INNsight articles by Duncan Curley

Patent claims to enantiomers form one of the bulwarks of the research-based industry’s life cycle management techniques.  A notorious example is citalopram, first marketed by the Danish company Lundbeck as an antidepressant in 1989.  The optically active enantiomer, (+) citalopram or escitalopram, was launched as a new product in 2002.  Escitalopram (marketed in the UK as Cipralex®) is presently the world’s top selling branded anti-depressant (in volume terms) and it is well known that the turnover of Lundbeck (and its US licensee, Forest Laboratories) depends heavily on this single product. 

Given the size of the market, it is perhaps not surprising that the molecule has attracted a great deal of interest from a number of generic companies.  On 4 May 2007, Mr Justice Kitchin handed down a judgment of the UK Patents Court on the escitalopram enantiomer patent: European Patent (UK) No. 0,347,066.  The validity of this patent was challenged by three generic companies: Generics [UK], Arrow Generics and Teva.  Over two hard-fought weeks in court, the Judge had to referee a contest involving three expert witnesses from each side and evidence from Lundbeck on the commercial success of the product.  Three separate grounds of challenge to the patent’s validity were made: lack of novelty, lack of inventive step (obviousness) and insufficiency. 

In relation to novelty, it was accepted that the two pieces of prior art cited by the generic companies disclosed the citalopram racemate, but neither piece of prior art disclosed the active (+) enantiomer.  The generic companies argued that the main claim of Lundbeck’s enantiomer patent extended to the (+) enantiomer, when present in the racemate.  Lundbeck said that the main claim of the enantiomer patent was limited to the isolated, pure (+) enantiomer.  The Judge agreed with Lundbeck’s interpretation.  Reading the claim in the context of the patent specification as a whole, through the eyes of the skilled person, the Judge held that the invention was directed to the isolation of the individual enantiomers of citalopram and the use of the isolated (+) enantiomer to make a pharmaceutical composition.  The attack based on lack of novelty therefore failed. 

The main battleground in the case was obviousness.  The generic companies put forward two arguments.  First, it was obvious to separate the enantiomers of citalopram using chiral HPLC and to use the pure material obtained after chiral chromatography to make a pharmaceutical composition (the “chiral HPLC” case).  Second, it was obvious to try and produce a pharmaceutical composition containing escitalopram by the synthetic method described in Lundbeck’s enantiomer patent. 

The Judge rehearsed the UK court’s structured approach to the assessment of inventive step.  The UK test for obviousness is generally thought to be one of the most liberal and least subjective.  It can of course be easy to say that an invention is obvious after the event, when one knows what the invention is.  The UK court deals with this by adopting a highly structured approach that requires the court: (i) to identify the inventive concept of the claim (ii) to assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and impute to him what was, at that date, common general knowledge in the art (iii) to identify the differences between the prior art under consideration and that in the inventive concept of the claim (iv) to ask whether the differences would have been obvious or whether they required invention. 

There was a major dispute between the parties about whether it was common knowledge by June 1988 (the priority date) that the biological activity of enantiomers was likely to be different and that it would desirable to resolve a racemate in order to find out the properties of the individual optical isomers.  The generic companies said it was, Lundbeck said not.  The Judge found that any medicinal chemist in 1988 would have appreciated that the enantiomers of citalopram might well have different activities.  Furthermore, an inactive enantiomer was, at best, “ballast” but it might be toxic or have some other negative effect.  In conclusion, investigation of the enantiomers of citalopram was an obvious goal for the ordinary skilled medicinal chemist in 1988.  Yet this was not enough to prove the generic companies’ case on obviousness, because their arguments were premised on the basis either that it was obvious to separate the enantiomers using chiral HPLC or that it was obvious to try the particular chiral synthesis claimed in the patent. 

Having noted that neither of the cited prior art documents described any method for obtaining single enantiomers of citalopram, the Judge then dealt with the generic companies two arguments.  First, in relation to the chiral HPLC case, it was found that at the priority date, chiral HPLC was a preparative technique that was in its infancy.  It was not something that was within the common general knowledge of the skilled person.  After “some hesitation”, the Judge concluded that it was not obvious to resolve citalopram on a preparative scale using chiral HPLC in 1988.  Second, in relation to the “obvious to try” case, the Judge concluded that the synthetic reaction schemes described in Lundbeck’s enantiomer patent would not have been obvious in 1988.  The latter conclusion was supported by evidence from Lundbeck as to their protracted efforts to obtain optically pure (+) citalopram in their research laboratories. 

Lundbeck also relied upon the success of escitalopram as a commercial drug product in order to support their case on inventiveness.  A case on commercial success requires there to be a “long felt want”, i.e. a known problem in need of a solution.  The invention has to have achieved a striking commercial success and the claimed monopoly must be limited to the specific product that has the qualities that have given rise to the success.  The worldwide sales of escitalopram demonstrated that the product had indeed been a great commercial success, but the Judge was not satisfied as to the reasons for this.  Was the success of escitalopram due to the invention or other factors, such as advertising and promotion?  The position was doubtful and so the commercial success of the drug was not taken into account in assessing obviousness. 

The generic companies’ last chance to knock out the patent was therefore insufficiency.  On the face of it, the argument did not look promising.  There were no technical deficiencies in the description or in the claim language that made the monopoly uncertain.  It seemed that the invention had been clearly and completely described for it to be performed by the person skilled in the art (as required for sufficiency).  The generic companies’ argument on insufficiency was based on a ruling from the House of Lords in a biotech case from 20 years ago, Biogen v Medeva.  It went as follows: citalopram was an obvious target for resolution into its enantiomers.  If Lundbeck had in fact made a technical contribution to the art of any kind, then their contribution was the method that they had invented of resolving the racemate into its two enantiomers.  Yet the claims were directed to the enantiomer - (+) citalopram - whether obtained using Lundbeck’s synthetic route or by any other means.  The claims were therefore too broad.  In a surprising twist at the end of his judgment, the Judge concluded that this argument was sound and that the product claims to (+) citalopram were insufficient and therefore invalid.  The other main independent claim to the synthetic route for the preparation of the pure (+) enantiomer was held valid. 

Given what is at stake, it seems inevitable that there will be an appeal by Lundbeck to the Court of Appeal.  There will be risks to both sides on appeal.  From the innovator’s perspective, Lundbeck may have to work hard to preserve the Judge’s findings on inventive step and obviousness, although the Judge was careful to base his conclusions on his assessment of the expert evidence.  This may deter the Court of Appeal from interfering with the Judge’s conclusions on obviousness, since appellate judges rarely overturn the assessment of the evidence carried out by the first instance court.  The finding on insufficiency is also likely to be subjected to a serious challenge on appeal, since it is rare for the Biogen principle to be invoked successfully in a chemical case, as opposed to a biotech case.  It will be fascinating to see how the Court of Appeal deals with the somewhat unconventional conclusions in the judgment on this important blockbuster product.