Obviousness - Hospira v Cubist Appeal

Skeletal Formula of Daptomycin
Author Fvasconcellos
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Court of Appeal (Lord Justices Lewison and Kitchin) Hospira UK Ltd v Cubist Pharmaceuticals LLC [2018] EWCA Civ 12 (18 Jan 2018)

Daptomycin is an antibiotic used to treat systemic and life-threatening infections caused by multiple drug resistant bacteria. Its effectiveness depends on its purity. The invention for which the patent in suit was  granted was a way of purifying the antibiotic. In Hospira UK Ltd v Cubist Pharmaceuticals LLC [2016] EWHC 1285 (Pat) (10 June 2016), Hospira UK Ltd, (a British subsidiary of Pfizer) sought the revocation of that patent.  Mr Justice Henry Carr found that the patent was invalid and ordered its revocation. Cubist Pharmaceuticals LLC (a subsidiary of Merck & Co.) appealed against that judgment and order in Hospira UK Ltd v Cubist Pharmaceuticals LLC [2018] EWCA Civ 12 (18 Jan 2018),

The Issue
The only issue in the appeal was whether the invention was obvious over an article by by Sung-Chyr Lin and Horng-Jyh Jiang entitled "Recovery and Purification of the lipopeptide biosurfactant of Bacillus subtilis by ultrafiltration" that had appeared in Biotechnology Techniques (Vol 11, No 6, June 1997, pp. 413–416, Springer Link).

The Patent
The invention relates to a process for preparing a highly purified form of daptomycin.

The process relies upon a tendency of daptomycin molecules to form spherical structures called micelles under certain conditions.  The process works as follows.  Daptomycin molecules in solution are formed into micelles which are relatively large structures. The solution is passed through an ultra-filtration membrane which catches the micelles and larger impurities but allows impurities that are smaller than the micelles to flow through.  The micelles are then disassembled into their component molecules. A solution of the disassembled daptomycin and any remaining impurities are passed through another membrane. This time the daptomycin flows through but the impurities are trapped.

The process depends on creating the conditions for inducing the formation and disassembly of micelles. Micelles are formed when a solution reaches a critical micelle concentration or "MCL". At trial, Mr Justice Henry Carr found that persons skilled in the art would have known that the MCL depends on a number of factors such as temperature, the concentration of solvent or electrolyte.  The invention involves altering the pH of a daptomycin solution to change its CMC.  

Mr Justice Henry Carr described the invention as follows at paragraph [350] of his judgment:

"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 of the patent was 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 Prior Art
In their article Lin and Jiang had already discussed the general idea of harnessing the ability to adjust the CMC of a surfactant solution in a process of purification though the surfactant in that case was surfactin and the adjustment of the CMC was achieved by adding methanol. Mr Justice Henry Carr identified the differences between claim 1 of the patent and the method disclosed in the article as: 
  • Lin and Jiang are concerned with the purification of surfactin rather than daptomycin; and
  • they used the addition of methanol rather than the alteration of pH to adjust the CMC.
The judge concluded that claim 1 was obvious in the light of Lin and Jiang.

The Law
In Medimmune Ltd v Novartis Pharmaceuticals UK Ltd and Others   [2012] EWCA Civ 1234, [2013] RPC 27. Lord Justice Kitchin had set out the relevant legal principles as follows:

"84. The starting point is that an invention must involve an inventive step, and it is to be taken to involve an inventive step if it is not obvious to a person skilled in the art having regard to matter which properly forms part of the state of the art at the priority date (sections 1(1) and 3 of the Patents Act 1977, corresponding to Articles 52 (1) and 56 of the European Patent Convention).
85. It is often convenient, but by no means essential, to consider an allegation of obviousness using the structured approach explained by this court in Pozzoli v BDMO SA [2007] EWCA Civ 588, [2007] FSR 37 at [23]:
'(1) (a)  Identify the notional 'person skilled in the art';
(b) Identify the relevant common general knowledge of that person;
(2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;
(3) Identify what, if any, differences exist between the matter cited as forming part of the 'state of the art' and the inventive concept of the claim or the claim as construed;
(4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?'
86. Step (2) may pose some problems. In some cases, as in this one, the parties agree what the inventive concept is. This has the advantage of limiting the obviousness analysis to the essence of the invention. But often the parties do not agree and in such cases it will usually be a futile exercise for the court to seek to resolve their disagreement, for ultimately all that matters is what the patentee has claimed. As Lord Hoffmann said in Conor v Angiotech [2008] UKHL 49, [2008] RPC 716 at [19]:
'… the patentee is entitled to have the question of obviousness determined by reference to the claim and not to some vague paraphrase based upon the extent of his disclosure in the description.'
87. I would add, so too is the defendant. The patentee may have drawn his claim so broadly that it includes products or processes that owe nothing to the inventive contribution he has made, rendering the claim particularly vulnerable to an allegation of obviousness.
88. Step (3) presents little conceptual difficulty. It simply requires the court to identify the differences between the prior art and the claim.
89. It is step (4) which is key and requires the court to consider whether the claimed invention was obvious to the skilled but unimaginative addressee at the priority date. He is equipped with the common general knowledge; he is deemed to have read or listened to the prior disclosure properly and in that sense with interest; he has the prejudices, preferences and attitudes of those in the field; and he has no knowledge of the invention.
90. One of the matters which it may be appropriate to take into account is whether it was obvious to try a particular route to an improved product or process. There may be no certainty of success but the skilled person might nevertheless assess the prospects of success as being sufficient to warrant a trial. In some circumstances this may be sufficient to render an invention obvious. On the other hand, there are areas of technology such as pharmaceuticals and biotechnology which are heavily dependent on research, and where workers are faced with many possible avenues to explore but have little idea if any one of them will prove fruitful. Nevertheless they do pursue them in the hope that they will find new and useful products. They plainly would not carry out this work if the prospects of success were so low as not to make them worthwhile. But denial of patent protection in all such cases would act as a significant deterrent to research.
91 For these reasons, the judgments of the courts in England and Wales and of the Boards of Appeal of the EPO often reveal an enquiry by the tribunal into whether it was obvious to pursue a particular approach with a reasonable or fair expectation of success as opposed to a hope to succeed. Whether a route has a reasonable or fair prospect of success will depend upon all the circumstances including an ability rationally to predict a successful outcome, how long the project may take, the extent to which the field is unexplored, the complexity or otherwise of any necessary experiments, whether such experiments can be performed by routine means and whether the skilled person will have to make a series of correct decisions along the way. Lord Hoffmann summarised the position in this way in Conor at [42]:
'In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation's Patent [1967] RPC 479, by saying that the notion of something being obvious to try was useful only in a case where there was a fair expectation of success. How much of an expectation would be needed depended on the particular facts of the case.'
92. Moreover, whether a route is obvious to try is only one of many considerations which it may be appropriate for the court to take into account. In Generics (UK) Ltd v H Lundbeck, [2008] EWCA Civ 311, [2008] RPC 19, at [24] and in Conor [2008] UKHL 49, [2008] RPC 28 at [42], Lord Hoffmann approved this statement of principle which I made at first instance in Lundbeck:
'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 involved in pursuing them and the expectation of success.'
93. Ultimately the court has to evaluate all the relevant circumstances in order to answer a single and relatively simple question of fact: was it obvious to the skilled but unimaginative addressee to make a product or carry out a process falling within the claim. As Aldous LJ said in Norton Healthcare v Beecham Group Plc (unreported, 19 June 1997):
'Each case depends upon the invention and the surrounding facts. No formula can be substituted for the words of the statute. In every case the Court has to weigh up the evidence and decide whether the invention was obvious. This is the statutory task.;
94. It is the nature of this multi factorial evaluation of evidence against a simple statutory test which underpins the reluctance of an appeal court to interfere with a trial judge's decision on an issue of obviousness unless he has erred in principle. Lord Hoffmann put it this way in Biogen v Medeva [1997] RPC 1:
'The question of whether an invention was obvious had been called "a kind of jury question" (see Jenkins L.J. in Allmanna Svenska Elektriska A/B v. The Burntisland Shipbuilding Co. Ltd. (1952) 69 R.P.C. 63, 70) and should be treated with appropriate respect by an appellate court. It is true that in Benmax v. Austin Motor Co. Ltd. [1955] A.C. 370 this House decided that, while the judge's findings of primary fact, particularly if founded upon an assessment of the credibility of witnesses, were virtually unassailable, an appellate court would be more ready to differ from the judge's evaluation of those facts by reference to some legal standard such as negligence or obviousness. In drawing this distinction, however, Viscount Simonds went on to observe, at page 374, that it was "subject only to the weight which should, as a matter of course, be given to the opinion of the learned judge". The need for appellate caution in reversing the judge's evaluation of the facts is based upon much more solid grounds than professional courtesy. It is because specific findings of fact, even by the most meticulous judge, are inherently an incomplete statement of the impression which was made upon him by the primary evidence. His expressed findings are always surrounded by a penumbra of imprecision as to emphasis, relative weight, minor qualification and nuance (as Renan said, la vérité est dans une nuance), of which time and language do not permit exact expression, but which may play an important part in the judge's overall evaluation. It would in my view be wrong to treat Benmax as authorising or requiring an appellate court to undertake a de novo evaluation of the facts in all cases in which no question of the credibility of witnesses is involved. Where the application of a legal standard such as negligence or obviousness involves no question of principle but is simply a matter of degree, an appellate court should be very cautious in differing from the judge's evaluation.'
95. More recently, in Human Genome Sciences Inc v Eli Lilly [2011] UKSC 51, Lord Walker reiterated (at [168]) the task of the trial judge is to evaluate the evidence against a statutory test expressed in simple terms, whose meaning is not necessarily made much clearer by elaborate judicial exposition. Then (at [169]-[170]) he emphasised the importance, in cases of this sort, of deference to the conclusions of the trial judge."

Lord Justice Floyd added at paragraph [9] of Hospira UK Ltd v Genentech Inc. [2016] EWCA Civ 780, [2017] RPC 13:

"9. I start with the well-known passage from the judgment of Kitchin J (as he then was) in Generics (UK) Ltd v H. Lundbeck A/S [2007] EW HC 1040 (Pat), at [72], which has been approved at the highest level:
'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 involved in pursuing them and the expectation of success.'
10. It follows that the court is required to embark on a multi-factorial assessment. The approach of the appellate court to such questions is well-known: the decision is not open to independent evaluation in this court unless the judge has made an error of principle: see Biogen Inc v Medeva Plc [1997] RPC 1 at [45] per Lord Hoffmann.
'It is also well-settled that "obvious to try" is not a substitute test for obviousness: see e.g. per Lewison LJ in Medimmune Ltd v Novartis Pharmaceuticals UK Ltd [2012] EWCA Civ 1234, [2013] RPC 27 at [181]. There is only one statutory question, namely whether the invention was obvious at the priority date. In the same case at [90] to [95] Kitchin LJ explained that whether the invention was obvious to try was merely one of many considerations which it may be appropriate for the court to take into account in addressing the statutory question. It must in any case be coupled with a reasonable or fair prospect of success. At [91] Kitchin LJ emphasised:
'Whether a route has a reasonable or fair prospect of success will depend upon all the circumstances including an ability rationally to predict a successful outcome, how long the project may take, the extent to which the field is unexplored, the complexity or otherwise of any necessary experiments, whether such experiments can be performed by routine means and whether the skilled person will have to make a series of correct decisions along the way."
12. Thus a judge's assessment whether an approach has a reasonable or fair prospect of success is itself another multi-factorial assessment, where this court should again pay proper respect to the evaluation of a trial judge.
13. There is also no single standard of what amounts to a fair expectation of success. Thus Jacob LJ's statement in Saint Gobain PAM SA v Fusion-Provida Ltd [2005] EWCA Civ 177 at [35] that it must be 'more-or-less self-evident that what is being tested ought to work' is far from being a test of universal application. In Novartis AG v Generics (UK) Ltd (trading as Mylan) [2012] EWCA Civ 1623 Kitchin LJ (with whom Lewison and Munby LJJ agreed) warned against imposing a straitjacket on the law by adopting any form of words as a standard. He said at 55:
'What is a reasonable or fair expectation of success will again depend upon all the circumstances and will vary from case to case. Sometimes, as in Saint Gobain, it may be appropriate to consider whether it is more or less self-evident that what is being tested ought to work. So, as this court explained in that case, simply including something in a research project in the hope that something might turn up is unlikely to be enough. But I reject the submission that the court can only make a finding of obviousness where it is manifest that the test ought to work. That would be to impose a straitjacket on the assessment of obviousness which is not warranted by the statutory test and would, for example, preclude a finding of obviousness in the case where the results of an entirely routine test are unpredictable."
14. Indeed, so much was confirmed by Lord Hoffmann in Conor Medsystems v Angiotech Pharmaceuticals [2008] UKHL 49, [2008] RPC 28 at [42], approving Jacob LJ's comprehensive review of the authorities in this area in the Court of Appeal in that case, including his view that "how much of an expectation depended upon the particular facts of the case.'
I5. t is also often debated whether the correct question is whether the skilled person would, or whether he or she could, arrive at the claimed invention without inventive effort. A 'would' test can be misleading, as it is liable to bring in irrelevant considerations, such as whether it would be worthwhile commercialising an otherwise technically obvious product, see per Oliver LJ in Windsurfing International Inc v Tabur Marine (Great Britain) Ltd. [1985] RPC 59 at 72. In Actavis UK Ltd v Novartis AG [2010] EWCA Civ 82; [2010] FSR 18, reliance was placed in argument on the EPO Guidelines for Examination which stress that the question is:
'… whether there is any teaching in the prior art as a whole that would (not simply could, but would) have prompted the skilled person … to modify or adapt the closest prior art … thereby arriving at something falling within the terms of the claims, and thus achieving what the invention achieves'.
16. At [46] Jacob LJ (with whom Lloyd and Stanley Burnton LJJ agreed) rejected the suggestion that this passage went as far as to suggest that it had to be shown that the skilled person would go ahead and implement the idea commercially. I would however not accept (and I do not think that the court in Actavis v Novartis was accepting) that it must be established in every case that the skilled person would necessarily have arrived at the precise combination claimed. That would be to place another straitjacket on the law of obviousness. The skilled person may be faced with a range of obvious possibilities, making it statistically unlikely that he will settle on any one of them. They will all be obvious: see for example the well known discussion in Brugger v MedicAid[1996] RPC 635 at 661 lines 6-21, per Laddie J. In Hallen Co. v Brabantia (UK) Ltd. [1991] RPC 195 this court rejected a suggestion that a 'would' test was always to be preferred. At page 212, Slade LJ, giving the judgment of the court, said:
'We accept that the "could" test is a minimum condition that must be satisfied on the facts before obviousness can be established in any given case. With this qualification, we agree with the judge's comment … that the proper question depends on the facts of each case, though always bearing in mind that, under section 3 of the 1977 Act, the onus ultimately falls on the defendants to show that the alleged invention was obvious to a person skilled in the art, having regard to any matter which formed part of the state-of-the-art at the priority date.'
17, Finally, the judgment of this court in Pozzoli v BDMO [2007] EWCA Civ 588 continues to provide a useful structured approach for judges and tribunals to approach the issue of obviousness."

The Appeal
Cubist contends that the judge fell into error in applying those principles. It argued that he failed to assess properly whether persons skilled in the art would have considered that:
(i)   daptomycin was likely to be a surfactant which would form micelles; and
(ii)  the method of forming and breaking micelles disclosed in Lin and Jiang could be successfully replaced by a different method involving changing the pH.

The Judgment
The Court of Appeal rejected both submissions.  

As to the first, Lord Justice Kitchin said at paragraph [42] that Mr Justice Henry Carr was entitled to find that a skilled address would confirm that daptomycin was a surfactant by using routine and straightforward techniques, including shaking and conductivity testing. 

As to the second it had been accepted by Cubist  that it was part of the common general knowledge of persons skilled in the art that varying the pH of a lipopeptide biosurfactant would vary its propensity to exhibit surfactant properties including the formation of micelles. They would have known of the ability of pH to control the CMC and it would have occurred to them to try pH in order to make micelles. They would have wanted to find an alternative to methanol and they would have had every incentive to try pH. Given those circumstances, the judge was entitled to reach the conclusions that he did.

Comment
Though there is precious little law in the Court of Appeal's judgment, this case illustrates the application of principles developed over the years since Windsurfing and particularly in the last 10 since Pozzoli. Anyone wishing to discuss this case or obviousness generally should call me during office hours on 020 7404 5252 or send me a message through my contact form.

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