That (es)citalopram patent again

Last week The SPC Blog featured news that The Dutch first instance decision in ratiopharm et al v Lundbeck, concerning the validity of Lundbeck’s escitalopram patent (EP 066) had been handed down by the Hague District Court, which held all the claims of Lundbeck’s escitalopram patent (and the Dutch Supplementary Protection Certificate which was based upon it) invalid for lack of inventive step. The SPC Blog's informants -- Richard Ebbink and Mark van Gardingen, Brinkhof -- mentioned that the court's decision contained many references in the decision to the 4 May 2007 decision of Mr Justice Kitchin of the Patents Court for England and Wales [noted here by the IPKat], with which decision the Dutch Court “respectfully disagreed”.

The IPKat has since heard from Jaap J.E. Bremer (BarentsKrans N.V.), who writes:

"You may be interested to know that my colleague Marleen van den Horst and I represented two out of three claimants (A.E. Tiefenbacher GmbH and Centrafarm B.V.) in these proceedings before the Court of The Hague. The Dutch Court clearly distinguished its judgment from the UK decision and the distinction was justified by new experimental evidence as well as expert evidence provided by Tiefenbacher, 

In the UK case, Kitchin J heavily relied on the interpretation by Prof Davies, Head of Chemistry at Oxford University, of certain organic chemistry rules called the "Baldwin Rules", which were created by Davies' predecessor at Oxford, Prof. Baldwin. In the Dutch proceedings, Tiefenbacher managed to have Prof Baldwin act as a expert witness to explain his own rules. He had not been involved in the UK proceedings. This lead to a very interesting confrontation in the Courtroom between the current Oxford Chemistry Professor and his predecessor. The explanation of the Baldwin Rules by Professor Baldwin himself (to set straight what went astray in the UK) was a very important factor in getting the Dutch Court to distinguish the case from Kitchin J's decision".

The IPKat has since received a short English-language summary of the Dutch decision from Jaap and Marleen: 

Tiefenbacher and Centrafarm, represented by M.H.J. van den Horst and J.J.E. Bremer and ratiofarm, represented by R.E. Ebbink and M.G.R. van Gardingen,
plaintiffs

against

Lundbeck, represented by P.A.M. Hendrick, T.M. Blomme and A.F. Kupecz,
defendants

The District Court has decided to invalidate Lundbeck’s patent EP ‘066 (escitalopram) briefly summarized the reasoning of the court is as follows.

Novelty

Claims 1-5

The court does not agree with Tiefenbacher et. al. that the publication of Smith constitutes a direct and ambiguous disclosure of the compound in the form of a technical teaching. From Smith, it cannot be derived if and, if so, how the enantiomer has actually been obtained in individualized form. Therefore the argument that claim 1 and depending claims 3 and 5 lack novelty is denied.

Inventive step

Claims 1-5

However, the court does agree with Tiefenbacher et. al. that claims 1-5 lack inventive step. The court concludes that the skilled person was motivated at the priority date to separate the enantiomers of racemic citalopram. Reference is made to publications of Ariëns and the Thalidomide incident and the expert report of Dr. Newton. The court also agrees with Tiefenbacher that the FDA regulations provided a strong incentive to investigate the activity of the separate enantiomers and therefore to separate the enantiomers. Reference is also made to Dr. Newton's declaration about his experience at Glaxo at the priority date. The court further finds that the skilled person would apply a number of methods that are part of his general knowledge, namely (i) resolution by converting the racemic mixture into a mixture of diastereomers, followed by separation (for instance through fractional (re) crystallization) and conversion to the pure enantiomer, (ii) creation of a salt or derivate of the racemic material, followed by resolution and (iii) stereo selective synthesis, for instance by separation of a racemic intermediate or precursor, followed by stereo selective conversion to the enantiomer.

The result of experiments conducted by Matrix laboratories at the request of Tiefenbacher show that the skilled person would at the priority date, by making use of fractional crystallization using obvious citalopram derivates and the usual chiral acids and solvents have obtained enantiomeric pure escitalopram through routine systematic experiments without undue burden. The court concludes that Lundbeck has done less than the average skilled person would have done using his general knowledge in search of the enantiomers of citalopram. Lundbeck’s objections to the submission of the Matrix experiments, and Lundbeck’s other arguments in defence of alleged inventive step are denied. The court remarks that, even if the skilled person would not have achieved in obtaining escitalopram through resolution of a derivate, he would still have tried to obtain escitalopram through stereo selective synthesis, which would also have been successful, as will be discussed in more detail in the context of claims 6 and 7.

The court concludes that claims 1 to 5 lack inventive step.

Claims 6 and 7

Tiefenbacher et. al. have also argued that claims 6 and 7 lack inventive step. The court agrees with Tiefenbacher et. al. that EP 943 should be considered the closest prior art. EP 943 describes a method for obtaining racemic citalopram, making use of the diol as an intermediate product and in which the last step consists of the ring closure of the diol. Parties agree that it would be obvious to the skilled person that, in order to achieve a stereo selective ring closure of the diol, the SN2-reaction would be the only possibility. However, the court does not agree with Lundbeck’s argument that the skilled person would never the less not expect that the synthesis of citalopram by means of an SN2-reaction would in fact be executed whilst maintaining stereo specificity. Lundbeck argued that the skilled person would foresee so many problems, that he would not have a reasonable expectation of success and would therefore not execute the SN2-reaction. The court agrees with Tiefenbacher that there is no reason for the skilled person to assume that the Baldwin Rules would only apply to saturated systems. Reference is made to the publications setting out the Baldwin Rules and the statements made by Professor Baldwin during the Court hearing. The Court explicitly distinguishes its decision from the - earlier - UK High Court decision on the basis of this new evidence presented by Tiefenbacher. The court disagrees with the argument of Professor Davies that the configuration necessary for the Walden inversion would not occur in the diol, since it does not take into account intra molecular movements which will always result in the occurrence of the correct configuration for the SN2-reaction to take place. Again, the court refers to the UK judgement and distinguishes its decision from this judgment, with the arguments that Kitchin J has been lead by Davies to incorrectly conclude that “the most favourable configuration for an SN2-reaction can be achieved in the case of a saturated system but not in the case of the unsaturated diol of the patent”. Reference is also made to three-dimensional models of the molecule, which have not been used in the UK court proceedings. All the other arguments of Lundbeck to support its statement that the skilled person would have doubts whether the SN2- reaction could be executed successfully (inter alia steric hinderance), ester swapping, the argument that tertiary alcohols would be bad nucleophiles etc. are rejected by the court with reference to publications of Jacobus, Cannone, Rosen and the declaration of Dr. Newton.

On the basis of the above, the court concludes that also claims 6 and 7 lack inventive step. Since the patent is considered invalid in its entirety, the supplementary protection certificate is also null and void. The court orders Lundbeck to pay an amount of € 709,000 as legal costs.

The full test of the decision is available in Dutch here

The IPKat understands that this decision is likely to the subject of some serious discussion at this week's Fordham Conference, which he very much regrets not being able to attend in person.