Teva UK Limited & Teva Pharmaceuticals Limited v Leo Pharma A/S & Leo Laboratories Limited  EWHC 3096 (Pat) is a decision by Mr Justice Birss in the Patents Court, England and Wales. This case is about treatment of psoriasis with a combination medicinal formulation comprising two substances known to treat psoriasis (a corticosteroid and a vitamin D analogue) and a particular solvent that is able to stabilise the combination formulation. The invention lies in the putting together of the two therapeutic substances in the same formulation and the choice of the solvent. The decision mostly concerns whether this was inventive. Since the invention could be seen as an ‘incremental’ one which concerns optimising use of known drugs, rather than the discovery of new drugs, this decision provides insights as to how such incremental inventions will fare for inventive step in the Courts of England and Wales. More broadly the decision adds to the case law of how inventive step is assessed in a complex pharmaceutical setting.
Other recent pharmaceutical cases concerning inventive step
There have been several cases in recent times where inventive step been determined in the context of a pharmaceutical invention. In Novartis AG v Generics (UK) Limited (t/a Mylan)  EWCA Civ1623, discussed by the IPKat (see here) the Court of Appeal had to review the decision of Floyd J (here) in assessing inventive step where the compound went through several steps during research and development. Whether or not the compound would have passed each test would have been difficult to predict, and yet the compound was found to be obvious.
In Hospira UK Ltd v Genentech Inc  EWHC 1094 (Pat), noted by the IPKat here, Birss J had to deal with inventive step of an ‘incremental’ invention, and he found the inventive concept, which related to a dosage regimen, to be obvious.
In Glenmark Generics (Europe) Limited & others v The Wellcome Foundation Limited & Glaxo Group Ltd,  EWHC 148 (Pat), reported by the IPKat here, Arnold J decided that a combination product for treating malaria was obvious.
From these cases we can see how inventive step is being assessed by these courts where the invention concerns a multi-step R&D process. In addition it seems clear that incremental inventions in the pharmaceutical field are being found invalid for inventive step.
The present invention
In this case Leo was defending two patents, EP 1178808 and its divisional EP 2455083. The claims of EP 1178808 relate to a pharmaceutical composition comprising vitamin D or an analogue of it, a corticosteroid and a specific solvent. EP 2455083 relates to a more specific embodiment where the vitamin D analogue is calcipotriol and the corticosteroid is betamethasone. These therapeutic substances were known for treating psoriasis, and the solvent, polyoxypropylene 15 stearyl ether, was disclosed in a prior art publication ‘Turi’, US patent 4,083,974. There are several aspects to the contribution being made by the invention. One lies in realising that providing the two therapeutic substances in a single formulation would increase patient compliance in comparison to asking patients to take two separate products. However, given that the two substances are stable at different pHs, they cannot simply be added to each other in an aqueous formulation. A second aspect of the contribution is making a non-aqueous formulation choosing to use polyoxypropylene 15 stearyl ether as a solvent.
The expert witnesses and the ‘team’ for inventive step
The expert witnesses gave evidence on treatment of psoriasis with the two substances, whether they would consider combining them in a single formulation an whether the co-formulation would be stable. Under cross-examination it became clear that the expert reports contained ‘sweeping generalisations’ and in their testimonies they were guilty of ‘overstatement’. However Birss J was appreciative of the contribution of all the experts which allowed him to determine the common general knowledge in the art and on the skilled person being a team that included a skilled clinician and a skilled formulator of pharmaceutical compositions.
Common general knowledge
Birss J held that, from the common general knowledge, it was known that patient compliance was important in psoriasis and that using a single combination formulation would increase compliance over prescribing two different ones. However he did not accept Leo’s argument that the common general knowledge of the skilled clinician would assume that combining the two substances in a single composition was not possible. Birss J built up a complex picture of the common general knowledge of a skilled formulator and how such a person would tackle the making of non-aqueous solutions containing substances sensitive to pH. A key point was that the skilled formulator is an empiricist who would proceed to test solvents that might have worked.
The information in the patents
Leo’s patents make note of the fact that patient compliance could be improved by using a single combination product. They also give the results of stability tests and provide evidence of a better therapeutic effect than using the substances separately. The patents also refer to ‘synergy’ occurring, but this aspect was not pursued by Leo in the trial to show inventive step. Had it been, it would have been a valuable addition to the case law in this area.
The appropriate inventive step test
Birss J recited the much-quoted statement from Generics v Lundbeck which opens:
‘The question of obviousness must be considered on the facts of each case. The court must consider the weight attached to any particular factor in the light of all the relevant circumstances.’
He considered this to mean that ‘obvious to try’ is simply ‘one of a variety of factors’ to be considered. He added:
‘Obvious to try cases usually involve consideration of the level of expectation of success but one cannot lay down a general characterisation of what the true level of expectation must be in every case beyond stating that it must be a fair one. In that way the differences between different cases is taken into account. It is wrong to ask whether something might achieve a particular desired effect. It is correct to ask whether it was obvious that it would achieve that effect.’What does Birss J mean? Is he saying one should not judge inventive step by asking whether the skilled person would have predicted it would have worked but instead, once the invention has been found to work, one should then ask ‘was it obvious that it would have worked’? Is that the correct approach to ‘expectation of success’? Readers' comments in this point would be most appreciated.
From Birss J’s comment it seems that ‘expectation of success’ is something complex and very fact-specific. I also wonder whether the learned judge should have defined what ‘success’ would be in the present case. Was it simply production of a stable combination composition or was it providing better therapeutic results?
Was the invention obvious?
Birss J started his inventive analysis from the position that a combination formulation was desirable from the common general knowledge to increase patient compliance. The skilled clinician would expect the combination formulation to be more effective than using the therapeutic substances separately. It was well known, for example, that the corticosteroid would reduce the irritation caused by calcipotriol.
Leo argued there would be ‘prejudice’ against use of corticosteroids due to potential side effects over the long term. However Birss felt there would not be prejudice against short term use or in the combination.
Birss J then switched his analysis to the perspective of the skilled formulator. It was obvious to use a non-aqueous solution to overcome the issue of the substances being stable at different pH’s. The issue came down to whether the solvent disclosed in Turi would be obvious to use in the formulation. Turi disclosed a non-aqueous composition containing the solvent and betamethasone (one of the therapeutic substances used in the present invention) and based on this Birss J concluded that the skilled formulator would not ignore it or dismiss it.
Leo criticised the benefits described in Turi as ‘illusory’, but Birss J felt this was an overstatement. Leo also put forward arguments based on the fact that the solvent disclosed in Turi was not widely used and this might would add potential cost, time and uncertainty, for example if a regulator required extensive testing of the solvent. However, Birss J felt that whilst factors such as this can be relevant they rarely outweigh technical considerations.
A crucial point for inventive step was the skilled person’s perception of how difficult it would be to solve the pH problem. The expert witnesses had disagreed on this issue, but Birss J felt that Teva’s case on this was more persuasive. The skilled formulator presented with Turi would proceed to test the solvent it disclosed and result would be positive. A clinical study would then be carried out using the combination formulation and this would confirm it was an effective treatment. This meant the invention was obvious.
Inventive selections and the Technograph test
Birss J went on, tantalisingly, to discuss the situation in which the selection of the solvent would be inventive. If evidence had been provided that a ‘vast range of obvious agents had not worked’ then this could have been ‘compelling evidence of non-obviousness’. However Leo had not done this.
Birss J also asked whether his analysis was an example of the unfair step-by-step approach identified in Technograph Printed Circuits Ltd v Mills and Rockley (Electronics)Ltd  RPC 346. In that case Lord Diplock had said:
"The cross-examination of the respondents' expert followed with customary skill the familiar "step by step" course. I do not find it persuasive. Once an invention has been made, it is generally possible to postulate a combination of steps by which the inventor might have arrived at the invention…if he had started from something that was already known…"Birss J felt he had not made this error since his analysis had considered the normal steps in development of a pharmaceutical product and thus could not have been influenced by hindsight.
1. How should ‘expectation of success’ have been addressed for this case? Should Birss J have analysed this based on ‘would the skilled formulator have expected the solvent disclosed in Turi to have worked?’ instead of ‘would the skilled formulator have tested the solvent disclosed in Turi?’. Often in pharmaceutical cases there is little chance of success for any one candidate, but the skilled person would have had reasons to test it.
2. If the inventive step analysis follows the normal steps in development of a pharmaceutical product, is there a danger of failing the Technograph test? How can one determine one has not failed the Technograph test?
3. Are other incremental inventions also likely to be found obvious? It seems that often for such inventions the contribution is modest and there is a lot of relevant prior art.
4. What does it take for a combination product to be inventive? Does it need to have an element of inventive selection or a demonstration of synergy?