Hospira UK Ltd v Cubist Pharmaceuticals LLC
| Jurisdiction | England & Wales |
| Judge | Lord Justice Lewison,Lord Justice Kitchin |
| Judgment Date | 18 January 2018 |
| Neutral Citation | [2018] EWCA Civ 12 |
| Court | Court of Appeal (Civil Division) |
| Docket Number | Case No: A3 2016 4260 |
| Date | 18 January 2018 |
[2018] EWCA Civ 12
IN THE COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM THE HIGH COURT, CHANCERY DIVISION
PATENTS COURT
MR JUSTICE HENRY CARR
Royal Courts of Justice
Strand, London, WC2A 2LL
Lord Justice Lewison
and
Lord Justice Kitchin
Case No: A3 2016 4260
Thomas Hinchliffe QC and Stuart Baran (instructed by Carpmaels & Ransford LLP) for the Appellant
Richard Meade QC and Isabel Jamal (instructed by Taylor Wessing LLP) for the Respondent
Hearing dates: 12 December 2017
Judgment Approved
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 proprietor of the patent, Cubist Pharmaceuticals LLC (“Cubist”), now appeals against that decision and order.
Daptomycin is a useful and commercially successful antibiotic. It is effective against certain Gram-positive bacteria which can cause serious infections, including MRSA-borne endocarditis. It was originally developed by Eli Lilly (“Lilly”) but was abandoned, at least in part because of the limitations of the purification process that Lilly was using. The purity of a compound is clearly of great importance if it is to be administered to humans as a medicine and Lilly thought that daptomycin could only be produced with a purity of 90–93% and at a relatively low yield.
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. Before explaining how this process works and why the judge found it to be obvious, I must say a little about the technical background.
Daptomycin is a surfactant, that is to say a compound that tends to lower the surface tension between two liquids or between a liquid and a solid. A biological surfactant is called a biosurfactant. Each molecule of a surfactant has a characteristic structure with a lyophilic (solvent loving) and a lyophobic (solvent hating) part. When such molecules are present in a solvent at a sufficient concentration (called the critical micelle concentration or CMC) they gather together with their lyophobic parts facing inwards and their lyophilic parts facing outwards in such a way as to form spherical aggregates or micelles. The judge illustrated this with a diagram which I reproduce below:
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 might be affected by altering the temperature or by adding solvent or electrolyte. There was a dispute as to whether manipulating pH was also a well-known way of influencing micelle formation. 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.
Daptomycin is also a lipopeptide. Lipopeptides are molecules consisting of a lipid (such as a fat) connected to a peptide (a short chain of amino acids). The peptide portion is hydrophilic and the lipid portion is hydrophobic. The judge found that it was widely known that lipopeptides as a class were biosurfactants although he also accepted that the skilled person could not be certain that any individual lipopeptide was a surfactant without testing it.
There were various standard tests at the priority date to determine whether a molecule was a surfactant. Each was easy to perform. One was the “shake test”. A surfactant will produce a stable foam on shaking, whereas a non-surfactant will either not produce a foam, or will produce a transient foam that quickly disappears. Another was described by Professor Myerson, the expert witness for Cubist. He said that his preferred approach was to measure the CMC of a fluid by electrical conductivity, and this would at the same time establish whether it was a surfactant. Both of these tests were common general knowledge at the priority date and could be performed simply in any reasonably equipped laboratory.
There was a dispute as to whether it was common general knowledge that daptomycin was a surfactant. It was known to be a lipopeptide, it has a hydrophilic head and a hydrophobic tail and Dr Baker, the expert witness for the claimant (“Hospira”), said it has a primary structure which is and was even more suggestive of it being a surfactant than that of a well-known biosurfactant called surfactin. The judge accepted this evidence. He found that the skilled team would not have been certain that daptomycin was a biosurfactant but, given its primary structure, they would have had a strong expectation that it was. This could have been confirmed by any of the simple tests.
I come next to the patent. 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. The judge fairly explained the process in these terms:
“350. … The daptomycin is first formed into micelles by lowering the pH. The solution is then passed through an ultrafiltration membrane. The daptomycin micelles are retained on the filter, but smaller impurities pass through. Then the daptomycin that was retained on the membrane has its pH adjusted upwards to pH 6.5, causing the daptomycin micelles to break apart. The solution is passed through another ultrafiltration step. This time, the daptomycin monomers are able to pass through the filter, but larger impurities are retained on the filter, thereby separating them from the daptomycin.”
Claim 1, the only claim said to be independently valid, is as follows:
“1. A method for purifying daptomycin comprising:
(a) subjecting the daptomycin to conditions in which a daptomycin micellar solution is formed by altering the pH;
(b) separating the daptomycin micelles in the daptomycin micellar solution from low molecular weight contaminants by a size separation technique;
(c) subjecting the daptomycin to conditions in which a daptomycin monomeric solution is formed by altering the pH; and
(d) separating the monomeric daptomycin molecules in the daptomycin monomeric solution from high molecular weight molecules or aggregates by a size separation technique.”
The difficulty facing Cubist, however, was that the general idea of harnessing the ability to adjust the CMC of a surfactant solution in a process of purification had already been disclosed in Lin and Jiang, although the surfactant being purified there was surfactin and the adjustment of the CMC was achieved by adding methanol. The judge summarised the disclosure in this way:
“354. Lin & Jiang describe a process for purifying surfactin …. First, they formed micelles and removed certain low molecular weight impurities via ultrafiltration. Lin & Jiang then removed high molecular weight impurities that were retained on the ultrafiltration membrane together with the surfactin micelles by adding methanol to the ultrafiltration membrane to break the micelles into monomers, such that the monomeric surfactin passed through the filter, while the high molecular weight impurities were retained on the filter.
Lin and Jiang concludes with this more general teaching:
“This process can be further modified and employed for the recovery and purification of most surfactants from aqueous solutions at concentrations above the critical micelle concentration.”
The judge identified the differences between claim 1 of the patent and Lin and Jiang entirely correctly as being first, that Lin and Jiang is concerned with the purification of surfactin rather than daptomycin and secondly, that Lin and Jiang uses the addition of methanol rather than the alteration of pH to adjust the CMC and so dissociate the micelles in its second step.
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.
The judge concluded that claim 1 was obvious in the light of Lin and Jiang. His reasoning ran as follows. First, although Lin and Jiang describes a method of purifying surfactin, the skilled team would have appreciated that this method could be used more generally. Indeed, the authors expressly state that their method can be modified and...
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