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emphasised the importance of avoiding hindsight when considering apparently obvious steps from something known.
The Judge found that a motive existed to resolve citalopram into its enantiomers and that testing their activity was trivial. Investigation of citalopram’s enantiomers was an obvious goal for the ordinary skilled medicinal chemist in 1988. The activity of citalopram was well known; any medicinal chemist in 1988 would have appreciated that the enantiomers might have different activities; an inactive enantiomer was, at best, ballast but may be toxic; the regulators considered that an investigation of the enantiomers was desirable and this might in due course become mandatory.
Could the skilled person have achieved resolution of citalopram in June 1988?
• Citalopram could not easily be resolved by making diastereoisomers, the method the skilled person would naturally try.
• An earlier patent revealed a diol (Fig. 2b) as a chiral intermediate in the citalopram synthesis. A route from the diol to (+)- citalopram was argued as being obvious to the skilled person.
o Attempting to form salts with the diol was routine albeit unpredictable. The salts crystallised differentially permitting resolution of the diol enantiomers. However, the Judge felt that the skilled person would not blindly go ahead with crystallisation experiments without first satisfying himself that there was a real prospect of an SN2 reaction working for the final step, and without the benefit of hindsight, the CGK was that the SN1 reaction would be favoured with the expectation of losing stereochemistry. This was not a route the skilled person would attempt.
• The obviousness argument based on chiral HPLC included prior art showing the available chiral stationary phases (‘CSPs’) and expert evidence as to the identification of the appropriate CSPs and parameters to conduct this separation. Post-priority publications were also relied on to show that separation could actually be obtained on CSPs available at the relevant time.
o The Judge concluded: “this is one of those cases where each step seems very simple and logical with the benefit of hindsight. …by the mid 1990s many techniques were routine which were still very much at an experimental stage in 1988…I do not believe it was obvious to resolve citalopram on a preparative scale using chiral HPLC in 1988…The ordinary
Figure 2 (a) escitalopram (b) racemic diol intermediate in the synthetic route to citalopram
skilled analytical chemist would have had no practical experience of preparative chiral HPLC and the ordinary skilled medicinal chemist would probably not have heard of it. The team would have been faced with a research programme with an uncertain outcome.”
Insufficiency was argued based on a House of Lords decision, Biogen v Medeva [9]. The Judge held that the claim to (+)-citalopram and the claim to a pharmaceutical composition containing (+)-citalopram cover all ways of making (+)-citalopram which was an obviously desirable goal. The Judge’s interpretation of Biogen was that the first person to find a way of achieving an obviously desirable goal is not permitted to monopolise every way of doing so. Lundbeck found a way of making (+)- citalopram, this was their technical contribution, and these claims extended beyond that.
The Judge therefore found the patent novel and non-obvious but invalid for insufficiency.
The Court of Appeal [10] overturned the Judge’s insufficiency finding, stating that Biogen was limited to the form of claim in that case. When a product is new and inventive, the technical contribution is the product, and not the process by which it is made, even if that process is the only inventive step. This point was appealed to the House of Lords.
In the House of Lords [11], the Lordships agreed with the Court of Appeal that the way in which the Judge had applied Biogen went beyond that which was intended – Biogen only applied to the very unusual type of claim in that case and not to a straightforward product claim.
Lundbeck’s patent for (+)-citalopram is valid.
The UK Intellectual Property Office granted a Supplementary Protection Certificate (‘SPC’) for escitalopram, so despite the racemate
being synthesized in 1972, no person other than Lundbeck can produce or market (+)- citalopram in the UK until May 2014. Clearly this raises policy issues. Should an obviously desirable product, resolved using known tools be entitled to such protection as to prevent others obtaining it in ways owing nothing to the “invention”?
Germany, April 2007 [12]
German case law states that a chiral compound is no longer novel in the form of one of its enantiomers if the skilled person’s attention is concretely drawn in a prior publication to the enantiomer and if said person can prepare the compound by virtue of this concrete instruction and his general expert knowledge. The single enantiomer does not have to have been prepared before the priority date [13]. Obtaining the single enantiomer from an already known mixture of enantiomers is not questioned by the fact that its isolation involves a number of complicated ideas and analyses. If these are routine measures, standard for the skilled person, attributed to his average expert skill and do not require undue efforts of an inventive quality, the single enantiomer is regarded as readily accessible.
The German court considered that even if the common method of forming diastereomeric salts with a chiral acid is inadequate for resolution, the skilled person would employ the chiral chromatography method known to him and established pre- priority. Wainer [14] was referred to for commercially available CSPs which the skilled person would use at the priority date. The ability to obtain (+)-citalopram was further evidenced by later published documents reporting chiral separation of citalopram. (Haupt [15], Rochat [16]).
In contrast to the UK, the German court held that analytical amounts were sufficient. The testing of commercially available CSPs, including selecting the appropriate parameters, was not considered
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