Life Sciences Update. Patent litigation. A periodical update on legal and regulatory developments in the life sciences sector

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1 Life Sciences Update May 2009 A periodical update on legal and regulatory developments in the life sciences sector In this edition, we have reported on a range of recent developments, at EU and national level, relating to pharmaceutical patent litigation, regulatory updates and recent industry news. We hope you enjoy reading this update and are happy to address any comments or questions you may have, either through your usual contact or through any of the contacts on the back page of this update. In addition, the following Life Sciences partners and associates will be attending BIO in Atlanta this year and would be happy to meet with you: Sally Shorthose (UK) Patrick Kelleher (UK) Grace Chen (Beijing) Marc van Wijngaarden (The Netherlands) Hans Prins (The Netherlands) Mauro Turrini (Italy) Paul Hermant (Belgium) Ina vom Feld (Germany) Please do come to visit us at Booth #1817 at any time or for drinks on Tuesday 19 May from pm. We look forward to seeing you there. International Life Sciences Group Patent litigation Contents Patent litigation The Netherlands: the Escitalopram judgment of the Dutch Patent Court 1 UK: The High Court s reference to the ECJ in Synthon B.V.v Merz Pharma GmBH & Co KGaA 4 UK: Scinopharm v Eli Lilly: Patents Court upholds patent covering process for stereoselective synthesis of Gemcitabine [2009] EWHC 631 (Pat) 8 An appraisal of the House of Lords Generics et al v Lundbeck Judgments 8 Regulatory news EU: First Order rendered by the President of the Court of First Instance in a Paediatric case (Case T-52/09 R) 11 EU: Advocate General recommends a narrow interpretation of the first marketing authorisation in the Community for the purposes of the regulatory data protection regime 14 Industry news EU: EPO, Quality over Quantity: on course to raise the bar 15 EU: Financial incentives for medical practitioners to prescribe specific medicines and the Community Code on Medicinal Products for Human Use 16 Sweden: a new Government Bill on the sales of non-prescription drugs 17 UK: Creation of an Office for Life Sciences 17 Contacts 18 The Netherlands: the Escitalopram judgment of the Dutch Patent Court By decision of 8 April 2009, the Hague Patent Court has revoked the Dutch part of Lundbeck s European Patent EP covering its blockbuster drug Cipralex on the basis of lack of inventive step. Great interest was given to this decision, because in respect of the UK part of this patent the UK Court in the first instance (Kitchin J) has considered the claims novel and inventive, but not sufficiently disclosed. In appeal, sufficiency of disclosure was however accepted, which has recently been confirmed by the House of Lords. Contrary to the UK courts, the Bundespatentgericht has found the German part of the patent invalid, partly for lack of novelty, and partly for lack of inventive step.

2 The initiative in this Dutch matter was taken by Tiefenbacher and Ratiopharm, which had both, but separately, instituted revocation actions against EP (EP 066). During the action, the two cases were joined, and the underlying Dutch decision was rendered in both cases at the same time. Against both companies, Lundbeck had instituted a conditional counterclaim for infringement. EP 066 relates to escitalopram, which is the active ingredient of Lundbeck s drug Cipralex. Escitalopram is an enantiomer of citalopram (Cipramil ). Citalopram is a chemical compound that comprises an asymmetric carbon atom so that it exists in two different spatial or stereospecific configurations (enantiomers).. Citalopram is a racemic (50/50) mixture of both enantiomers (S- or (+)-citalopram and R- or (-)-citalopram). Biological processes involving enzymes and receptors, generally follow a so-called keyslot mechanism. Compounds with a specific spatial configuration will participate in such processes. Thus, in relation to racemic drugs (like citalopram) potentially either of the enantiomers or both are the active substance. It is possible that one enantiomer is active and the other toxic (thalidomide - Softenon ). These considerations were known in the art. Guidelines of the FDA stressed the importance of investigating the enantiomers for activity and toxicity. Furthermore, several racemic drugs had been investigated for the activity of both enantiomers. The claims of EP 066 are directed to the active enantiomer S-citalopram (claims 1-5), to a process for stereoselective synthesis of S-citalopram (claim 6) and to a stereoselective process intermediate (claim 7). Novelty In relation to novelty the Court had to decide whether prior art disclosure of the racemic mixture (citalopram) and of the spatial configuration of R-citalopram are novelty destroying in respect of S-citalopram. Tiefenbacher et al had argued that at the priority date the structure of citalopram was known, and that it was clear to a person skilled in the art on the basis of that structure that it contains one chiral centre and, consequently, has two enantiomers. In addition, they referred to a prior art document disclosing the spatial structure of the R-enantiomer, arguing that from this, the existence and the structure of the S- enantiomer (i.e. the mirror image) can be derived. They added thereto that at the priority date of the patent the individual enantiomers of citalopram could have been obtained using techniques, which were part of the skilled person s common general knowledge at that date. The Hague court followed the case law of the Technical Board of Appeal (T1046/97), and held that the disclosure of a racemate is not in itself harmful to the novelty of an enantiomer of the same. This will only be the case if there is a direct and unambiguous disclosure of this very compound in the form of a technical teaching. That it is theoretically possible to resolve a known racemate into the individual enantiomers is not relevant for the assessment of novelty. The disclosure of the structural formula of the R-enantiomer of citalopram was not considered detrimental to novelty either. After all, following the same EPO reasoning, it was held that from the disclosing document it cannot be deduced whether, and if so how, that enantiomer, let alone the S- enantiomer, was actually obtained in individualised form. Inventive step In relation to inventive step the Hague court first held that at the priority date of EP 066, the skilled person who had possession of the racemic citalopram was sufficiently motivated by the prior art to separate citalopram into its two enantiomers and to determine the activity of the enantiomers. The court considered in this respect that [..] at the priority date it was generally known that [..] as to drugs with compounds with a chiral centre, the bond with enantiomers or diastereoisomers can be established differently [..] and that their biological activity can therefore be different. In addition, on the priority date, various racemic mixtures had been separated and the difference in activity between the individual enantiomers had been established, including, in particular, with regard to the medicine thalidomide (Softenon ). Although it has to be acknowledged to Lundbeck that it could not be predicted in advance what the efficacy of the different enantiomers would be, the different biological activities - including undesired effects certainly had to be taken into account as being a realistic possibility. Having acknowledged motivation, the court then posed the question in respect of 2

3 product claims 1-5 whether at the priority date of EP 066 the skilled person was also able to separate citalopram on the basis of his common general knowledge and without inventive intellectual effort. Three possible separation techniques were considered available and part of the skilled person s common general knowledge: resolution via diastereoisomers of citalopram or derivatives thereof (salts of the enantiomers with another enantiomer, such as chiral acids); separation via citalopram salts; and stereoselective synthesis. The procedural parties agreed that it could not be determined in advance whether a technique, and if so, which technique, would lead to obtaining an enantiomer. In the absence of success in his attempts with the available alternatives, the skilled person would not endlessly keep going down the same path, although he would in any event apply all of the aforementioned techniques. Only if the three identified techniques did not lead to the enantiomers, would the skilled person take another route. Evidence was filed by the patentee showing that resolution via diastereoisomers of citalopram was not successful using many well known chiral acids. The patentee had also filed evidence of unsuccessful resolution via diastereoisomers of derivatives of citalopram. These derivatives were desmethylcitalopram (citalopram without the methyl group, which methyl group can be easily reintroduced) and the precursor of citalopram (the diol intermediate that forms citalopram by ring closure via the diol groups). However, this experimental evidence consisted of only one or two of the many well known chiral acids. In response, Tiefenbacher et al filed evidence showing that with one of the other chiral acids desmethylcitalopram was separated into the diastereoisomers and thereafter converted into the individual enantiomers. On the basis of this responsive evidence the court held that it was sufficiently shown that with routine and systematically executed experiments, the skilled person would have obtained escitalopram within an acceptable time and thus without undue burden. As a consequence, claim 1 and the dependent claims 2-5 were held obvious. In addition, the court has pointed out that even if it were assumed that the skilled person would not have succeeded at the priority date in separating citalopram by resolution of a derivative, he would then still have tried to obtain the enantiomers by means of a stereoselective synthesis. Taking an optically pure precursor as the basis and, following that route, he would actually have obtained escitalopram. In relation to claims 6 (the stereoselective synthesis of escitalopram) and 7 (an enantiomer-pure diol) of EP 066, the court identified EP (EP 943) as the closest prior art. EP 943 discloses a method for obtaining (racemic) citalopram using the diol as intermediate product, whereby the last step consists of the ring closure of the diol. The difference identified by the court between EP 943 and EP 066 is that the method according to EP 943 uses an S N 1 reaction (under influence of an acid, first an atom (group) is separated from the carbon atom where the substitution takes place as leaving group) and obtains racemic citalopram, whilst according to the method of claim 6 of EP 066, the optically pure escitalopram is obtained because, based on the optically pure diol, a stereoselective S N 2 reaction (takes place in a basic environment) is applied. On basis hereof, the court has formulated the following objective problem: how can the ring closure method described in EP 943 be adjusted in such a way that the optically pure enantiomer is obtained? In other words, could the ring closure be carried out in a stereoselective manner (S N 2) starting from one of the enantiomers of the diol intermediate? Lundbeck argued that the skilled person would not expect that the synthesis of citalopram by means of an S N 2 reaction would actually proceed stereospecifically. It asserted that the outcome of such an S N 2 reaction cannot be predicted in advance and that, at the priority date, the skilled person would have anticipated so many problems that he would not have a reasonable expectation of success and therefore would decide against performing an S N 2 reaction. The court, however, considered that it was common general knowledge that the ring closure can be carried out in a stereoselective manner (S N 2 reaction), applying the known Baldwin rules on ring closure reactions. According to the court, these rules indicate that for the diol intermediate stereoselective ring closure (5 Exo-Tet ring closure) was always favoured, not only in respect of simple, saturated systems, as Lundbeck had argued, but also in respect of unsaturated systems. 3

4 Here the Dutch Court deviated from (respectfully disagreed with) the English Court at first instance. The reasons for this deviation were given in the decision. According to the Hague court, the English judge started from the wrong presumption that for the diol intermediate the favoured transition stage for an S N 2 reaction could not be attained. This presumption was based on a diagram D in a declaration of an expert opinion filed in the UK action. The Dutch court considered this (static) diagram incorrect, also on basis of a three dimensional model of the diol intermediate shown during the oral hearing. Such a three dimensional model was not shown to the UK judge. On the basis thereof, the Hague court came to the conclusion that the argument of Lundbeck, as adopted by the English first instance court, that the Baldwin rules do not apply to unsaturated systems (like the diol intermediate), is wrong. In addition thereto, the Hague court noted that if the skilled person had had any doubt that the Baldwin Rules also apply to unsaturated systems he would have sought confirmation for successful stereoselective ring closure of unsaturated systems which are chemically close to the diol intermediate, and he could and would have found sufficient confirmation thereof in professional peer reviewed journals. On the basis of primarily these considerations the Hague court concluded that the skilled person would understand, on the basis of his common general knowledge, that by means of an S N 2 reaction he would be able to convert the optically pure diol obtained without any inventive intellectual efforts into optically pure citalopram. On the basis of the Baldwin rules and various publications in the state of the art he would expect this to be successful and he would not anticipate any other problems of such a nature that he would nevertheless refrain from performing the S N 2 reaction with the enantiomeric diol. Further, according to the Hague court, the performance of such an S N 2 reaction and the further steps for obtaining escitalopram did not require any inventive intellectual efforts, and the skilled person would thus have obtained escitalopram. As a consequence claim 6 (and claim 7) were considered obvious, and the patent (and related SPC) revoked. It is not known to this author whether an appeal has been instituted against this decision. Marc van Wijngaarden, The Hague UK: The High Court s reference to the ECJ in Synthon B.V.v Merz Pharma GmBH & Co KGaA 1 Introduction EC Council Regulation 1768/92 (the Regulation ) sets out a regime for the granting of Supplementary Protection Certificates ( SPCs ) which provide for up to five year s additional protection beyond patent expiry for medicinal products. SPCs are granted in order to compensate the patentee for the lost period of effective monopoly caused by the time taken to complete the necessary safety and efficacy testing to obtain a marketing authorisation so that the product can be placed on the market. The requirements for safety and efficacy tests were first sought to be harmonised by Directive 65/65/EEC and are now set out in Directive 2001/83 (as amended). Key provisions of the Regulation Article 2 sets out the scope of the Regulation and provides that: Any product [i.e. the active ingredient or combination of active ingredients of a medicinal product] protected by a patent in the territory of a Member State and subject, prior to be placed on the market as a medicinal product, to an administrative authorisation procedure as 1 [2009] EWHC 656 (Pat) 4

5 laid down in Council Directive 65/65/EEC...may, under the terms and conditions of this Regulation be the subject of a certificate. Article 3 of the Regulation sets out the following conditions for obtaining an SPC in a given Member State (with each condition being satisfied in that Member State in which the application is submitted and being applicable on the date of application): (a) the product must be protected by a basic patent in force; (b) a valid authorisation to place the product on the market in accordance with Directive 65/65/EEC...must have been granted; (c) the product must not have already been subject of an SPC; and (d) the authorisation referred to in (b) must be the first authorisation to place the product on the market. Article 13 deals with the duration of the SPC to be granted and provides that an SPC shall be granted for the period of time that elapses between the date of the application for the basic patent covering the product and the first marketing authorisation to place that product on the market in the Community, less 5 years, but subject to a maximum of 5 years. As such, a maximum of 15 years exclusivity from first marketing authorisation in the Community can be obtained, thereby reflecting Recital 8 of the Regulation. Article 19 sets out the transitional provisions and essentially provides an additional condition that must be met in order to obtain an SPC. It provides that: Any product which on the date of accession is protected by a valid patent and for which the first authorisation to place it on the market as a medicinal product in the Community or within the territories of Austria, Finland or Sweden was obtained after 1 January may be granted a certificate. Article 19 therefore excludes from the scope of the Regulation products which were first authorised before 1 January Background to the dispute Synthon BV v Merz Pharma From before 1976, Merz had placed on the market in Germany a medicinal product, the active ingredient of which was memantine hydrochloride. Under the German domestic Act on Restructuring of Medicinal Product Law of 1976, products then already on the market and which remained on the market on 1 January 1978 were automatically granted a deemed market authorisation (for up to 12 years) without further enquiry or safety and efficacy testing, provided the German authority was notified of the product within 6 months of 1 January Memantine met these requirements and was accordingly authorised to be placed on the market in Germany without going through the safety and efficacy investigation required by Directive 65/65. In Luxembourg, the Luxembourg Medicines Act of 1983 implemented the provisions of Directive 65/65 into Luxembourg national law and came into full force on 30 June Despite this implementation, on 19 September 2003, the Luxembourg authority granted a marketing authorisation for memantine without undertaking an independent assessment of its safety and efficacy as required by Directive 65/65 but instead relied on the earlier deemed authorisation in Germany. Both the German and the Luxembourg marketing authorisations were withdrawn in 2002 and on 15 May 2002, were replaced by centralised marketing authorisations granted for memantine by the EMEA. These EU marketing authorisations were granted following an assessment of safety and efficacy data as required by Directive 65/65 and were therefore the first authorisations within the Community to do so. On 14 April 1989, Merz applied for European Patent (the basic patent), which was granted in The basic patent was for a second medical use of memantine rather than for the product memantine itself. On 13 November 2002, Merz applied to the UK Patent Office for an SPC, which was granted as SPC No GB 02/046 on 14 August In its application, Merz identified the 2002 authorisation as the first authorisation to place the product on the market in the Community, not the earlier German or Luxembourg authorisations. The Patent Office accordingly granted Merz an SPC for maximum term of 5 years (and therefore expiring in April 2014), notwithstanding that memantine had in fact 2 Other dates apply in certain Member States 5

6 been on the market in the EU long before the application for the basic patent was even made. The dispute in this case was whether Merz should have been granted this SPC. Synthon contended that the SPC should either be found invalid or have a zero year term. ECJ decisions considered by Floyd J Article 13 of the Regulation was considered in joined cases C-207/03 and C-252/03 Novartis v Comptroller and Ministre de L Économie v. Millennium Pharmaceuticals Inc (the Liechtenstein case). In his Opinion, the Advocate General makes it clear that the purpose of Article 13 is to set up a single system of extended protection and, to ensure that this extended period of exclusive use lasts for the same time throughout the Community, and by virtue of the EEA Agreement, the EEA. The decisive factor he considered was the date on which that use commences, namely the date from which the drug can be lawfully marketed in a part of the EEA, regardless of where, and regardless of the enabling document which could indeed be something other than a national authorisation issued by a Member State under 65/65 provided the document allowed the lawful marketing of the product in part of the EEA. What constituted a first marketing authorisation in the Community was also considered by the ECJ in the context of the transitional provisions in Article 19 in Case C- 127/00 Hässle v Ratiopharm. In Germany, the relevant date for the Article 19 transitional provision was 1 January Authorisations in accordance with 65/65 had been granted in France and Luxembourg before that date but Hässle wished to reference a later German authorisation granted after 1 January 1988 arguing that something more than a 65/65 authorisation was required for Article 19, in this case a subsequent authorisation under the national pricing authorisation. The Court rejected this argument holding that to do otherwise would be to put a different meaning to the words authorisation to place... on the market in Article 3 and Article 19. The Court rejected the contention that for the purposes of Article 19 something more than an authorisation under 65/65 was required. Floyd J was of the opinion that the issue in the Hässle case was however distinguishable from the issue in the current case, which is whether something less than a 65/65 authorisation should also be taken into account. National decisions considered by Floyd J Floyd J then considered the relevant national decisions, the first of which was the decision of the German Bundespatentgericht (German Federal Patent Court) in Neuraxpharm Arzneimittel and others v Merz where the court considered the validity of the corresponding German memantine patent and SPC. The Bundespatentgericht held the underlying patent invalid on conventional patent law grounds, which is itself a ground of invalidity of the SPC. It was therefore not necessary for the court to go on to consider arguments relating specifically to the validity of the SPC, but it did so nonetheless. The court first rejected an argument that the SPC was invalid under Article 3(d) because the 2002 authorisation was not the first authorisation. They found that the earlier German authorisation was not granted in compliance with 65/65 and so should not be taken into account. The Court nevertheless held that the SPC was invalid under Article 2 as the product was one which had not undergone a 65/65 compliant authorisation procedure in Germany before being placed on the market and so Merz s application for an SPC was outside the scope of the Regulation altogether. In a separate decision in Merck v Almirall on 18 July 2006, the Bundespatentgericht held (following the ECJ in Hässle) that the first authorisation to place a product on the market was construed for the purposes of Article 19 as referring only to a 65/65 compliant one and Article 13 had to be construed in the same way. As such two earlier marketing authorisations in Portugal and Spain, which were not 65/65 compliant as neither country had implemented 65/65 into its national law at that time, were not to be counted for the purposes of Article 13. In contrast, the Court of First Instance of Brussels, when considering the validity of the corresponding Belgian SPC for the same drug, held that the earlier Portuguese marketing authorisation should be taken into account, instead following the Advocate General s Opinion in Novartis that national marketing authorisations could be taken into account. Considerations in the current case Having considered the relevant case law, Floyd J concluded that three issues (as set out below) were relevant. 6

7 In each case, whilst expressing his own views as to the correct answers, he considered that a reference to the ECJ was necessary. Issue (i) - Was the Luxembourg authorisation an authorisation in accordance with 65/65? If so, the SPC should not have been granted and is invalid. Synthon argued that because the Luxembourg authorisation was granted at a time when 65/65 had been implemented into national law, it was not for the Court to look behind that authorisation to enquire whether the Luxembourg authorities had in fact carried out an investigation into the safety and efficacy of the product as required by 65/65. Merz disagreed. Floyd J preferred Synthon s argument, and as such, took the view that the Luxembourg authorisation, having been granted under Luxembourg law which had already implemented 65/65, was the first authorisation to place the product on the market in the Community for the purposes of Article 13. The SPC should therefore be zero term but in any event invalid as this date of the Luxembourg authorisation would cause Merz s SPC to fall foul of Article 19. Issue (ii) - Even if the German and Luxembourg authorisations were not in accordance with 65/65, can they nevertheless be taken into account when applying Article 19 and Article 13? Synthon argued that the German and Luxembourg authorisations, even if not compliant with 65/65, should be taken into account for the purposes of Articles 13 and 19 as they were permitted by national law and equivalent to 65/65 compliant authorisations. Synthon argued that where the Regulation meant to refer to a specific kind of authorisation it did so expressly, but where it did not, then authorisations, including national authorisations which were not 65/65 compliant, were intended to be included. This was the case for Articles 13 and 19. Merz disagreed, relying on the ECJ s decision in Hässle in which it held that the marketing authorisation referred to in Article 19 was a 65/65 authorisation and there was no basis to justify the words authorisation to place..on the market being interpreted differently depending on which provision of the Regulation they appeared in. Floyd J noted that the Advocate General s decision in Novartis provided some basis for a retreat from Hässle and that there were also the conflicting national German and Belgian decisions. In light of these uncertainties, Floyd J considered that a reference to the ECJ would be necessary. Issue (iii) - Are products, which have been authorised to come on to the market for the first time without needing to go through a 65/65 administrative procedure, within the scope of the Regulation at all as a result of Article 2? Merz s argument was consistently that the German and Luxembourg authorisations were not authorisations compliant with 65/65. Synthon argued that even if Merz were correct in this, then as memantine had first been placed on the market in Germany and Luxembourg without needing to go through the safety and efficacy testing procedure laid down by 65/65 (as was common ground), then Merz s application for an SPC was outside the scope of Article 2 altogether. Floyd J considered that to construe the Regulation so as to benefit products which had not first to undergo an authorisation procedure as laid down by 65/65 would be to extend the scope of the Regulation beyond its intended purpose. Floyd J noted that care had not been taken in Article 2 to make clear whether it referred to a first authorisation in the Community or simply the first authorisation in the Member State where the application was made. One would need to look at the context and purpose of Article 2 to decide which was intended. Article 2 constrains the operation of the Regulation to cases where in order to obtain a first marketing authorisation in the Community the need to go through the administrative authorisation procedure under 65/65 arose. If it did not arise, there would be no compensation needed for lost time. It is clear from the Regulation that where there is an earlier 65/65 compliant authorisation in another Member State that this can reduce or extinguish altogether the SPC protection afforded to a product which otherwise meets the national SPC requirements set out in Article 3. If an earlier 65/65 compliant authorisation can have such an effect, then it is even more compelling that a product placed on the market in the Community without even the need for such an authorisation should also extinguish the available SPC protection. 7

8 Questions referred to the ECJ The questions referred by Floyd J are: 1) For the purposes of Articles 13 and 19 of Council Regulation (EC) No 1768/92, is an authorisation a first authorisation to place. on the market in the Community, if it is granted in pursuance of a national law which is compliant with Council Directive 65/65/EEC, or is it necessary that it be established in addition that, in granting the authorisation in question, the national authority followed an assessment of data as required by the administrative procedure laid down in that Directive?" 2) For the purposes of Articles 13 and 19 of Council Regulation (EC) No 1768/92, does the expression "first authorisation to place on the market in the Community include authorisations which had been permitted by national law to co-exist with an authorisation regime which complies with Council Directive 65/65/EEC? 3 Is a product which is authorised to be placed on the market for the first time in the EEC without going through the administrative procedure laid down in Council Directive 65/65/EEC within the scope of Council Regulation (EC) 1768/92 as defined by Article 2? 4. If not, is an SPC granted in respect of such a product invalid? Ewan Grist & Mary Smillie, London UK: Scinopharm v Eli Lilly: Patents Court upholds patent covering process for stereoselective synthesis of Gemcitabine [2009] EWHC 631 (Pat) In his judgment of 27 March 2009 Mr Justice Kitchin dismissed a revocation action in which it was alleged that Eli Lilly s European Patent (UK) 0,577,303 is obvious and insufficient. A Supplementary Protection Certificate covering Gemcitabine (a cytotoxic used in the chemotherapy of certain types of cancer) expired on 5 March 2009 but Scinopharm sought to revoke the process patent, which covers the high yield process used by Eli Lilly to manufacture Gemcitabine. Gemcitabine is a nucleoside analogue, specifically the anomer of 2'-deoxy-2',2'- difluorocytidine. 2'-deoxy-2',2'- difluorocytidine exists in two chiral forms, the anomer and the anomer (which is active form). The key issue on the question of obviousness was whether it would have been obvious using common general knowledge and certain prior art references to select reagents and conditions that would promote a stereoselective S N 2 reaction to produce the active anomer (Gemcitabine) in higher yield than the inactive anomer, as opposed to trying to optimise the yield of the anomer in a non-stereolselective S N 1 reaction. The judge identified the invention as the discovery that anomer enriched mesylate of the carbohydrate moiety (2'-deoxy-2',2'- difluororibose) could be reacted with the nucleobase moiety (cytosine) under nucleophilic displacement conditions which favour the S N 2 pathway (and hence chiral inversion) to provide anomer enriched 2'- deoxy-2',2'-difluorocytidine. On the evidence the judge found that it was not obvious that a S N 2 reaction would provide a high yield process for the synthesis of the anomer. The judge also found that although the specification of the patent does not identify all those process steps needed to achieve the result of the claimed invention, the specification does provide a large number of examples and the skilled person would be able to identify general conditions which would enable him to work the invention across the scope of the claimed subject matter, including Gemcitabine in particular. Gerry Kamstra, London An appraisal of the House of Lords Generics et al v Lundbeck Judgments Summary of Generics UK, Arrow and Teva v Lundbeck ( Lundbeck ) In February 2009 the House of Lords unanimously dismissed an appeal by a number of pharmaceutical companies 8

9 against the Court of Appeal s decision to not revoke Lundbeck s escitalopram patent on grounds of insufficiency. The effect of the judgment was that Lundbeck s patent protecting escitalopram, an enantiomer of an anti-depressant called citalopram, was upheld as sufficiently disclosing the product. This was so even though only two methods of making escitalopram were detailed in the specification, and despite the fact that the enantiomer previously known to be present in a racemate and was expected to be responsible for the activity of the racemate, and that inventive step only lay in the method of producing the enantiomer. The various speeches in the House of Lords separated the concepts of novelty, obviousness and sufficiency and their approach was to look at each one of the issues separately. There are a number of ways in which this clarification of the correct approach may impact patent invalidity claims and a number of further questions to be answered. Biogen In 1996 the House of Lords handed down its opinion in Biogen Inc v Medeva plc [1997] RPC 1. The patent in Biogen related to a product-by-process claim covering a class of products, but only one process for producing one of the products was described in the patent specification. Lord Hoffmann giving the leading speech, considered whether and to what extent a claim to more than one product or process was sufficient, stating that - if the claims include a number of discrete methods or products, the patentee must enable the invention to be performed in respect of each of them - and that - the extent of the monopoly claimed [should not] exceed the technical contribution to the art made by the invention as described in the specification. Lord Hoffmann stated that there are two ways in which the breadth of a patent claim may exceed its technical contribution to the art embodied in the invention: (1) The patent may claim results which it does not enable, such as making a wide class of products when it enables only one of those products and discloses no principle which would enable others to made (2) or it may claim every way of achieving a result when it enables only one way and it is possible to envisage other ways of achieving that result which makes no use of the invention. Over time these became known in the English courts as Biogen insufficiency and for a claim to a class of products or processes to be valid the skilled person must be enabled by the description in the patent to make or perform the invention to the full breadth of the claim. What was not clear however, as we now know, was the extent to which the principles laid down in Biogen applied to a claim for a product that was known to exist but had not yet been made. Facts in Lundbeck In 1979 Lundbeck s patent for what was to become the antidepressant drug, citalopram was published. Citalopram is a racemic mixture comprising of 2 mirror-image enantiomers, commonly labelled (-) and (+). By 1987, and with, at least on the evidence in the English case, difficulty, Lundbeck had developed a method to isolate the therapeutically more effective (+) enantiomer of citalopram, escitalopram 3. Therefore, Lundbeck was granted a patent containing product claims to the (+) enantiomer, to a pharmaceutical composition containing the enantiomer and a process claim for the method for producing the enantiomer. It was held at first instance that this enantiomer would have been expected, by analogy with other such compounds, to be responsible for the activity of the racemate. Accordingly, any invention in the escitalopram patent had to lie in the method of isolating or producing it from the racemate. Two methods of producing escitalopram were disclosed in the escitalopram patent specification, but it could have been envisaged, as proved to be the case, that others would be discovered in the future. Novelty and obviousness Escitalopram was novel as, applying the House of Lords decision in Synthon v SmithKline Beecham [2005] UKHL 59, there 3 In a subsequent decision of the District Court of the Hague on 8 April 2009 in parallel litigation on the Dutch designation of the patent in issue in the English case, and on the basis of new evidence that was not before the English court, it was held that it would not have been so difficult as the English court had concluded to resolve the racemate into its constituent enantiomers, and accordingly that all claims of the corresponding Dutch patent were obvious. 9

10 had previously been no disclosure enabling an ordinary skilled person to make escitalopram. It was also inventive as although the desire to make escitalopram clearly existed, the method of doing so involved a non-obvious and therefore inventive step. Insufficiency at first instance Although subsequently reversed in the Court of Appeal, the insufficiency challenge succeeded at first instance with Kitchen J applying his interpretation of the principle from Biogen to hold that patent protection should only be afforded to products that it was obvious to seek to make to the extent that the method for their preparation is disclosed in the patent. He said that The first person to find a way of achieving an obviously desirable goal is not permitted to monopolise every other way of doing so. Kitchen J treated the technical contribution to the art as being identical to the inventive step, which in this case was the method of isolating the (+) enantiomer. He then held that any claim to the product that was not further restricted to this specific inventive step, was insufficient. Insufficiency in the Court of Appeal The correct position, which was approved in the House of Lords, was initially stated by Lord Hoffmann, who was on this occasion sitting in the Court of Appeal. Even if a product s existence and utility may have been known, once the product satisfies the requirements of novelty and inventive step, the technical contribution to the art is the product itself and not the process by which it was made, even if that process was the only inventive step. Lord Hoffmann referred to the established principle that if the invention is a way of making a new and non-obvious compound, one disclosed method is enough to render the patent sufficient. Kitchen J s judgment stated if the invention is a way of making an obvious compound, one disclosed method will not suffice. In Lord Hoffmann s opinion, there is nothing in the relevant section of the Patents Act which connects the requirements of sufficiency to inventive step. Jacob LJ added that it was not necessary for the patent specification to cover all uses of a product or ways of producing a product and that the concept that the patentee should not have more then he deserves does not form part of the statutory test for insufficiency. However Lord Justice Jacob also emphasised the difference in this context between a claim to a single product and one to a class of products by saying that if a man finds a particular way of making a new substance which is 10 times harder than diamond, he cannot just claim "a substance which is 10 times harder than diamond." He can claim his particular method and he can claim the actual new substance produced by his method, either by specifying its composition and structure or, if that cannot be done, by reference to the method but no more. Insufficiency in the House of Lords Their Lordships reasons for dismissing the final appeal were very much in line with those of Lord Hoffmann in the Court of Appeal; however, certain principles were further explored particularly by Lords Walker, Mance and Neuberger. Lord Walker elaborated on the argument before the House as to whether the inventive concept (often regarded as the relevant term for what must be disclosed for obviousness) means the same as the technical contribution to the art (often used as the relevant term to assess insufficiency). He stated that neither expression is a statutory term and that both had been used by Lord Hoffmann in his Biogen judgment. Lord Walker recognised that the two expressions are certainly connected, but he did not see it as helpful to treat them as having precisely the same meaning: Inventive concept is concerned with the identification of the core of the invention the idea or principle, of more or less general application which entitles the inventor s achievement to be called inventive. The invention s technical contribution to the art is concerned with the evaluation of the inventive concept how far forward has it carried the state of the art? The inventive concept and the technical contribution may command equal respect but that will not always be the case. Lord Neuberger recognised that the monopoly to be granted to the patentee is to be assessed by reference to the technical contribution made by the teaching of the patent. He said that it was clear that the technical contribution made by the patent was to make available, for the first time, a product that had previously been unavailable. On that basis Lundbeck were entitled to claim the (+) enantiomer. Lord Neuberger said that the extent of the monopoly claimed [should not] exceed the technical contribution to the art made by the invention as described in the specification, 10

11 and that the technical contribution can often be equated with non-obvious novelty what is new to the art and not obvious is really another way of identifying the technical contribution. He continued to explain that he thought Kitchen J s error was attributable to the focussing by Lord Hoffman in Biogen on the inventive step and highlighted that there is a difference between the inventive step or inventive concept, on the one hand, and the technical contribution to the art, on the other hand. Lord Neuberger was in agreement that it is the inventive concept or inventive step that is required to be fully disclosed in the patent specification for the patent to be non-obvious. The technical contribution to the art on the other hand is more relevant as a marker as to what the judgment on questions of insufficiency should be based. This means that obviousness and insufficiency are, in effect, determined by reference to different aspects of the patent. The impact of Lundbeck on use of an insufficiency squeeze Following Lundbeck it appears that the technical contribution and inventive concept can be different in nature depending on the type of claim under consideration. A common and orthodox tactic in patent litigation is to attempt to place the patentee in a squeeze, such as the obviousness/insufficiency squeeze. In operation of the obviousness/insufficiency squeeze it is argued that either i) the specification of the patent does not enable the technical contribution to be worked by the person skilled in the art; or ii) if it does, only as a result of taking the common general knowledge into consideration, the technical contribution to the art is purely common general knowledge and therefore the patent is obvious. Although Lundbeck was not a case in which any insufficiency/obviousness squeeze was used, it appears on the face of the House of Lords judgment that Lundbeck might have an impact on the situation in which such squeezes can be run. The basis for drawing such conclusion is that their Lordships are clear that in their opinion there may be, in particular cases, a difference between the technical contribution to the art and the inventive concept. However, Any difference between these two concepts would only appear in limited circumstances and is dependent on the type of claim. Therefore, in respect of certain types of product and product-by-process claims the inventive concept and technical contribution are not the same. Accordingly, the same basis does not exist to assess obviousness and insufficiency in such a case the squeeze described above may not be effective. The error at first instance in Lundbeck lay in treating product claims as if they were process claims and by considering that the technical contribution and inventive concept are always the same. Geoff Hussey & Gavin Lawson, London Regulatory news EU: First Order rendered by the President of the Court of First Instance in a Paediatric case (Case T-52/09 R) Background of the case Under the Paediatric Regulation 4, the European Medicines Agency (EMEA) for the first time since its creation in 1993, has an autonomous decision making power (that is to say, not linked to a subsequent European Commission endorsement/decision) and it is now, therefore, subject to direct legal action before the European Courts. On 11 February 2009, Nycomed A.p.S. 5, the Danish subsidiary of the Nycomed group (the Applicant or Nycomed ), brought an 4 5 Regulation (EC) No 1901/2006 amending Regulation (EC) No 726/2004 (see in particular article 73a thereof), Nycomed Danmark ApS, established in Roskilde (Denmark), represented by C. Schoonderbeek and H. Speyart van Woerden, v European Medicines Agency (EMEA), represented by Nathalie Rampal Olmedo and Vincenzo Salvatore, in an application, first, for suspension of the operation of the EMEA s decision of 28 November 2008 rejecting the application for a product-specific waiver concerning perflubutane and, secondly, for the grant of interim measures. 11

12 action seeking the annulment of an EMEA decision dated 28 November 2008 (the Decision ) rejecting Nycomed s application under Article 11(1)(b) of the Paediatric Regulation for a waiver of the obligation to produce the results of all studies performed and details of all information collected in compliance with an agreed paediatric investigation plan (PIP) for its product Imagify 6. Moreover, by separate document, lodged at the Court Registry the same day, Nycomed brought an application for interim measures [the subject matter of the Order here at issue], requesting the President of the Court essentially to: (a) suspend the operation of the Decision and (b) order the EMEA to initiate provisionally the centralised marketing authorisation procedure for Imagify, and (b1) if that marketing authorisation procedure should lead to an opinion of the EMEA within the meaning of Article 5(2) of Regulation No 726/2004 [CHMP final opinion] before judgment has been delivered in the main proceedings, stay the procedure before it, pending the main proceedings and, as the case may be, the grant of a waiver; or (b2) if that procedure for marketing authorisation has not led to such an opinion before judgment has been delivered in the main proceedings, terminate the procedure if the main application for annulment is dismissed, or stay the procedure before it, pending the grant of a waiver, if the main application is successful. According to Article 7(1) of the Paediatric Regulation (in force as from 26 July 2008): [a]n application for marketing authorisation under Article 6 of Directive 2001/83/EC in respect of a medicinal product for human use which is not authorised in the Community at the time of entry into force of this Regulation [26 January 2007] shall be regarded as valid only if it includes, in addition to the particulars and documents referred to in Article 8(3) of Directive 2001/83/EC [full dossier application], one of the following: (a) the results of all studies performed and details of all information collected in compliance with an agreed paediatric investigation plan; (b) a decision of the Agency granting a product-specific waiver; (c) a decision of the Agency granting a class waiver pursuant to Article 11; (d) a decision of the Agency granting a deferral. As an exception to the above, according to Article 11(1)(b) of the Paediatric Regulation: [p]roduction of the information referred to in point (a) of Article 7(1) [i.e. the results of all studies performed and details of all information collected in compliance with an agreed PIP] shall be waived for specific medicinal products or for classes of medicinal products, if there is evidence showing any of the following: [omissis] (b) that the disease or condition for which the specific medicinal product or class is intended occurs only in adult populations. In light of the aforementioned legal framework, Nycomed applied for a waiver in respect of an ultrasound echocardiographic imaging agent to be marketed under the brand name Imagify, intended, according to the Applicant, to diagnose coronary artery disease ( CAD ) in adults 7. Through the Decision, the EMEA denied that waiver to Nycomed on the grounds that the disease or condition for which the medicinal product is intended is not CAD but myocardial perfusion defects, which also occur in children. The Applicant claimed that the Decision is unlawful in that it is based on an interpretation and application of the concept of disease or condition for which the medicinal product is intended within the meaning of Article 11(1)(b) of the Paediatric Regulation, which, according to the Applicant, was incorrect in that it does not take into account the therapeutic indication applied for in the concomitant Community market authorisation application. The Applicant further submitted that the Decision is unlawful in that it is an attempt by the EMEA to misuse its powers pursuant to Articles 11(1)(b) and 25 of the Paediatric Regulation in order to attain an aim which is not contemplated by those provisions, namely, the obligation to propose a PIP for indications which are not covered by the concomitant application for market authorisation. Findings of the President of the Court By Order of 24 April 2009, the President of the Court of First Instance dismissed the application for interim relief filed by 6 7 Case T-52/09, currently pending. The CAD is a chronic disease characterised by obstruction of the coronary arteries, in patients suffering from chest pain and in whom inducible ischemia, that is reduced blood flow to an organ caused by stress or increased physical activity, is suspected. 12