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.

Anticipating something new in Germany

Authors: Christopher Hayes and Jens Toftelund Madsen (H Lundbeck A/S, Copenhagen, Denmark)

Eli Lilly & Co v (1) Egis Gyogysergya Rt; (2) Neolab Ltd and interveners (i) Stada Arzneimittel AG; (ii) ratiopharm GmbH; (iii) Hexal AG; (iv) Sandoz Pharmaceuticals GmbH. X ZR 89/047 December 16 2008

he Xth Senate of the German Supreme Court (Bundesgerichtshof) has allowed an appeal against the decision of the 3rd Senate of the Federal Patent Court (Bundespatentgericht) which rendered Eli Lilly's patent for the pharmaceutical compound olanzapine null and void.

Legal context

The Bundespatentgericht (BPatG) had interpreted previous case law as having established the principle that a disclosure of a general chemical formula of a genus of chemical compounds is a disclosure of all members of that genus even where all members have not been expressly described. Therefore, if the compound could be made without effort, such a disclosure was novelty-destroying. In overturning the first instance decision, the Bundesgerichtshof (BGH) restated the principles of novelty in German patent law, bringing them firmly back into line with the jurisprudence of the European Patent Office (EPO) and its contracting member states.

The following key points should be noted:

* The BGH has overruled previous case law regarding novelty and anticipation.
* With regard to chemical compounds, for a publication to be a novelty-destroying anticipation it must clearly and expressly disclose the compound in question.
* This decision incorporates the EPO's ‘photographic’ approach to novelty into German patent law.
* This decision harmonizes the EPO's approach with Germany and demonstrates the uniformity of outcome when applied in Germany and the UK.

Facts

Eli Lilly is the proprietor of European Patent 454,436, which claims the chemical compound the generic name of which is olanzapine, a schizophrenia treatment marketed by Eli Lilly under the brand name Zyprexa®. Using the problem-solution approach, the problem is defined as obtaining an antipsychotic medication with a reduced propensity for extra-pyramidal side effects; olanzapine was the solution to this problem in the patent in suit.

Analysis

First instance decision

The validity of the olanzapine patent was successfully challenged before the Bundespatentgericht (BPatG, 4 June 3Ni21/04 (EU)). The BPatG accepted that the patent in suit was anticipated by the prior publication of a scientific paper by Chakrabati.

Chakrabati contained a general chemical formula, akin to a so-called Markush formula, and which contained olanzapine. There was no express disclosure of olanzapine by Chakrabati, nor was there an indication that the authors had made or tested olanzapine in their scientific model.

In reaching its decision, the BPatG applied earlier decisions of the BGH, notably Fluoran (BGHZ 103, 150) and Elektrische Steckverbindung (Electrical Plug Connection) (BGHZ 128, 270 Elektrische Steckverbindung), to reach the conclusion that Chakrabati was a novelty-destroying disclosure. This was because a person skilled in the art starting from the general formula could work out each compound contained within the formula and therefore could conceptualize olanzapine.

The BPatG went further: based on Chakrabati, it would have been obvious for the person skilled in the art to make olanzapine. There were methods disclosed in Chakrabati which could have been used to deliver olanzapine to the person skilled in the art. In effect, the BPatG's reasoning was that a person skilled in the art could fill in the gaps in Chakrabati from the specific compounds and methods disclosed in the publication to produce olanzapine. The same logic was applied to a number of prior art publications which also disclosed Markush formulae, which were even broader in scope than Chakrabati. The BPatG therefore held that these were also novel-destroying anticipations.

Decision of the Bundesgerichtshof on novelty

The BGH looked at the alleged Chakrabati anticipation in detail. In Chakrabati, several compounds of the genus were expressly described, although olanzapine itself was not. The BPatG held that the skilled reader would be able to fill in the missing pieces from Chakrabati using his own technical knowledge would therefore be led to olanzapine.

The BGH stated that in determining whether a publication was novelty-destroying, the Court should not undertake a process whereby the skilled addressee's technical knowledge could be used to work the invention. Rather, it must determine what is ‘directly and clearly’ derived from the publication.

At paragraph 26, the BGH explains this, pointing out that it is acceptable to read the claims and specification and to include those pieces of knowledge so plainly evident to the skilled reader or absolutely necessary to make the invention work, should not be construed as supplementing the requirements for anticipation. Indeed, the BGH states that Electrical Plug Connection lays down the principle that the modifications were so obvious to the skilled reader that he reads the publication essentially almost along with his own thoughts, even if he is unaware that he is doing this. Therefore, for the purposes of determining whether an anticipation is detrimental to novelty, it is not permissible to supplement the publication further.

The BGH then turned to Fluoran, which the lower Court had interpreted as stating a principle that, in a genus patent, all members of that genus are disclosed, whether expressly described or not. This, the BGH held, was not a correct statement of the law. Further, in distinguishing Fluoran, the BGH noted at paragraph 28 that Fluoran was issued under the 1968 Patent Act, the appeal being only on a point of law, and the Senate held that it was bound by the factual findings of the BPatG. In summary, the deciding factor was whether there was a concrete disclosure of the specific compound.

Simply because someone of skill had the ability to make a greater or lesser number of the compounds disclosed by a general formula did not, for the purposes of the evaluation of novelty, equate to a specific disclosure of all compounds covered by the general formula. To be considered a valid anticipation, the specific compound must be disclosed. To the extent that the Fluoran case purported to lay down a different principle, the BGH stated that this did not represent the law of novelty in German patent law.

Applying this reasoning also to UK patent 1,533,235, which did not expressly describe olanzapine, the BGH held that this patent, or patents derived from this priority application, nor the publication by Schauza & Mager did not constitute a specific disclosure of olanzapine, and hence could not form a novelty-destroying anticipation.

Decision of the Bundesgerichtshof on inventive step

A further publication by Chakrabati (Schauza & Mager Pharmazie (1983) 38) also describes a structure–activity relationship analysis of various compounds, in order to aid in the development of an antipsychotic with a lower propensity for extrapyramidal side effects. Some compounds showed promise under this paradigm, and warranted further study. Since olanzapine was not one of the compounds reported, there was nothing presented in Chakrabati that would make the choice of olanzapine an obvious choice for further analysis.

While acknowledging that the subgroup of compounds to which olanzapine belonged appeared to have the greater potential for further development, the BGH stated that this was not in and of itself obvious to the skilled reader, who would not discount other subgroups of compounds for further testing from the outset without testing them further.

The choice of synthesizing this subgroup of compounds would have been obvious to a person skilled in the art only if he had a reason to synthesize them in the first place. No such rationale was held to be provided in the prior art. The validity of the inventive step contained within the patent in suit was therefore also upheld.

Harmonisation with EPO law

In reaching its decision, the BGH has importantly stated that there is no divergence between German national and EPO jurisprudence on this point regarding novelty in patent law. At paragraph 29, the BGH states that the jurisprudence of the German courts is aligned with that of the EPO and that, according to EPO case law, a ‘photographic’ disclosure is required to be potentially novelty-destroying.

Comparison with the UK olanzapine decision

In the corresponding UK case on olanzapine (Dr Reddy's Laboratories (UK) Ltd v Eli Lilly & Company Ltd [2008] EWHC 2345 (Pat)), Floyd J reached the same conclusion regarding novelty and inventive step, upholding the validity of the olanzapine patent. At paragraph 29, the BGH made reference to the analogous litigation in the UK, stating that the German law of novelty was in line with the EPO jurisprudence and that the EPO approach was also being implemented in the UK. Using this harmonized approach, the BGH and the High Court in the UK reached the same conclusion regarding this patent, with both courts citing the same EPO decisions as the foundation for their reasoning.

Practical significance

As a result of the strict interpretation and application of Fluoran in Germany, the German patent courts had been viewed by innovator companies as being quite anti-patent and markedly divergent from the jurisprudence of the EPO regarding novelty of chemical compounds. This decision of the highest national court in Germany restates the law of novelty in German patent law.

This decision brings the determination of novelty under German case law firmly into line with the EPO, and with contracting member states such as the UK. From the point of view of innovator companies (and their competitors), this decision brings clarity and certainty that compounds previously disclosed in a Markush formula will be viewed in the same way in Germany as in other EPO member states. Thus, the novelty of such compounds is not destroyed by the mere disclosure of the Markush formula in an earlier publication.

While there will invariably be the occasional debate within society as to where the threshold for novelty should be set for patentable inventions, it should be accepted that, wherever this level is placed, it is desirable that it be consistent. Different jurisdictions should not have different novelty requirements; particularly if they are contracting states to the European Patent Convention, since national laws should be interpreted in an analogous manner.

At first glance, the main consequence of this decision appears to lower the bar for novelty in Germany, which will be welcomed by innovator companies. The significance of this decision has much wider ramifications. As noted above, this decision brings this aspect of German patent law into harmony with the EPO, and the jurisprudence of other contracting member states.

Regardless of where along the spectrum the threshold for novelty is set, it should be consistently applied both within the jurisdiction and across jurisdictions, particularly as the vast majority of patent litigation is multi-jurisdictional in nature. This decision therefore should be welcomed as it brings clarity and certainty with regard to patents for chemical compounds previously disclosed in a Markush formula or contained within a general chemical formula.