses and reports the results in “Table 2” (although it appears that the intended reference is to Table 3) in terms of IC_50, ED₅₀and TD₅₀ values for the compounds tested.

The Patent states at [0091] that the compounds of the invention are effective antiviral compounds and effective HIV protease inhibitors.

At [0092]-[0094] the specification explains that the compounds of the invention can exist as stereoisomers, and that they can be used in the form of salts or acids. Finally, at [0095]-[0103], various different dosages and routes of administration are suggested.

It is common ground there is no reference to darunavir anywhere in the specification.

Claim 1 is to a compound presented by Formula I wherein:

“P¹ and P² independently represent hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, amino alkanoyl, and mono- and disubstituted aminocarbonyl and mono- and disubstituted aminoalkanoyl radicals wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl radicals, or where said aminoalkanoyl radical is disubstituted, said substituents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals are optionally substituted with a group selected from alkyl and halogen radicals, -NO₂, -C≡N, CF₃, -OR⁹, -SR⁹, wherein R⁹ represents hydrogen and alkyl radicals;

R³ represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical; and

R⁴ represents represents radicals as defined by R³ except for hydrogen;

wherein aryl wherever occuring may optionally carry one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl;
wherein heterocycle or heteroaryl may optionally be substituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo and/or on a secondary nitrogen atom by alkyl, aralkoxycrbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom by oxido and which is attached via a carbon atom;

and the pharmaceutically acceptable salt, ester. or prodrug thereof.”

The other relevant claims of the Patent are:

A granted patent is presumed to be valid until the contrary is shown. It is curiously hard to find clear modern authority for this obvious proposition, although it is long established (see Halsey v Brotherhood (1880) 15 ChD 514 at 521 (Sir George Jessel MR)) and was authoritatively stated to be the law under the Patents Act 1949 in American Cyanamid Co v Ethicon Ltd [1975] RPC 513 at 539 (Lord Diplock). By contrast with section 72 of the Trade Marks Act 1994, which expressly provides that registration of a trade mark is prima facie evidence of the validity of the registration, there is no corresponding provision in the Patents Act 1977. It is nevertheless implicit in the provisions of the 1977 Act, in particular section 63 (relief for infringement of partially valid patent), section 65 (certificate of contested validity), section 72 (power to revoke patents on application) and, above all, section 74 (proceedings in which validity of patent may be put in issue, as to the effect of which see Organon Teknika Ltd v F. Hoffmann-La Roche AG [1996] FSR 383). For the avoidance of doubt, the presumption of validity simply means that the burden of proving that a patent is invalid lies upon a party asserting invalidity to do so by one of the procedures permitted under section 74 of the 1977 Act. It has no bearing on the standard of proof, which is the ordinary civil standard of the balance of probabilities.

In the present case it is important to note, for reasons that will become apparent, that the Claimants have not put the validity of the Patent (as distinct from the SPC) in issue.

The structural formula of darunavir is shown below.

Darunavir is a compound represented by Formula I and Formula II, wherein P¹, P², R², R³ and R⁴ comprise substituent groups within claims 1, 2, 5, 10 and 11 as follows:

Counsel for the Defendants’ primary submission was that it was possible to decide this case without reference to any witness evidence. For reasons that will appear, I agree with this. Accordingly, I will describe the evidence briefly. Before doing so, I should note that the parties agreed a technical primer which explains many of the technical terms used in the Patent. While this is a helpful document, it was not strictly necessary. I should also record that neither side requested to cross-examine the other side’s witness(es).

The Claimants served an expert report from Professor Robert Adlington, a Professor of Organic Chemistry at the University of Oxford and a Tutorial Fellow at Lady Margaret Hall. He graduated from Imperial College London with a First in Chemistry in 1977 and completed a PhD in synthetic organic chemistry at the same institution in 1980. From September 1980 to October 1990 he carried out postdoctoral research with Professor Sir Jack Baldwin FRS in Oxford. He became a University Lecturer and Tutorial Fellow in October 1990. His principal research interests were in synthetic organic chemistry. In 2000 they shifted to biomimetic chemistry (the chemistry of how nature synthesises molecules). As counsel for the Defendants pointed out, he does not claim expertise in the field of medicinal chemistry.

Prof Adlington’s evidence is directed to four main topics. First, he was asked to estimate the numbers of compounds covered by the claims. As he explains, this is a difficult exercise, because Formulae I and II include five possible substituent groups, each of which may be of multiple types with the types being defined in wide, and sometimes conflicting and/or open-ended, terms. Accordingly, he was forced to make assumptions, and even then was only able to make estimates. The estimates cover huge ranges. Thus in the case of claim 1 he arrived at lower estimate of 7 x 10¹³⁵ compounds and an upper estimate of 1 x 10³⁷⁷ compounds. Even in the case of claim 11, his lower estimate was 5 x 10⁹⁶ compounds. Even that number is so large that it would not be possible for a robot simply to list all of the compounds working at the rate of one a second 24 hours a day for the 20 year life of the Patent. Prof Adlington’s evidence is that some of these compounds would be difficult to synthesise or inherently unstable.

Secondly, Prof Adlington was asked to identify the number of compounds specifically disclosed in the Patent. His evidence is that there are approximately 100 such compounds.

Thirdly, Prof Adlington gives some evidence about the relationship between darunavir and the Patent. In summary, he says that darunavir is covered by claims 1, 2, 5, 10 and 11, but is not disclosed in the Patent. The closest compound to darunavir that is disclosed in the Patent is a compound which is disclosed in [0012] at lines 32-33 and also included in claim 4 as the seventh compound listed (“Compound 7”). Darunavir itself does not fall within the scope of claim 4. There are no biological data on Compound 7 in the Patent.

The difference between Compound 7 and darunavir is the P¹ substituent group. In Compound 7, it is an aralkoxycarbonyl, specifically benzyloxycarbonyl, which has the following structure:

By contrast, in darunavir, the P¹ substituent group is a heterocyclyloxycarbonyl. Even assuming the skilled reader opts for the heterocyclyloxycarbonyl substituent group over the other groups for P¹ listed in the claims, Prof Adlington’s evidence is that he is then faced with a choice of at least 8 x 10³⁶ possibilities for that group alone. The specific P¹ group in darunavir comprises a fused bis-tetrahydrofuran, joined to an oxygen atom and a carbonyl group. It is represented by the following structure:

None of the compounds individually disclosed in the Patent contain this specific heterocyclyloxycarbonyl substituent, or indeed anything similar to it. Prof Adlington’s evidence is that it is an unusual substituent and one which he had not previously encountered.

Fourthly, Prof Adlington gives some evidence about the development of darunavir, based in part upon some published papers he was provided with by the Claimants’ solicitors and in part upon some further papers he found through his own researches. These indicate that the structure of the P¹ substituent group of darunavir was first published in Arun K. Ghosh et al, “Structure-Based Design of HIV-1 Protease Inhibitors: Replacement of Two Amides and a 10π-Aromatic System by a Fused-Bistetrahydrofuran”, J. Med. Chem., 37, 2506-2508 (1994), and that the synthesis of darunavir and its use as a protease inhibitor was first reported in Arun K. Ghosh et al, “Potent HIV protease inhibitors incorporating high affinity P₂-ligands and (R)-(hydroxyethylamino) sulfonamide isostere”, Bioorganic & Med. Chem. Letters, 8, 687-690 (1998). Professor Ghosh and his co-workers are credited in a number of publications as having discovered darunavir. The compound is even said to have been named after Prof Ghosh (darunavir). The work reported in Ghosh et al (1998) was supported by the US National Institute of Health, and the authors thanked Oklahoma Medical Research Council for expression vector for HIV-1 protease and Searle for the enzyme assays used. The commercial development of darunavir is reported to have been undertaken by Tibotec (now part of Johnson & Johnson).

The Defendants objected to the admissibility of three sentences of Prof Adlington’s report on the ground that those sentences expressed opinions (namely that the Patent did not teach how to synthesise all the compounds claimed without undue burden and that it was not plausible that all those compounds would function in the same way or have retroviral protease inhibiting functionality) which were only relevant to the sufficiency of the Patent, which is not in issue. In my view this objection is well founded for reasons which will become clear.

The Defendants did not serve any expert evidence in chief. In reply to Prof Adlington’s report, however, they served a report from Dr Sally Redshaw. She graduated with a First in Chemistry from the University of Nottingham in 1975 and obtained a PhD from the same institution in 1978. From 1978 to 2001 she was a Team Leader in the Medicinal Chemistry Department at Roche. During that time, she worked on a number of drug targets, including HIV protease inhibitors, and was involved in the design of the HIV protease inhibitor saquinavir. From 2001 to 2008 she worked as Manager in the Medicinal Chemistry Department of the Neurology Centre for Excellence for Drug Discovery at GlaxoSmithKline. She now works as a drug discovery consultant.

Counsel for the Defendants submitted that Dr Redshaw was representative of the person skilled in the art to whom the Patent was addressed, where Prof Adlington was not. I agree with this, but as Dr Redshaw says, there is a considerable overlap between the disciplines of medicinal chemistry and organic chemistry (particularly synthetic organic chemistry). I consider that Prof Adlington was qualified to give the evidence he gave.

Dr Redshaw does not directly take issue with any of Prof Adlington’s evidence. In relation to the first topic covered by Prof Adlington, she says that this is not an exercise which the skilled person would undertake. She also says that some of the compounds would be recognised as being likely to be so insoluble that they could not be tested, and hence the skilled person would not try to make them. Her evidence is that a skilled person considering which substituents to include at positions P¹, P², R², R³ and R⁴ would focus on substituents which:

As counsel for the Claimants pointed out, none of those considerations, except perhaps the first and the last, is referred to in the Patent, and the second and fourth considerations are inconsistent with the definitions of the substituent groups contained in the Patent. One is bound to wonder why these limitations were not included in the Patent. In any event, as Dr Redshaw accepts, even on this basis, the claims would still cover a “large” number of compounds, although she makes no attempt to estimate how large.

In relation to the fourth topic covered by Prof Adlington, Dr Redshaw says that she has been provided by the Defendants’ solicitors with a paper (M. Pezechk et al, “A new route to perhydro- and tetrahydro- furo-2,3b furans via radical cyclisation”, Tetr. Letters, 27, 3715-3718 (1986)) which discloses the heterocyclyloxy portion of the P¹ group in darunavir (but not the whole P¹ group) as an intermediate in a reaction scheme for the synthesis of insect anti-feeding compounds. She does not say that she was aware of this before being shown the paper, still less that she had encountered the P¹ group in darunavir before becoming aware of darunavir.

As counsel for the Claimants pointed out, Dr Redshaw does not say that the considerations summarised in paragraph 52 above would lead a skilled reader of the Patent to darunavir or anything like it.

The Defendants served four witness statements containing evidence of foreign law as follows:

The Claimants contend that the evidence of Messrs Sipes, Kato and Kim is inadmissible since (i) it is expert evidence for which no permission has been given and (ii) it is irrelevant to any issue. The Defendants contend that the evidence is admissible because it is factual evidence, but they agree that there is no issue between the parties as to foreign law. In my view these statements do not contain evidence which is relevant to any issue of fact between the parties, whether as to foreign law or otherwise. Accordingly, they are not admissible as evidence. That does not matter, however. In substance, these statements are a vehicle for putting comparative law materials before the court. Usually, that is done without the formality of a witness statement e.g. by relying upon an appropriate textbook or court decision (if necessary, in translation). Of course, if there is a dispute as to foreign law, then expert evidence as to the foreign law is required. If, however, there is no dispute as to the foreign law, and the question for the English court is whether or not the foreign law is of persuasive assistance in solving the problem faced by the English court, then evidence is not required. In the present case, there is no dispute as to the foreign law. I do not find it of any real assistance, however, since the dispute between the parties depends entirely on the proper interpretation of Article 3(a) having regard to the guidance which has so far been given by the CJEU.

The Claimants contend in summary that darunavir is not specified or identified in any of the claims of the Patent: although darunavir falls within the claims due to their immense breadth, it is not specifically identified by name or structure in the claims or anywhere in the specification, nor is there any teaching in the Patent which points to darunavir, and in particular its novel and unusual P¹ group. The Claimants say that a Markush claim does not specify or identity a product unless the skilled person would consider the product to be part of the subject-matter of the patent based on their reading of the specification and their common general knowledge as at the priority date without undue burden or further invention, and that this test is not satisfied in the present case. Accordingly, the Claimants contend that darunavir is not “protected" by the Patent within the meaning of Article 3(a). The Claimants accept, however, that it is not acte clair that this is how Article 3(a) should be interpreted. Accordingly, they contend that a question should be referred to the CJEU for a preliminary ruling.

The Defendants contend in summary that, although the correct interpretation of Article 3(a) remains unclear in certain respects, that does not matter for the purposes of the present case. The Defendants say that, upon any tenable interpretation of Article 3(a), darunavir is a product which is “protected” by (at least) claims 1, 2, 5, 10 and 11 of the Patent. In particular, the Defendants say that, although the claims of the Patent must be interpreted as at the priority date of the Patent, the question whether a product is “protected” by those claims falls to be judged once the product is known (in practice, once it has been authorised to be placed on the market as a medicinal product): see Teva v MSD at [108]-[110] and [142]. Accordingly, the Defendants contend that it is not necessary to refer any question to the CJEU for a preliminary ruling.

In my judgment the Defendants are correct. My reasons are as follows.

The broadest tenable interpretation of Article 3(a) is that it is sufficient that the product falls within at least one claim of the patent applying the Extent of Protection Rules. At present, it does not appear that this interpretation is correct, because the CJEU has so far held that more is required. But if this interpretation is correct, there can be no doubt that darunavir is “protected” by the Patent.

As noted above, the CJEU held in Medeva and its progeny that it was necessary for the product to be “specified” or “identified” in the wording of the claims. Counsel for the Claimants reminded me that I said in Novartis Pharmaceuticals UK Ltd v MedImmune Ltd [2012] EWHC 181 (Pat), [2012] FSR 23 at [53] that the test laid down in those cases “was unclear save in its rejection of the infringement test in combination cases” and that it was unclear whether it was “sufficient, say, for the claim to incorporate a Markush formula which covers a large number of compounds one of which is the product in respect of which an SPC is sought”.

Subsequently, however, the CJEU held in Lilly that it is not necessary for the active ingredient to be identified in the claim by means of a structural formula: it is sufficient for the active ingredient to be covered by a functional description provided that the claims “relate, implicitly but necessarily and specifically, to the active ingredient”. It is clear from this that the identification of the active ingredient in the claim by means of a structural formula is permissible, but not essential; that it is not necessary for the claim individually to name or depict the active ingredient; and that it is not necessarily an objection that the claim in question covers a large number of other compounds in addition to the active ingredient in question (since, if that was so, it would have provided a simple answer to the Lilly case).

I remain of the view which I expressed in Teva v Gilead at [81] that the test laid down with respect to functional descriptions in Lilly is an unclear test which is difficult to apply. This does not matter for the purposes of the present case, however. What matters is the light which Lilly sheds on the test laid down in Medeva. For the reasons given in the preceding paragraph, this suggests that it is sufficient for the claim to specify the product by means of a Markush formula which covers it (at least without resort to equivalents). If so, then darunavir is “protected” by the Patent.

I also remain of the view that a better test would be the one stated in paragraph 11 above, which in a case such as the present requires that the product falls within the claim and that it embodies the inventive advance (or technical contribution) of the claim. If that test is applied to the facts of the present case, the answer is clear. The inventive advance (or technical contribution) of claim 1 of the Patent lies in the identification of the compounds covered by claim 1 as having utility as HIV protease inhibitors. Darunavir embodies that inventive advance. It is not necessary on this approach to consider claims 2, 5, 10 and 11, but if it were necessary the answer would be the same.

In reality, the Claimants’ objection is that claim 1 is of excessive breadth because it encompasses a vast number of compounds which the skilled person could not make even a tiny fraction of and which it is not plausible would all be efficacious as protease inhibitors (and the same goes for claims 2, 5, 10 and 11). If well founded, however, that is an objection to the validity of the Patent. It amounts to saying that the claims are obvious on AgrEvo grounds or insufficient. But as I have already pointed out, the Patent is presumed to be valid unless and until the Claimants put its validity in issue, which they have not done.

I cannot see that there is any tenable interpretation of Article 3(a) which leads to the conclusion that darunavir is not “protected” by the Patent. The Claimants’ difficulty in this respect is illustrated by five points. First, counsel for the Claimants reminded me that a Markush formula was not a novelty-destroying disclosure of an individual compound covered by the formula (see Dr Reddy’s Laboratories (UK) Ltd v Eli Lilly & Co Ltd [2009] EWCA Civ 1362, [2010] RPC 9), but then she expressly disavowed the adoption of a disclosure test under Article 3(a). Secondly, it was only in counsel for the Claimants’ oral submissions that the test set out in paragraph 58 above was formulated, other tests having been proposed in her skeleton argument. Thirdly, counsel was unwilling definitely to commit to that test. Although I understood from her oral submissions that it represented her preferred test, she indicated that other tests might be possible. Fourthly, if one concentrates just upon that test, it is really a breadth of claim test. In my view it is not the function of patent offices when assessing applications for the grant of SPCs to have to consider whether the breadth of the claims of the basic patents relied on is justified. That would not make for a simple and transparent system, as envisaged in paragraph 16 of the European Commission’s Explanatory Memorandum proposing the predecessor to the SPC Regulation. By contrast, paragraph 39 of the Memorandum did envisage SPCs being granted where “a patent protects a series of products based on the same formula”. Fifthly, as counsel for the Defendants pointed out, it is implicit in the Claimants’ case that some compounds covered by claim 1 of the Patent are “protected” by the Patent, while others are not; but it is wholly unclear where and how the line between the two groups of compounds is to be drawn.

Finally, I would add that counsel for the Claimants prayed in aid of her submissions two considerations which in my judgment are irrelevant to the question of whether the SPC complies with Article 3(a). First, she relied on the fact that darunavir was first reported six years after the priority date of the Patent. This does not mean that it cannot be “protected” by the Patent, however. It is commonplace for preferred embodiments of an invention to be developed some time after the patent is filed. Secondly, she relied on the allegation that darunavir was independently developed by Prof Ghosh. Counsel for the Defendants disputed that darunavir was independently developed, and I do not consider that the evidence enables me to make a finding one way or the other. Even if it was independently developed, however, that has no bearing on whether it is “protected” by the Patent. The irrelevance of both these considerations to Article 3(a) is confirmed, if confirmation is necessary, by the CJEU’s decision in Lilly. As counsel for the Defendants pointed out, the Claimants do not allege that the SPC is invalid for non-compliance with Article 3(b) or (d) of the SPC Regulation (cf. the observations of the CJEU in Lilly at [43] and my observations in Novartis at [61] and in Teva v Gilead at [82]).

For the reasons given above, I conclude that the SPC complies with Article 3(a) of the SPC Regulation. Accordingly, the Claimants’ claim is dismissed. I will hear further argument as to what relief, if any, should be granted on the Defendants’ counterclaim.