Enantiomers are obvious even though they have unpredictable properties

Author: Suleman Ali (Holly IP, London)

Novartis AG v Generics (UK) Limited (t/a Mylan) [2012] EWCA Civ 1623, Court of Appeal for England and Wales, 12 December 2012

Journal of Intellectual Property Law & Practice (2013), doi: 10.1093/jiplp/jpt049, first published online: April 14, 2013

The Court of Appeal has upheld the finding of the High Court that an enantiomer and its use in therapy were obvious from disclosure of the racemate mixture, given that at the priority date it was standard practice in the art to resolve racemate mixtures and there was no difficulty in doing so.

Legal context

This case concerns inventive step of an enantiomer which has been resolved from a racemate mixture. Previously in H Lundbeck A/S v Generics (UK) Ltd [2008] EWCA Civ 311 and Generics (UK) Ltd v Daiichi Pharmaceutical [2009] EWCA Civ 646 the courts decided that enantiomers which had been resolved from racemate mixtures were inventive, essentially based on the difficulty of obtaining the relevant enantiomer. However, in the present case there was no difficulty in resolving the enantiomer at the priority date, and so the previous cases on enantiomers were not considered relevant. Instead the court assessed inventive step based on the criteria developed in case law for assessing inventive step of a new therapeutic molecule.

Inventive step in chemical and pharmaceutical cases will often depend on the route used to identify and characterize the relevant substance. It is also dependent on the properties the substance is found to have, though arguably the UK approach places less emphasis on this than the European Patent Office problem–solution approach to inventive step. The courts have recognized the difficulty in deriving a specific test for inventive step where the invention concerns substances that have been identified based on a series of tests in a research program, especially where the results of the tests are unpredictable. When faced with inventions where a specific substance is provided for a given use, the courts have tended to assess whether it was ‘obvious to try’ that specific substance, with ‘expectation of success’ sometimes also contributing to the analysis. The present state of the case law is expressed in the following passage from Generics (IK) Ltd v H Lundbeck A/S [2007] EWHC 1040 (Pat) which is quoted in the present judgment:

The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort in pursuing them and the expectation of success.

Facts

This is an appeal from a High Court decision in which Novartis's SPC certificate SPC/GB98/038 and the basis patent, UK Patent No 2,203,040, were found to be invalid due to lack of inventive step. The claims of the patent cover rivastigmine and its use in the treatment of Alzheimer's disease. Rivastigmine is one of the enantiomers of a compound that occurs in chiral forms, ie the compound has two distinct forms (called ‘enantiomers’) which are mirror images of each other. When such chiral compounds are first synthesized it is usually as a mixture of the two mirror forms and such mixtures are called ‘racemates’. At the priority date the racemate form of the compound was known and its use to treat Alzheimer's had been suggested. Thus the contribution made by the invention could on the face of it be seen simply as resolving the racemate to separate the chiral forms before using one of them, rivastigmine, in therapy. However, Novartis argued that selection of the racemate compound from the prior art was also an important part of the contribution.

At the priority date (4 March 1987) the resolving of racemic mixtures into enantiomers was common practice in the art and in the present case there was no difficulty in doing so. Novartis argued that the disclosure of the racemate in the prior art was in the context of a very early stage in the research, and at that stage the skilled person would not have chosen to resolve the racemate into enantiomers. Instead they would have investigated other compounds with similar structures and so it was not obvious to choose this particular racemate. Novartis further argued that extensive testing of the compound would still need to be done to determine whether it would be suitable for therapy, and there would not have been a fair expectation of the compound surviving such testing. In terms of the enantiomer itself, Novartis argued that the resolution of the racemate could not be deemed to be obvious because the properties of the enantiomers could not be predicted.

Analysis

In the judgment, Justice Kitchin discusses the relevant case law on how to approach inventive step for a therapeutic substance, and in particular discusses whether to apply a simple ‘was it obvious to try?’ approach to the steps of choosing the racemate compound and then choosing to resolve it into enantiomers. He also discusses how to consider the ‘degree of expectation of success’ that is required, but in line with the case law decides to reject using any particular test saying that ‘obvious to try’ and ‘fair expectation of success’ are not the same as the statutory question of whether the invention was obvious. He thus decides that it is more appropriate to judge obviousness based on the facts. However, his subsequent analysis of inventive step essentially amounts to an ‘obvious to try’ approach, at least in as far as selection of the racemate compound is concerned.

When looking at whether the skilled person would focus on the racemate compound, Mr Justice Kitchin's position was that the possibility of investigating other compounds did not preclude further testing of the racemate compound, which was presented as promising candidate in the prior art. When assessing the decision to resolve the racemate into enantiomers, he acknowledged that the properties of rivastigmine were not predictable, but that in itself did not make it inventive since the ‘experimentation is driven by rational technical considerations’. Further, there were good reasons for resolving the racemate into enantiomers since there was the possibility that one of them may have lower toxicity.

Novartis also ran the argument that the High Court had chosen the wrong technical effect when considering the problem–solution approach. In its view it was wrong to see the technical effect as what ‘one would expect from resolution of a chiral compound’. Instead it was use of rivastigmine for treatment of Alzheimer's disease. Mr Justice Kitchin dealt with this very briefly, essentially believing that this point added little to the previous arguments.

Practical significance

Given the facts of the case it is difficult to see how the court could have come to any other conclusion. However, taking the approach of deciding obviousness on the basis of ‘the facts of each case’ will inevitably lead to more uncertainty. In particular it is not clear when ‘fair expectation of success’ should form part of the assessment of inventive step, and for many chemical and pharmaceutical cases that will be the determining factor. Mr Justice Kitchin did not explain in his judgment why he did not consider ‘expectation of success’ when assessing choice of the racemate compound.

Clearly the judgment will have an impact on inventions concerning resolution of enantiomers, making it less likely that mere resolution of a racemate into enantiomers will be considered inventive if there are no difficulties in doing so. In particular it seems that inventive step arguments based on the advantageous properties of the resultant enantiomers will not succeed if the advantages are of the type that enantiomers could be expected to have, even though which advantage a specific enantiomer would have could not be predicted.