Leo v Sandoz
On 17 November 2009, the Court of Appeal handed down its judgment in Leo Pharma v Sandoz. The case was an appeal by Sandoz against Floyd J’s judgment of 15 May 2009 (the first instance decision was reported in the July edition of the Life Sciences Update). The only issue in the appeal was the validity of Leo Pharma’s European Patent (UK) No. 0 697 154.
The Court of Appeal referred to the principles applicable to an appeal and in particular the so-called Biogen principle. The principle relates to issues which involve mixed findings of fact and law and states that it can be shown that a judge has made an error if he reached a conclusion without taking into account all the relevant evidence, both technical and non-technical. As a result, this appeal was characterised as one based on perversity i.e., the judgment was one which no judge could reasonably have reached on the evidence before the court.
The 154 Patent itself was directed to a single crystalline chemical entity namely calcipotriol monohydrate (which was said to have superior stability and technical properties useful in the manufacture of suspension formulations). Calcipotriol and the process for making it had been disclosed in a much earlier Leo Pharma patent as well as in a paper by Calverley. In the Calverley paper, the internal designation MC903 had been used to refer to the anhydrous form of crystalline calcipotriol. The cited prior art relied upon by Sandoz (referred to as the acne use patent) contained six examples, four of which used MC903. Three of the examples concerned recipes for making creams and the fourth concerned a milling process.
The Court of Appeal agreed with Floyd J that on the evidence it was not established that by employing the milling example the monohydrate would inevitably follow. The Court stated that the appeal against the finding of lack of anticipation over the milling example in the acne use patent was hopeless and should have never have been advanced.
The appeal against the finding of non-obviousness was based on four different approaches:
- Obviousness over the acne use patent because it was obvious to conduct a full polymorph screen, during which the monohydrate and its properties would have been discovered;
- Obviousness over the acne use patent because a product screen would have revealed the monohydrate and its technical properties;
- Obviousness over the acne use patent because wet milling instead of dry milling would have produced the monohydrate and its technical properties would have then been revealed;
- Obviousness in the light of common general knowledge alone because experiments into crystallisation would have revealed the monohydrate and its technical properties.
The obviousness case was considered by the Court to be unusual. Sandoz argued that the skilled person would, using his technical knowledge, have come across the invention (namely the hydrate and its beneficial technical properties) without any expectation of successfully finding a better product.
The Court of Appeal considered the evidence in relation to each of the four obviousness attacks and held in each case that Floyd J had taken all the relevant factors into account, had weighed them up carefully and had come to a conclusion which could not be faulted.
For example, once Floyd J had found it was not universal practice to conduct a polymorph screen and that a skilled team would not regard such a screen was mandatory, he was correct to find it was not obvious to use the screen and so find the hydrate. Again, although the wet-milling was accepted at first instance to be an obvious variant to dry milling, as the hydrate would only have been produced 50% of the time, Floyd J was correct to conclude that it did not make the hydrate obvious.
Teva v Merck
In a judgment handed down by Floyd J on Friday 20 November 2009, Teva succeeded in invalidating at first instance a patent owned by Merck concerning a co-formulation for the treatment of glaucoma on the basis of obviousness.
In his judgment, Floyd J reviewed the law of obviousness in light of the House of Lords judgment in Conor v Angiotech. He then went on to apply the law to the facts in the case which were somewhat unusual in that the only clinical example of the use of the combination in the patent in suit was effectively the same as the single piece of prior art being cited in support of the obviousness case. The cited prior art was in fact an abstract of a paper to be presented at a conference after the priority date of the patent but published in the conference papers shortly before the priority date. In both cases, the use was of co-administration of the two actives rather than administration of a co-formulation of the two actives.
Although the abstract referred to one of the two actives by reference to an internal code, the judge held that there was no invention in ascertaining the identity of that active at the relevant time.
On the basis of his detailed findings on the state of the common general knowledge, the Floyd J concluded first that on the basis of the information contained in the abstract, it would have been “startlingly” obvious to the skilled team at the relevant time to have considered co-formulating the two actives and further, that it would have been obvious for the skilled team to have proceeded to co-formulate the two actives and then to have tested the co-formulation first pre-clinically on animals and then clinically on humans. He dismissed various arguments raised by the patentee as to the difficulties which would have been faced by the skilled team in both co-formulating the two actives and also carrying out the pre-clinical and clinical trials.
It was held that had the patent not been invalid for obviousness, it would regardless have been invalid for insufficiency on the basis that the patent contained no more information about the co-formulation than the abstract had done.
It was also held that an amendment to an independent process claim, so as to narrow the pH range of the co-formulation, was not permitted because it added matter to the application. In any event, Floyd J’s finding of obviousness applied to the amended claim as well as the unamended claim, it being obvious to co-formulate the two actives at a pH within both the wider and the narrower pH ranges.
As Floyd J noted in his judgment at paragraph 98: “One must proceed with caution when faced with an obviousness attack based on a suggestion that the skilled person would embark on a research program in the course of which he would discover that a product or compound was effective. This is particularly so where the technical effect is one which is newly discovered, or impossible or very hard to predict. That is because the expectation of success may be zero, or inadequate to drive the research forward. In the end it will all depend on weighing the various factors as they appear from the evidence in the case”.
On the basis of the particular piece of cited prior art, coupled with the evidence adduced by the parties through their experts at the trial, it was held that the expectation of being able to successfully co-formulate the two actives and test the co-formulation pre-clinically and clinically was sufficiently high to lead to a finding of obviousness. The judgment demonstrates however how difficult this task remains in most cases.
The Court of Appeal judgment in Leo Pharma v Sandoz re-iterates the difficulty of overturning on appeal a first instance finding on the issue of obviousness. The recent judgment of Floyd J in Teva v Merck provides an excellent illustration of how the courts now assess "obvious to try" attacks on inventive step in the light of Conor v Angiotech.
 Leo Pharma A/S, Leo Laboratories Limited v Sandoz  EWCA Civ 1188 17 November 2009
  RPC 1 at p.45 per Lord Hoffman
 Teva UK Ltd v Merck & Co, Inc  EWHC 2952 (Pat)
 ( EWJC 659 (Ch))