(1) Teva UK Ltd (2) Teva Pharmaceutical Industries Ltd v Leo Pharma A/s

LEO (with permission in part granted by Birss J and in part by this Court) appeals from the judgment of Birss J of 6^th October 2014 and the consequential order for revocation of Leo’s patents Nos. 1 178 808 and 2 455 083. The respondent, which sought revocation, is Teva.

Henry Carr QC and Tom Alkin argued the case for LEO and Daniel Alexander QC and Mark Chacksfield that of Teva.

The sole ground of attack which succeeded before the Judge was obviousness over a prior art citation called “Turi” (US Patent 4,083,974). The Judge did not go on to consider the alternative grounds of attack, namely insufficiency and added matter.

The rule as to appeals on a finding of obviousness are well-known and were not in dispute. For an appeal to succeed, an appellant must identify at least one point of principle in respect of which the Judge erred. If that can be done, then the question is open to independent evaluation by this Court, see Biogen v Medeva [1997] RPC 1 at p.45, per Lord Hoffmann, in a passage which has been cited countless times since, and St. Gobain v Fusion Provida [2005] EWCA (Civ) 17.

The structured approach to obviousness set out in Pozzoli v BDMO [2007] EWCA Civ 588, [2007] FSR 37 is often a helpful way of approaching the question, as indeed is the problem-solution approach of the EPO in a case where the patent addresses the real problem faced by the inventor and not some different artificially constructed problem (see Actavis v Novartis [2010] EWCA Civ 82, [2010] FSR 28 at [26-34]).

Next there is the oft-cited (including in the House of Lords in Conor v Angiotech [2008] UKHL 49, [2008] FSR 28) passage from Kitchin J in Generics v Lundbeck [2007] RPC 32 at [72]:

“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.”

Finally the “obvious to try” test for obviousness has limitations:

“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” per Lord Hoffmann in Conor v Angiotech at [42].

Psoriasis is an inflammatory skin disease affecting as much as 2-3% of the population, fortunately in the main mildly. There is no known cure but there are long term treatments to alleviate symptoms. Topical treatments were the first line of approach. This case is concerned with an ointment.

Patient compliance is an important factor, particularly for those with mild symptoms. As the Judge put it at [26]:

“Although in severe cases a patient would be likely to comply with the treatment in order to alleviate their symptoms, in the majority of cases where the psoriasis was mild and reasonably contained there would be a greater risk that a patient might not comply with the treatment if it was disruptive of their daily routine, unpleasant to apply, had adverse local side effects (e.g. irritation) or more serious side effects (e.g. skin atrophy or systemic effects).”

The key claims of the patents as amended, whose priority dates are 23^rd April 1999, for present purposes may be treated as simply being for an ointment consisting of two active ingredients, calcipotriol (a vitamin D analogue) and betamethasone (a corticosteroid, a base (e.g. Vaseline) and a commercially available solvent called Arlamol E. It was common ground that the key question was whether or not such an ointment was obvious at the priority date in April 1999.

Each active was, well before April 1999, well-established for use as the sole active in a psoriasis ointment or cream.

More particularly calcipotriol had been introduced with success by LEO in 1991 and rapidly become well-known and widely used. But it was not as potent as the steroids, including in particular betamethasone – a compound known and used topically for psoriasis before 1990.

Each ingredient has a different beneficial effect and so patients were often prescribed two topical products, one containing calcipotriol and the other betamethasone. One might use one in the morning and the other in the evening or one after another on successive days.

But what could not be done was to use them at the same time. Patients had to be warned that they could not be applied together. The reason was that each of the ingredients was unstable save in a narrow range of pH: alkali for calcipotriol and acid for betamethasone. The mono-creams used an aqueous solvent buffered to a pH which gave stability for the active concerned. The pHs for stability did not overlap.

Patient compliance for using both creams was thus rather complex. The compliance problem was greater for less serious cases (because people were more likely to forget a particular application) as the Judge had found.

By the mid-90s, if not before, clinicians were expressing a need for an ointment or cream containing both ingredients. Some added the view that this was not possible because of the pH problem. That in itself can be somewhat discounted because clinicians are not formulators. What cannot be discounted is that formulators must have known of the desire – the want – of clinicians for a combination product.

Now there was a way, in theory, that the problem might be solved. Everyone knew that you can only have a pH at all, acid, neutral or alkali, if water is present. So theory would suggest that the way forward was to produce a dual product containing no water – which boils down to the use of a non-aqueous solvent. If you could do that then in theory the mixture of active ingredients would be stable.

If it were as simple as that, then it would follow that any non-aqueous non-toxic solvent would do. Just picking any one of them at random would work. It would be a mere arbitrary non-inventive choice. It would not matter which such solvent was chosen, because the expectation would be that all would work. The particular choice would be analogous to the arbitrary choice of the diameter of a plate discussed in Actavis v Novartis [2010] EWCA Civ 82, [2010] FSR 28 at [36-38].

However it was far from established that any non-aqueous non-toxic solvent would produce a stable ointment. The Judge found that “there is no proper evidence either way as to whether they [i.e. other such solvents] would work or not.” Nor was it established that the skilled team would expect that any non-aqueous solvent would do. Keeping water wholly out was a known real problem.

The Judge said:

“39.

The concept of apparent pH reflects the fact that skilled formulators knew that even if a non-aqueous system was chosen (such as a paraffin based ointment) in practice it was unlikely to be possible to remove all the water from a system. Even if a lab based formulation was truly dry, some water was likely to be encountered during manufacture, processing and in the product’s lifetime. Thus I do not accept Professor Crowley’s view that by choosing to use an ointment a skilled formulator would simply put to one side any concerns about pH dependent stability. Such considerations would always play a part.

40.

However in the end the skilled formulator is an empiricist. Exactly how these various considerations will play out in practice is hard to predict in advance and always requires testing. For example that is why pre-formulation compatibility studies are always carried out.”

This is an important finding. For it follows that it cannot be said that a formulator would have anything like a strong expectation that any particular non-aqueous solvent would work – would result in a product stable for both calcipotriol and betamethasone. On the contrary he would have to undergo a research project. The Judge said the use of non-aqueous solvents would be “well-worth investigating” but that is not the same as saying any particular such solvent had a fair expectation of success.

Of course in the real world formulators would be likely to start any experimental programme using non-aqueous solvents with which they were familiar and which had been used in other pharmaceutical topical formulations. They may well have started with propylene glycol because by the priority date it was used in a third of the marketed corticosteroid formulations. It had a water content of 0.2%. But it did not work as LEO themselves found out.

Teva’s expert, Prof. Crowley, accepted that propylene glycol did not work. Mr Carr then put to him a Teva patent application addressing the problem of the incompatible actives. This proposed different solvents from Arlamol E, the solvent of the amended claims. The cross examination then went like this:

The Judge accepted this evidence, rightly calling it “important evidence in LEO’s favour.” But he missed its real significance. It was that to the skilled person, identifying a non-aqueous solvent which would actually work to produce a stable ointment, was not easy. Having the property of being non-aqueous was a necessary, but well short of sufficient, condition. Finding one was a research project. And that was because there was no sufficient expectation of success. Yes, a particular candidate might work, but it was far from certain that it would.

Indeed the formulator experts agreed that one would test a number of solvents. The Judge found “about 10-20” – again by implication it is clear that the expectation of success with any one of them was not high. The Judge said such testing “was entirely routine” but that does not alter the expectation. It was not even proved that there was a good expectation that if you did try 20 one of them would work.

The solution of the patents was to use Arlamol E. This had been disclosed as a solvent for a corticosteroid in the Turi patent published years before in 1978. Turi asserted wrongly, as would have been known not only by 1999 but well before, that propylene glycol was “irritating to the skin” and was a non-lubricant. It proposed Arlamol E as a solvent for an anti-inflammatory steroid.

In the real world Arlamol E was not significantly used for topical pharmaceuticals. It had use in cosmetics but did not, as the Judge found, form part of the common general knowledge of a formulator.

Nonetheless the Judge held that its use would have been obvious at the priority date of 1999. He seems to have accepted that Arlamol E would not in fact have been included in the 10-20 solvents which a real formulator would have tried (these being solvents they knew and had experience with such as propylene glycol). He reasoned thus:

“[79] The skilled formulator would decide what compounds to test based on the properties of the compounds. LEO emphasised Professor Brown’s evidence that familiarity with such compounds would be a critical element in the skilled formulator’s thinking. I accept that familiarity would always play a part in the choices made by real formulators working in real organisations since it maximises the chances of success by using tried and tested compounds which are often found to work. However I find that the notional skilled formulator would not be as conservative in his or her thinking as that evidence might suggest. The well known and frequently used excipients, such as propylene glycol, are such because they are often found to work well in topical formulations. The outcome of the tests would not be known in advance (otherwise there is no point in doing the test). The notional skilled formulator would test some familiar compounds but, subject to the regulatory point considered below, would not be put off from including unfamiliar compounds merely because of their unfamiliarity. The question is primarily a technical one and would be decided based on consideration of the known properties and desired characteristics of the compound.”

This is rather odd – he is saying that the notional person skilled in the art would be different from the real persons skilled in the art. But the law of obviousness attributes to the notional person the real prejudices and practices of persons skilled in the art. For instance the “bagridden” mindset of real vacuum cleaner designers was attributed to the person skilled in the art in Dyson v Hoover [2002] R.P.C. 22.

The Judge said that Arlamol E had the desired characteristics and so there were “sufficient grounds to include the compound in pre-formulation tests”. I do not see that follows. Many non-aqueous solvents may have had the desired characteristics – propylene glycol is a particularly good instance. But there was nothing disclosed about Arlamol E that made it anything like an outstanding candidate – any different from any other non-aqueous solvent.

The Judge said that “there was a sufficient prospect of a positive result in the tests with this compound to make it worth testing.” But that is to say no more than that there was a sufficient prospect of success with any non-aqueous solvent. On this analysis all such solvents were worth testing. Yet the evidence had shown that the “apparent pH” problem was real and that one could not say that just because a solvent was non-aqueous it would work.

In effect the Judge was saying that the idea of including this solvent as part of a research project amounted to obviousness. The “obvious to try” standard requires a higher expectation of success than that. Otherwise, as I observed in St Gobain at [35]:

“Mere possible inclusion of something within a research programme on the basis you will find out more and something might turn up is not enough. If it were otherwise there would be few inventions which were patentable. The only research which would be worthwhile (because of the prospect of protection) would be in areas totally devoid of prospect.”

Putting this point into a Pozzoli structured analysis, the difference between the prior art (Turi) and the invention was that Turi was a mono active product using Arlamol E. The invention is a double active product. Turi would be seen as using one of a large number of possible non-aqueous solvents. It might provide stability for the two actives, just as any of the others might. But there was no reasonably optimistic expectation that it would. Finding that it really did was an invention and an advance in human knowledge.

So I think the judge did err in principle and we are obliged and entitled to revisit the question of obviousness de novo.

I am confirmed in this view by a further consideration which the judge did not deal with. He dated all his findings about common general knowledge as at the priority date, April 1999. But it is clear that all these matters were known well before then too. The different creams containing the individual actives, the problems of incompatibility, the need for careful instructions about separate application from clinicians and the desire for an ointment containing both actives were all known by at least 1995. Yet no-one found a way to put the actives together in an ointment (with any non-aqueous solvent, not just Arlamol E) until LEO did it with the invention in the patents.

When the dual active product came onto the market in 2002 it was a success. The experts on both sides were agreed that it was a significant advance in the treatment of patients. That was not because of a synergistic effect (at least the Judge did not find there was one) but because of the much better patient compliance – something desired since at least 1995.

Mr Alexander suggested that there was no long-felt want, that the combination product came about exactly when you would expect, especially from LEO. They were really only undertaking a brand extension of their still patented calcipotriol. That simply does not square up with the dates and the facts that a combination product was wanted from at least the mid-1990s and, when achieved, was a real advance.

So we have here the classic sort of case where the courts have found invention over the years, a long-felt want, the desired solution and no explanation of why that solution was not done before when it could have been. The Judge’s failure to consider this seems to me to be another error of principle – he missed a relevant circumstance.

I add that I am not surprised that the EPO Opposition Division, even though supplied with the Judge’s judgment, rejected Teva’s opposition. It said:

“[3.3.1]… The purpose of the invention in the contested patent is to provide a stable combination therapy for psoriasis (sebopsoriasis and seborrhoic dermatitis) comprising components A and B. The skilled man would then start looking for documents disclosing combination therapies and see which are the challenges presented by the fact of combining both active agents.

D22 [Turi] does not have the same purpose of the invention. D22 [Turi] is directed to provide a composition comprising corticosteroids (monotherapy) for treating anti-inflammatory diseases. Nothing is said either about a possible combination of corticosteroids with a vitamin D analogue or about the compatibility problems that said combination would present. D22 [Turi] discloses a composition having a similarity in the composition because two of the three components are present, namely component B and C. However its suitability for the purpose of the invention is not disclosed. There is neither an indication of combining the corticosteroid with a vitamin D analogue and nor a link between said non-disclosed combination with the incompatibility problem addressed in the patent in suit. Thus, D22 [Turi] could not qualify as the closest prior art.”

And:

“The skilled person would not start from D22 [Turi] and combine its teaching with the common general knowledge resulting in a non-aqueous composition comprising components A, B and C for the topical treatment of psoriasis. Pointing the selection of Arlamol E as obvious in view of D22 is a conclusion going beyond what the skilled person would have objectively inferred from the prior art, without the benefit of hindsight knowledge of the invention. In D22 the problem was neither mentioned or even suggested and considering D22 as the closest prior art is merely the result of an ex-post facto analysis.” (emphasis added)

Accordingly I would reverse the Judge’s finding of obviousness.

I turn to added matter and insufficiency, matters not dealt with by the Judge. The Opposition Division dismissed these points in short order. It was right to do so.

First the added matter (EPC Art. 123(2)) point. The legal test is not in dispute. I summarised it in Richardson-Vicks’ Patent [1995] RPC 568 at 576

“I think the test of added matter is whether a skilled man would, upon looking at the amended specification, learn anything about the invention which he could not learn from the unamended specification.”

That has been accepted in subsequent cases, e.g. in Nokia v IPCom [2012] EWCA Civ 567, [2013] RPC 5 where a fuller discussion can be found at [46-60].

Mr Alexander accepted (as was demonstrated by Mr Carr) that the proposed amended claims formed a subset of the claims in the application as filed. But, he submitted, the particular combination now claimed was an important technical narrowing from that which was originally disclosed. In particular the original wide disclosure of the application was so wide it even included the use of aqueous solvents and long lists of ingredients. The narrow particular disclosure of the proposed amended patents amounted to a later “pick and mix” operation which in substance added new information by discarding much that would not work or might not work.

The difficulty with that argument is that the “pick and mix” cannot fairly be characterised as an intermediate generalisation not disclosed in the application. For it is a “pick and mix” to be found in the application itself. Betamethasone and calcipotriol are singled out as among the most appropriate actives, the solvent is said to be preferably non-aqueous, Arlamol E is the first example of a solvent in a specific list of solvents. Moreover Example 1 is an ointment with these two actives using Arlamol E as the solvent. True it is that it also includes an anti-oxidant but it is pushing one’s luck too far to say that omitting the necessity for this amounts to adding matter when the specification itself says “The composition may also contain other commonly used additives such as anti-oxidants.”

So there is nothing in this point. As to insufficiency, it was but faintly argued and really only as some sort of support for the main obviousness argument. Clearly the patents contain instructions which would enable a person skilled in the art to make the ointment now claimed.

I would allow the appeal.

I agree.

I also agree.