Microsoft word - headnote%20esc%20appeal%20nl[1]

NL - Lundbeck v. Tiefenbacher
Joined cases of H. Lundbeck A/S v. Alfred E. Tiefenbacher GmbH and H. Lundbeck A/S v.
Centrafarm Services B.V. and H. Lundbeck A/S v. Ratiopharm GmbH, Court of Appeal The
Hague, The Netherlands, 24 January 2012, Case Nos 312468 / HA ZA 08-1827, 314574/HA ZA 08-
2142 and 314783/HA ZA 08-2172

The Court of Appeal in the Hague has decided that Lundbeck’s patent for escitalopram, which patent had been invalidated in its entirety by the District Court in first instance, is partially invalid. The product claims for the active substance escitalopram were nullified for lack of inventive step, whilst the method claim describing a specific procedure for the synthesis of escitalopram and the claim relating to an intermediate product were considered valid. The SPC-specific nullity arguments were dismissed. In an eagerly awaited appeal judgment in the invalidity proceedings originally instituted by Tiefenbacher, Centrafarm and Ratiopharm against H. Lundbeck A/S’ European Patent EP 0 347 066 and SPC 300 155 for escitalopram, the Court of Appeal in The Hague has found EP ‘066 partially invalid, thereby quashing the first instance judgment of the District Court. This judgment is one of the many chapters of the ongoing international patent battle regarding this blockbuster antidepressant. EP ‘066 claims, in short, the pure enantiomer escitalopram (the S-enantiomer of the known racemic compound citalopram) and a method for its synthesis. The product claims were invalidated, but the method claim and a related product claim for an intermediate product were upheld. The Court of Appeal dismissed the claims based on lack of novelty, even though it had been established that the configuration of escitalopram had been disclosed in a prior art publication. However, since this disclosure did not contain any information as regards optical activity, the Court ruled that it had not been proved that anyone had actually had escitalopram ‘in his hands’ and therefore, had not been established that anyone had “obtained escitalopram in individualised form”. As regards inventive step, the Court of Appeal applied the problem and solution approach and took a publication disclosing racemic citalopram (US ‘193) as the closest prior art, thereby dismissing Lundbeck’s position that the starting point for the assessment of inventive step should be the large group of compounds with antidepressant effect. Since the patent said that the (technical) therapeutic effect resides almost entirely in the S-enantiomer of the racemic citalopram, the objective technical problem was defined as finding the new enantiomer of the known racemic compound that has an improved effect. The Court ruled that there were many prior art publications, including guidelines of regulatory authorities, provided a strong incentive for the person skilled in the art separate and test the enantiomers, with a reasonable expectation of success that a better product would be found. The person skilled in the art would, based on his common general knowledge in the art, immediately arrive at the S-enantiomer, and an improved effect of the (+)-enantiomer with a factor of around 2 as compared to the racemate was considered not surprising. Therefore, the product claims 1-5 were found to be invalid. The method claim (claim 6) of EP ‘066 in essence described a method for stereoselective synthesis of escitalopram by taking a racemic precursor (the ‘diol’) known from the synthesis of citalopram, separating this diol into its enantiomers and subsequently converting the enantiomerically pure diol into escitalopram by means of a specific ring closure reaction. The Court ruled that, unlike the claimants had argued, EP ‘943, which disclosed the racemic diol base, was not the closest prior art, since it does not describe the (-) enantiomer of the diol base, nor a method for preparing escitalopram. The closest prior art according to the Court was another document (Smith), which proposes a method for the preparation of escitalopram (but which does not mention the diol base). Although the Court considered the method of claim 6 of EP ‘066 for separating the enantiomers of the diol and the subsequent ring closure to be obvious, it nevertheless found claim 6 to be inventive, because the choice of the diol as a starting point was not obvious. The Court ruled that the skilled person could choose numerous options as a starting point for obtaining escitalopram, including various precursors and derivatives. It found that another derivative (incorrectly designated as a ‘precursor’ in the appeal judgment), desmethyl citalopram, was the more obvious option, since it was known that this derivative could easily be converted back to the original compound (citalopram) without risk to the integrity of the chiral centre or the cyano group. The skilled person would, in the Court’s view, assume that, based on the structure of the diol, performing the ring closure may well cause racemisation (i.e. the end product would be racemic citalopram instead of escitalopram). The selection of the diol base rendered the method according to claim 6 inventive. The Court further set out that, since the compound escitalopram itself was novel but not inventive, it was up to Lundbeck to prove that no other methods were known on the priority date that could be used to obtain the enantiomer, and that Lundbeck had not offered any such proof. In addition, Lundbeck had only added a method for the manufacture of this compound to the prior art, and therefore, in accordance with the proportionality principle, was not entitled to absolute substance protection, but only to patent protection for the method and the product obtained through the application of such method. The Court of Appeal also dismissed the SPC-specific arguments that had been brought forward, the main arguments being that a previous SPC had already been granted for the same product (art. 3 (c) SPC Regulation) and that the marketing authorisation designated in the SPC application was not the first marketing authorisation for the product (art. 3 (d) SPC Regulation). Both the earlier SPC and the earlier marketing authorisation referred to were for citalopram. The original claimants had argued that, since the therapeutic activity resided entirely in the S-enantiomer, the active substance (i.e. the product) was in fact the same in citalopram and in escitalopram. They had referred, inter alia, to a decision by the Dutch Medicines Evaluation Board, which had found that escitalopram was not a New Active Substance compared to citalopram. The Court ruled, however, that the MEB decision was not relevant, but that the question whether escitalopram was a new product or the same product as citalopram had to be answered on the basis of patent law. Although it is true that the person skilled in the art will be able to represent the spatial form of the S and R-enantiomers, this does not establish whether the S- or the R-enantiomer is the (+)- or (-) enantiomer, nor which of the two is the active compound, and whether or not there is an inactive or scarcely active compound which must in fact be regarded as an impurity. The method of claim 6 had made it possible to determine the specific spatial configuration of escitalopram. Since this spatial configuration of escitalopram rendered it novel, the Court considered that escitalopram and citalopram are different active ingredients. Finally, the Court discussed the recent University of Queensland and Medeva judgments of the Court of Justice and specifically, whether escitalopram oxalate mentioned in the SPC is 'a product' that is 'identified in the wording of the claims'. The Court decides that, although esclitalopram oxalate is not identified in a claim of EP ‘066 in so many words, it does form part of the subject matter of the upheld basic patent and is covered by the basic patent as specific embodiment of the non-toxic acid addition salts (which are identified in the claims in so many words). In light of this, and since the Court of Justice in University of Queensland and Medeva has not retracted its earlier Farmitalia ruling, the Court of Appeal decided that the criteria laid down in the SPC regulation and the relevant case law have been fulfilled and the invalidity grounds presented are denied.


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