The UK High Court has recently handed down a further decision relating to the validity of pharmaceutical combination patents. In the decision, Glenmark Generics (Europe) Limited & Others v The Wellcome Foundation Limited & Glaxo group Ltd, Arnold J revoked European patent (UK) No. 0670719 for obviousness. This article briefly summarises the facts of the case and considers its implications in the context of earlier related UK case law.
European patent (UK) No. 0670719 (the Patent) claimed a combination of the known anti-malarial drugs atovaquone and proguanil in a ratio of 5:2 and a pharmaceutical composition comprising the combination. The Patent provided protection for the marketed pharmaceutical product Malarone® (GlaxoSmithKline), the most successful anti-malarial prophylactic drug in the UK.
Two pieces of prior art were considered to be of most relevance to the validity of the Patent. These were a prior published abstract and a presentation, both of which disclosed data showing promising early results for clinical trials of an atovaquone/proguanil combination. No specific advantages were shown to be associated with the 5:2 ratio of drugs recited in the Patent claims. Thus, the question of validity hinged on whether it would have been obvious to combine the two drugs into a pharmaceutical composition having regard for the earlier reported clinical trials.
In this case, the "person skilled in the art" for the purpose of assessing obviousness, was held to be a team consisting of a clinician experienced in treating malaria, a clinical pharmacologist and a malaria biologist. The question to be decided was whether such a team would, on the basis of the prior published information concerning the antimalarial activity of atovaquone administered in combination with proguanil, have proceeded to develop a pharmaceutical combination containing the two drugs.
The 5:2 ratio of drugs recited in the claims was found to be of no technical significance. Therefore, although this feature was capable of rendering the claimed subject matter novel, it was irrelevant for the assessment of obviousness.
The submissions of the defendant that it would
not have been obvious to develop an atovaquone/proguanil combination were rejected by the Court for various reasons, most notably:
- The defendants had argued that if the therapeutic efficacy of the claimed combination was merely "additive" in nature (i.e. not synergistic), it would have been an irrational combination for further development. This argument was rejected as it was considered that there would be genuine reasons why a skilled team would further research a combination of drugs other than to find a synergistic combination.
- There was a dispute between the parties whether the data in the prior art presentation demonstrated synergism for an atovaquone/proguanil combination. On the evidence available, it was held that even though there was no explicit disclosure of "synergy" in the prior art, the skilled team would understand that synergy had been demonstrated in vitro and that the in vivo results showed some evidence of synergy. The Court held that the in vitro data was of sufficient promise that it would have motivated the skilled team to conduct in vivo trials.
- The defendant argued that the clinical trial results reported in the prior art presentation were conducted on a small, uncontrolled subject group and were incomplete. It was asserted that these limitations would discourage the skilled team from seeking to develop the claimed combination. This submission was rejected as it was considered that the skilled team would still form the view from the data set presented that the combination showed therapeutic promise.
- Various additional reasons were put forward by the defendant as to why it would have been difficult to further investigate the claimed combination and why the skilled person would not select the combination for development. These were rejected as mainly being commercial considerations for a large pharmaceutical company that were not relevant to the assessment of obviousness. It was considered technically straightforward to further investigate and trial the claimed drug combination and the evidence relied upon would provide the skilled team with the motivation to do so.
In conclusion, the claims of the Patent were found to be obvious because the skilled team would have concluded that the results of the prior art presentation were significant enough for a second phase clinical trial to be carried out. Conducting such a trial would have confirmed the synergistic antimalarial activity of the claimed combination, and the determination of optimum ratios of the two drugs for incorporation into a pharmaceutical composition. The Patent was therefore revoked in its entirety.
This decision is another example where a patent covering a commercially important pharmaceutical combination product has been found invalid by the UK High Court. Previously, UK Patent No. 2,235,627 which claimed a pharmaceutical composition comprising salmeterol and fluticasone propionate (the active ingredients of the respiratory product Seretide®) was also found to be invalid on the ground of obviousness. In that instance, the Court was particularly critical of technical data (not present in the application as filed) that was relied upon to support a purported unexpected technical effect (synergy) for the claimed combination of actives.
It will be interesting to see to what extent, if any, this case affects future decisions relating to the obviousness of pharmaceutical combination patents in the UK. In this instance, the fact that the prior published clinical data indicated a synergistic effect for the claimed combination appeared to be crucial to the outcome of the case. It remains to be seen whether a similar finding of obviousness would arise in a situation where there was no indication of synergy reported in the prior art, but where technical data to support a synergistic effect was disclosed in the patent application as filed.
Patents directed to combination products often provide valuable commercial protection for pharmaceutical companies upon expiry of any patent(s) relating to the individual active ingredients. The apparent vulnerability of such patents to attack on the ground of obviousness in the UK may, undesirably, act as a future disincentive for the development of new medicines based upon combinations of known drugs.
The full text of the UK High Court decision discussed in this article can be downloaded free of charge from the BAILLI website (http://www.bailii.org/).