COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM THE HIGH COURT OF JUSTICE
CHANCERY DIVISION PATENTS COURT
The Hon Mr Justice Warren
HC 07 C 01753
Strand, London, WC2A 2LL
B e f o r e :
THE RT HON LORD JUSTICE LLOYD
THE RT HON LORD JUSTICE STANLEY BURNTON
| Actavis UK Limited
|- and -
for the Appellant/Defendant
Roger Wyand QC and Piers Acland (instructed by Bird & Bird)
for the Respondent/Claimant
Hearing dates: 27/28 January 2010
Crown Copyright ©
Lord Justice Jacob:
The Patent and its background
 In recent years there has been a large increase in the development and use of sustained-release tablets which are designed to release the drug slowly after ingestion. With these types of dosage forms, the clinical utility of drugs can be improved by means of improved therapeutic effects, reduced incidence of adverse effects and simplified dosing regimens.
Mr Meade suggested that this paragraph should be read as specific to the invention and was saying that the invention would lead to improved therapeutic effects, reduced adverse effects and simplified dosing regimens. But it is clear that it is no more than a general background statement about the increasing use of sustained release drugs and the reasons therefor. It is saying you may or may not get improved therapy (for one or other or both reasons) and you will (obviously) get a simplified dosing regime. That was common general knowledge.
 . The actual approach taken for a given drug depends inter alia on the physical chemical properties of the drug. One of these is the solubility of the drug, which has a major impact on the pharmaceutical formulation strategy. A high solubility of the drug substance may induce problems, as discussed further below.
 As mentioned above, the drug release from sustained release formulations is related to the drug solubility. The higher the water solubility of the drug, the faster the drug release and the shorter the duration of drug delivery. A fast release of the drug might mean that the desired rate and duration can not be obtained and that the beneficial effects of sustained release administration are lost. Thus, a special challenge is met when trying to formulate water soluble substances for sustained release formulations. One way to try to solve this problem would be to include large amounts of slow release excipients in the formulation. However, this approach has drawbacks such as increased costs and increased size of the formulation. Increased physical size of the dosage form may present problems for some patients, since the tablet will be more difficult to swallow. Another possibility is to use a less water soluble salt. However, such a change requires a more extensive development work and may also lead to bioavailability problems due to incomplete dissolution.
 Fluvastatin is a water soluble drug. For example, the solubility of the sodium salt of fluvastatin in water extends to more than 50 g/l. Biopharmaceutical requirements of a sustained release product of this water soluble drug would then at first sight impose formulation problems as discussed above.
The Patent then explains why, in relation to each of the types of sustained release formulation, high solubility causes problems.
 Consequently, there is a need for pharmaceutical formulations of HMG-CoA reductase inhibitors which avoid the above mentioned drawbacks and are possible to prepare, e.g., without including large amounts of slow release excipients or the use of highly advanced techniques. Preferably, the production costs of the formulations should be low.
Clearly in context the "need" referred to is a need for slow-release formulations, not merely any kind of formulation. That is the problem the invention of the Patent seeks to overcome
 It has surprisingly been found that sustained-release compositions, comprising fluvastatin as a water soluble salt, exhibit particularly favorable release characteristics such as unexpectedly long duration and slow rate of drug release. In the present context, the term "water soluble" should be understood as a solubility of more than 30 mg/ml in water at +37°C.
 Consequently, the present invention provides a pharmaceutical composition for sustained release comprising a water soluble salt, preferably the sodium salt, of f1uvastatin as an active ingredient. The sustained-release f1uvastatin compositions for which these favorable properties are obtained are selected from the group comprising matrix formulations, diffusion-controlled membrane coated formulations; and combinations thereof.
 The pharmaceutical formulations according to the invention are useful for lowering the blood cholesterol level in animals, in particular mammals, e.g. humans. They are therefore useful as hypercholesterolemic and anti-atherosclerotic agents.
A sustained release pharmaceutical composition comprising a water soluble salt of fluvastatin as active ingredient and being selected from the group consisting of matrix formulations, diffusion-controlled membrane coated formulations and combinations thereof, wherein the sustained release formulation releases the active ingredient over more than 3 hours.
Obviousness: the Law
Art 52 Patentable Inventions
(1) European patents shall be granted for any inventions which are susceptible of industrial application, which are new and which involve an inventive step.
Art 56 Inventive Step
An invention shall be considered as involving an inventive step if, having regard to the state of the art, it is not obvious to a person skilled in the art.
So at bottom the question is simply whether the invention is obvious. Any paraphrase or other test is only an aid to answering the statutory question.
(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?
Obvious for the purposes of step 4 means technically rather than commercially obvious.
the patentee is entitled to have the question of obviousness determined by reference to his claim and not to some vague paraphrase based upon the extent of his disclosure in the description.
 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  RPC 479, by saying that the notion of something being obvious to try was useful only in a case in which there was a fair expectation of success. How much of an expectation would be needed depended upon the particular facts of the case.
11.7 Problem-and-solution approach
In practice, in order to assess inventive step in an objective and predictable manner, the examiner should normally apply the so-called "problem-and-solution approach".
In the problem-and-solution approach, there are three main stages:
(i) determining the "closest prior art",(ii) establishing the "objective technical problem" to be solved, and(iii) considering whether or not the claimed invention, starting from the closest prior art and the objective technical problem, would have been obvious to the skilled person."
In the context of the problem-and-solution approach, the technical problem means the aim and task of modifying or adapting the closest prior art to provide the technical effects that the invention provides over the closest prior art. The technical problem thus defined is often referred to as the "objective technical problem".
The objective technical problem derived in this way may not be what the applicant presented as "the problem" in his application. The later may require reformulation, since the objective technical problem is based on objectively established facts, in particular appearing in the prior art revealed in the course of the proceedings, which may be different from the prior art of which the applicant was actually aware at the time the application was filed. In particular, the prior art cited in the search report may put the invention in an entirely different perspective from that apparent from reading the application only.
It is noted that the objective technical problem must be so formulated as not to contain pointers to the technical solution, since including part of a technical solution offered by an invention in the statement of the problem must, when the state of the art is assessed in terms of that problem, necessarily result in an ex post facto view being taken on inventive activity (T 229/85, OJ 6/1987, 237).
The expression "technical problem" should be interpreted broadly; it does not necessarily imply that the technical solution is a technical improvement over the prior art. Thus the problem could be simply to seek an alternative to a known device or process providing the same or similar effects or which is more cost-effective.
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. (Generics v Lundbeck  RPC 32 at ).
In the third stage the question to be answered 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, faced with the objective technical problem, to modify or adapt the closest prior art while taking account of that teaching, thereby arriving at something falling within the terms of the claims, and thus achieving what the invention achieves (see IV, 11.4).
In other words, the point is not whether the skilled person could have arrived at the invention by adapting or modifying the closest prior art, but whether he would have done so because the prior art incited him to do so in the hope of solving the objective technical problem or in expectation of some improvement or advantage (see T 2/83, OJ 6/1984, 265). This must have been the case for the skilled person before the filing or priority date valid for the claim under examination."
[6.5] There is no doubt that ketals are structurally closely related to the parent ketones and that, normally, there are no great difficulties to overcome in their preparation. Thus, the skilled person could have considered them as possible and perhaps easily obtainable derivatives of the said parent ketones. This, however, is not the proper question to be asked. According to the established jurisprudence of the Boards it has to be investigated, when it comes to the issue of inventive step, whether a skilled person would have prepared the compounds in question with a reasonable expectation that they would successfully solve the technical problem under consideration. In the absence of any useful information to that end (cf. the above paragraphs 6.1 and 6.2) the Board cannot see why the skilled person would have suggested the claimed ketals with the expectation that they would be useful in the treatment of pvd.
That is far from applying a test of "would actually make". It is saying no more than that there was no reason for the skilled person to propose the ketals to solve the problem. The other case adds nothing.
The Judgment under Appeal
 In the light of the totality of the evidence, the essentials of which I have discussed above, I reach the following conclusions:
a. The skilled team is to be seen as engaged upon the task of formulating fluvastatin for use in humans for the treatment of hypercholesterolemia. There is no suggestion that the team would be formulating the drug for the treatment of different animals or for the treatment of any other condition.b. Part of the common general knowledge of the team includes the fact that an immediate release formulation was already available. That formulation could be taken at a dose of up to 40 mg once a day and up to 80 mg per day in two doses.c. Whether or not the team was expressly directed to consider formulating fluvastatin in a sustained release dosage form, it would at least consider such a formulation as a possible way forward and not dismiss it out of hand.d. The skilled team would seek to identify the benefits (or incentives) and problems (or disincentives) of a sustained release formulation.e. The team would regard improved patient compliance as a benefit which would certainly be obtained if a satisfactory formulation of an 80 mg dose could be successfully achieved.f. The team would be concerned about clinical efficacy. It would be uncertain about whether improvement could be achieved. It could not be ruled out. But it certainly could not be said with any confidence that any improvement would be achieved, nor that there was a strong expectation that it would be achieved.g. The team would also be concerned with side-effects. Again, it would be unable to predict with anything approaching certainty that any reduction in the risk of side-effects would be achieved, but there would be some hope of reduced risks of hepatotoxicity (on a population basis as explained above) and a reasonable expectation of improvements in myopathy. However, neither of these was seen as serious problems with fluvastatin at the priority date.h. The team would have, as a result of common general knowledge and secondary common general knowledge, an expectation of being able to develop an 80 mg sustained release formulation which released over at least 3 hours in vivo and would be confident that it would have some clinical efficacy. But it would have no confidence that it would achieve better, or even the same, efficacy as the existing maximum dosage of 2 x 40 mg daily immediate release. It would expect, but could not be certain, that this would not produce a greater risk of side-effects than the existing maximum dosage.i. It would have been rational, from a technical perspective, for the team to have produced a sustained release formulation for 80 mg once daily dosage with a view to improved patient compliance, anticipated reduction in side-effects and possible improved efficacy. But in the light of the uncertainties, such a course might well be seen as commercially unjustifiable; but that would be a matter for the decision of commercial people not of the skilled team.j. The team, if it were asked to do so, would be confident of producing a sustained release formulation of fluvastatin at various doses which had the release characteristics in vitro described in the Patent. It would be confident that such a formulation could be taken by humans and would have some therapeutic effect albeit perhaps of lesser efficacy than the equivalent dosage taken in immediate release form as a single dose (up to 40 mg daily) or two doses (up to 80 mg daily). There would, however, be no reason for producing such a formulation for its own sake if it were thought impossible or highly unlikely that such a formulation would have, or would lead to a product which would have, improved efficacy and/or reduced side-effects.
 The Patent claims that, surprisingly, fluvastatin sodium exhibits particularly favourable release characteristics. The evidence, however, shows that the high absolute solubility of a drug is a problem only at very high and very low levels. The evidence also shows that the high (but not very high) solubility of fluvastatin would not have been seen as a serious problem at least in vitro; it would only have been seen as limiting the available technology for producing a sustained release formulation releasing in vitro over a period of 3 hours or more.
 .. the skilled team (including clinician) would be confident that some level of dose could be given in sustained release form which it would also be confident (i) would have some efficacy (perhaps not as good as the existing immediate release formulations) and (ii) would not produce unacceptable side-effects.
 In my judgment, this absence of motivation does not prevent claim 1 from being technically obvious. The skilled team would, for reasons already given, not reject a sustained release formulation out of hand. Even though its focus will be on the end result of an 80 mg once daily formulation having improved efficacy and less serious side effects, coupled with better patient compliance, the concept of sustained release will be present. It does not need a commercial boss to ask the question "Can you make a formulation [within claim 1]" for the skilled formulator to appreciate its technical obviousness any more than it needs a commercial boss to ask a similar question of the plate designer for that designer to appreciate the technical obviousness of the odd-sized plate. I conclude that claim 1 is obvious over the common general knowledge.
Lord Justice Stanley Burnton:
Lord Justice Lloyd: