The UK Supreme Court has handed down its judgement in Actavis v ICOS  UKSC 15 unanimously upholding the earlier decision of the Court of Appeal that the patent to a specific dosage regimen of tadalafil was obvious. However, in doing so the UK Supreme Court has allayed the concerns of innovators and big pharma by confirming there is no automatic bar to dosage claim discoveries, made through well-established or routine procedures provided they involve an inventive step.
Background to the dispute
This case concerned the dosage patent EP(UK) 1,173,181 (the '181 Patent') and in particular claims relating to a specific low 5mg dose of the drug tadalafil marketed under the brand name CIALIS and used to treat erectile dysfunction or 'ED'. The CIALIS drug is a competitor (second in class) of the well-known branded drug VIAGRA. However, VIAGRA had certain side effects. Both tadalafil and sildenafil, the active ingredients in VIAGRA, are inhibitors and work by blocking phosphodiestaerase, which otherwise would lead to failure of the dilation of blood vessels.
The 181 Patent is owned by ICOS and is exclusively licensed to Eli Lilly. During pre-clinical and clinical studies, Eli Lilly found that a daily low oral dose of 5mg was therapeutically effective, and minimised the adverse reactions of using the VIAGRA drug.
The decisions of the lower courts
Actavis and others (being generic companies) sought to revoke the 181 Patent to clear the way before their own generic product launches. The main attack was lack of novelty and inventive step (with priority, added matter and insufficiency included in the attack) over the nearest prior art (the 'Daugan Patent'), which disclosed a class of compounds including tadalafil for treating ED. The Daugan Patent had disclosed doses of tadalafil in the range of 0.5 to 800mg but only provided data for a 50mg dose and not a 5mg dose. A key issue was whether routine dose-ranging studies required for clinical development and regulatory approval would have ordinarily extended to the 5mg dose, and so involved an inventive step.
ICOS argued that the low dose would not have been obvious before conducting the Phase II trials, and counterclaimed for infringement.
In the High Court, Mr. Justice Birss considered that the results of the clinical studies were not predictable in advance. He accepted expert evidence that it was not established that the skilled team would always seek to identify the minimum effective dose of a particular drug. Accordingly, the 5mg daily dose was not obvious, and involved an inventive step.
The Court of Appeal disagreed and overturned the High Court's decision. Lord Justice Kitchin (as he then was) held that the Daugan Patent would have motivated the skilled team to conduct clinical dosing studies and discover the low 5mg dose, and so the 181 Patent was obvious.
In reaching this conclusion, Lord Justice Kitchin explained how drug discovery is an iterative process, progressing from one phase to another based on the results of the preceding phase. So long as the skilled team continues to be motivated along the development pathway with an expectation of successfully concluding each stage, then consequently there can be no invention. In this case, the finding along the way of the reduced side effects associated with the low dose was simply a bonus in following the obvious-to-try clinical development, and so did not constitute an inventive step.
The decision of the UK Supreme Court
The appeal raised two main issues: first, how does the test for inventive step apply to a dosage patent resulting from routine testing; and second, was the Court of Appeal entitled to interfere with Mr. Justice Birss' assessment of obviousness and reverse his finding?
In addressing the first issue the UK Supreme Court restated and reviewed the approach to be taken to obviousness, both in the UK courts (which use the re-stated Windsurfing test in Pozzoli SPA v BDMO SA  EWCA Civ 588) and in the EPO (which uses the 'problem solution' approach). ICOS and Eli Lilly argued that the Court of Appeal's approach to obviousness had gone further than required. However, Lord Hodge (giving the sole judgment of the Court) set out a non-exhaustive list of factors to be considered in an obviousness assessment, but cautioned they should not be applied in a mechanistic way. These are:
- Was it 'obvious to try';
- Was the research that was conducted routine in nature;
- The burden and cost of the research;
- The necessity for, and the nature of, the value judgments the skilled team would have made in the course of a testing program;
- The existence of alternative or multiple paths of research;
- The motivation of the skilled person;
- Whether the results are unexpected or surprising (expectation of success);
- Hindsight, which includes knowledge of the invention, should not be used;
- Whether a feature is an added benefit in context (a bonus), or obvious for another purpose;
- Of particular relevance to this case, the fact that claims to dosage regimens have been held valid, drafted as either Swiss-type or EPC 2000 claims.
The UK Supreme Court upheld the decision of the Court of Appeal that all of the claims lacked an inventive step. It agreed with the Court of Appeal's finding on the logical sequence of testing that, on the facts, the skilled team would use routine, established practices involved in pharmaceutical research, and that the Daugan Patent would have motivated them to identify the low dose. In doing so, the Court cautioned that this was "only one of several factors to be weighed in the assessment and it has no primacy and certainly no paramount status as a consideration."
However, the UK Supreme Court rejected Actavis' argument that "the skilled person's repertoire" should include all obvious modifications or additions to the state of the art. The Court considered such an approach may prevent protection being obtained for selection or improvement patents.
On the issue of whether the Court of Appeal could interfere with the trial judge's decision, the UK Supreme Court held that the trial judge had erred in principle by failing to appreciate that having identified a therapeutic plateau, the skilled team would have continued to test lower dosages until coming upon the 5mg dose. Accordingly, the Court of Appeal had been right to re-weigh the relevant factors and interfere with the trial judge's factual findings.
Finally, it is interesting to note that the UK Supreme Court discussed how the decisions of foreign courts were not necessarily helpful in determining the issues before it, due to potential differences in evidence and the approach to which that evidence may be tested in different courts. Where this leads to will be monitored carefully, since previously the English Courts have striven to be harmonised with the approaches and case outcomes in other EPC jurisdictions (and the EPO Technical Boards of Appeal).
Whilst this decision is disappointing news for the patentees in this case, the UK Supreme Court's decision should provide some reassurance to the wider innovative pharmaceutical industry. Lord Hodge explicitly stated that "...efficacious drugs discovered by research involving standard pre-clinical and clinical tests should be rewarded with a patent if they meet the statutory tests."
The decision is a useful reminder of the factors to be considered when assessing obviousness, but emphasises how the approach should not be a mechanistic one: the relevant factors will depend on each case's specific facts. What will be particularly interesting in the future is to see how this applies to pharmaceutical drug discovery and clinical development, particularly with automation and artificial intelligence playing an ever increasing role.
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