Actavis Group PTC EHF & Ors v ICOS Corporation & Anor [2019] UKSC 15

ICOS/Eli Lilly's patent claimed a 1-5mg daily dose of tadalafil (Cialis) for treating erectile dysfunction. Generic manufacturers challenged it as obvious. The Supreme Court upheld the Court of Appeal's finding that the dosage patent lacked an inventive step, as routine dose-ranging trials would inevitably have led to the 5mg dose.

Facts

The appeal concerned EP(UK) 1,173,181 (“the 181 patent”), owned by ICOS Corporation and exclusively licensed to Eli Lilly, which claimed a pharmaceutical unit dosage of 1-5mg of tadalafil for oral administration up to a maximum of 5mg per day for treating sexual dysfunction, including erectile dysfunction (ED). Tadalafil, marketed as CIALIS, is a PDE5 inhibitor and a “second in class” drug following sildenafil (VIAGRA).

The earlier Daugan patent (EP 0 839 040), whose validity was not contested, had disclosed tadalafil as a PDE5 inhibitor for treating ED, with dosages generally in the range of 0.5mg to 800mg daily and an exemplified 50mg tablet, but did not specify an appropriate dosage regime. ICOS acquired the Daugan patent from Glaxo and undertook extensive research, ultimately discovering that a 5mg daily dose was safe, effective, and unexpectedly produced minimal side effects, enabling daily (chronic) rather than on-demand dosing.

Actavis and other generic manufacturers sought revocation of the 181 patent, principally on the ground of obviousness. At first instance, Birss J held claim 7 to involve an inventive step. The Court of Appeal (Kitchin LJ leading) reversed, holding claims 1, 7 and 10 invalid for lack of inventive step.

Issues

The appeal raised two principal questions:

• How the test of obviousness under section 3 of the Patents Act 1977 applies to a dosage patent where the compound and its therapeutic use were already disclosed in valid prior art (Daugan), but the specific dosage regime was discovered through routine pre-clinical and clinical trials.
• Whether the Court of Appeal was entitled to reverse the trial judge’s evaluative finding that the patent involved an inventive step.

Arguments

Appellants (Lilly/ICOS)

Lilly argued that the statutory question was whether, at the priority date, before any research was undertaken, it was obvious that a 5mg/day dose would be safe, effective and have minimal side effects. Since the skilled team had no reasonable expectation of efficacy at such a low dose, and since the research involved expensive and unpredictable work involving multiple value judgments and surprising results (notably the therapeutic plateau and reduced side effects), the invention was not obvious. Lilly invoked the EPO’s problem-and-solution approach and emphasised the terms of the claim.

Respondents (Actavis and others)

The respondents contended that it was obvious to take tadalafil forward into a routine pre-clinical and clinical trials programme. A 5mg dose would inevitably be tested in standard dose-ranging studies aimed at establishing the dose-response relationship and identifying the lowest effective dose. The unexpected side-effect benefit was a mere “bonus” that could not confer patentability on an otherwise obvious dosage regime. Mr Speck relied on the principle that information within the “skilled person’s repertoire” cannot ground a patent.

Judgment

Lord Hodge (with whom Lady Hale, Lord Kerr, Lord Sumption and Lord Briggs agreed) dismissed the appeal.

The overarching principle

The Court reaffirmed the “patent bargain”: a monopoly is granted in return for disclosure of an invention that makes a technical contribution to the art. This principle, recognised in both UK and EPO jurisprudence, underpins the requirements of novelty, inventive step, industrial application and sufficiency.

Approach to obviousness

Lord Hodge rejected both extreme positions. Lilly’s approach wrongly excluded from consideration uninventive steps that the skilled team would take post-priority date to implement Daugan. Actavis’s “repertoire” formulation was too broad to serve as a general test. The statutory question under section 3 of the 1977 Act must be answered by reference to all relevant circumstances, with no single factor having paramount status.

The Court identified multiple relevant factors, none decisive alone: whether the step was “obvious to try” with a reasonable expectation of success; the routine nature of research; burden and cost; necessary value judgments; existence of alternative paths; motive; unexpected or surprising results; the warning against hindsight; and whether a feature is merely an added “bonus” benefit.

Dosage patents

Dosage patents can be valid, but as Jacob LJ noted in Actavis v Merck, investigating appropriate dosage regimes is standard practice and “nearly always such dosage regimes will be obvious”. The target of the skilled team’s research — the lowest effective dose — is largely pre-determined.

Role of the appellate court

An appellate court may reverse a trial judge’s evaluation of obviousness if there is an error of principle, which includes failing to take account of relevant matters, taking into account irrelevant matters, or reaching a conclusion outside the bounds of reasonable disagreement.

Application to the 181 patent

Critically, Birss J had found that it was “very likely” the skilled team, having discovered an unexpected therapeutic plateau between 25mg and 100mg doses, would conduct further dose-ranging studies including 5mg and 10mg doses. Dr Saoud (Lilly’s own expert) accepted that testing lower doses was “a no brainer”. The Court of Appeal was entitled to treat the judge’s failure to appreciate the logical consequences of this central finding as an error of principle permitting its own evaluation.

The lower dose being significantly below the 50mg sildenafil dose carried no weight once it was found the team would very likely test it. The lack of expectation of efficacy at 5mg carried little weight where the team would investigate that dose as part of the dose-response inquiry. The surprising reduced side effects were a mere added benefit which did not save the claim, since the selection of the dose was obvious for another purpose (completing the dose-ranging studies). The daily dosing regime flowed inevitably from discovery of tadalafil’s half-life in Phase I, and in any event claims 7 and 10 were not confined to daily dosing.

Lord Hodge also held that the “could-would” problem-and-solution approach of the EPO would likely yield the same result: the skilled team would have been prompted to test the 5mg dose in pursuit of the underlying technical problem (identifying an appropriate dosage regime).

Foreign judgments

The Court noted that Dutch, German, Belgian and Portuguese courts had reached the same conclusion, while Danish, Polish and Czech courts had differed. Lord Hodge emphasised caution in relying on parallel foreign decisions given differences in evidence and factual findings.

Implications

Legal principles

The judgment confirms that obviousness is a fact-sensitive multi-factorial evaluation with no factor having paramount status. The Windsurfing/Pozzoli structure and the EPO’s problem-and-solution approach are useful tools but neither should be applied mechanistically; both are glosses on section 3 of the 1977 Act. Uninventive steps taken after the priority date to implement valid prior art are not excluded from the obviousness assessment.

The decision reaffirms that dosage patents face a particularly difficult obviousness hurdle where the compound and therapeutic use are already disclosed, because identifying the appropriate (usually lowest effective) dose is the pre-determined target of routine clinical research.

Significance

The judgment is important for pharmaceutical patent practice. It confirms that a surprising or unexpected technical effect discovered during routine trials will not necessarily confer patentability where the dose would have been identified in any event in the course of standard dose-ranging studies — this being an “added benefit” or “bonus” analogous to the PTFE-coated corkscrew in Hallen v Brabantia.

However, Lord Hodge emphasised that the Court of Appeal’s reasoning should not be read as supporting any general proposition that the product of routine enquiries cannot be inventive. Efficacious drugs discovered through standard pre-clinical and clinical tests remain patentable where they meet the statutory tests, and selection and improvement patents remain available where the selection or improvement is justified by a hitherto unknown technical effect.

Limits

The decision turns on the specific findings that (i) the skilled team would very likely have proceeded to test lower doses after discovering the therapeutic plateau and (ii) the target (lowest effective dose) was pre-established. It does not rule out patentability for dosage regimes where the research path is not similarly foreseeable, nor where the skilled team would not be motivated to conduct the relevant tests. The judgment leaves intact Jacob LJ’s recognition in Actavis v Merck that in unusual cases a novel non-obvious dosage regime may be patentable.

The decision provides important guidance for generic manufacturers challenging secondary patents on dosage regimes and for originator pharmaceutical companies relying on such patents to extend effective market exclusivity.

Verdict: Appeal dismissed. The Court of Appeal’s decision that claims 1, 7 and 10 of the 181 patent were invalid for lack of inventive step was upheld.

Source: Actavis Group PTC EHF & Ors v ICOS Corporation & Anor [2019] UKSC 15