Daptomycin - UK

On Jan 17, 2018 UK court of appeal handed down its decision in Daptomycin case & affirmed the patent court’s decision of finding claimed invention obvious.

This appeal concerns a method of purification of the antibiotic daptomycin. Although at trial the judge, Henry Carr J, was concerned with multiple issues on several patents, the sole issue on this appeal is whether the method claimed in European Patent (UK) 2,264,047 ("the patent") is obvious over an article in the journal Biotechnology Techniques by Sung-Chyr Lin and Horng-Jyh Jiang entitled "Recovery and Purification of the lipopeptide biosurfactant of Bacillus subtilis by ultrafiltration" ("Lin and Jiang"). In his decision dated 10 June 2016 the judge held that the patent was invalid and on 17 October 2016 he made an order for its revocation. The judge found that the skilled team would have known that the formation of micelles was dependent upon a number of factors and that the CMC (critical micelle concentration) might be affected by altering the temperature or by adding solvent or electrolyte. In the end both experts gave evidence to the effect that the CMC could be adjusted by altering the pH and the judge found that it was routine to investigate how changes in pH affected the stability of a solution of a surfactant and the CMC. The proprietor of the patent, Cubist Pharmaceuticals LLC ("Cubist") appealed against that decision and order.

The patent describes a new way to purify daptomycin which relies upon the ability of daptomycin molecules under particular conditions to form into structures called micelles and then, under different conditions, to dissociate. This permits the use of a two stage purification process in which impurities, whether smaller or larger than the daptomycin molecules, are removed. The specification explains that the invention relates to a process for preparing a highly purified form of daptomycin which involves altering the pH of a daptomycin solution to change its CMC. Hospira contended that it would have been perfectly obvious to the skilled team that the purification method described in Lin and Jiang could be used for the purification of daptomycin, and it would have been an entirely routine matter for the team to use the alteration of pH rather than the addition of methanol to adjust the CMC. Cubist responded that it would not have been obvious to the skilled team that the Lin and Jiang method could be applied successfully to the purification of daptomycin because the team would not have expected the method to remove pyrogens, an impurity associated with daptomycin; the team would not have thought it likely that daptomycin was a surfactant which would form micelles; and it would not have been obvious to the team to use pH instead of methanol to adjust the CMC.

During appeal Cubist contended that the trial  judge was not entitled to find that the skilled team would have had a real expectation that daptomycin was likely to be a surfactant which would form micelles, or that the team would have been able to confirm that by straightforward routine testing. Court of appeal affirmed lower judge’s finding & said that the skilled team would have had a real expectation that daptomycin was likely to be a surfactant in view of “shake test”. As a surfactant, it would form micelles under appropriate conditions. Also “electrical conductivity test” would also have confirmed that daptomycin was a surfactant. In this test the change in conductivity of a solution of a material is measured as the concentration of the solution is increased (or another relevant condition such as pH is changed), and the CMC is identified by an inflection in the curve.

On the issue of micelle formation by pH adjustment, Cubist contended that the judge made two errors in reaching his conclusion that the skilled person would replace the methanol used to control micelle formation and dissociation in the process of Lin and Jiang with pH adjustment, namely (a) that he wrongly concluded that pH adjustment was a common general knowledge technique for altering the CMC of a surfactant; and (b) that he failed to consider whether the skilled person would have had the required fair expectation of success that pH adjustment would work as a way of adjusting the CMC. Court of appeal again sided with trial judge on this issue & held that “there can be no doubt that the judge was aware that expectation of success may be a relevant matter to consider in assessing whether an invention was obvious. He expressly directed himself that where it is alleged that a step is obvious to try, the question is whether the skilled person would do so with a fair expectation of success, and that what amounts to a fair expectation of success will depend upon all of the circumstances of the case. Here he carried out his evaluation having regard to all of the evidence before him and all of the material circumstances”.

Finally court of appeal held that claimed invention was obvious in the light of Lin and Jiang and that trial judge’s finding was properly reasoned & he made no error of principle. Thus the appeal was dismissed.