Actavis & Ors v Eli Lilly And Company

Factual and Procedural Background

This opinion concerns patent litigation relating to tadalafil, a pharmaceutical compound used to treat male erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia. The patents and exclusive licenses are held by Lilly and ICOS. The claimants in the case are pharmaceutical companies Actavis, Actelion, Teva, and Generics (UK) (Mylan), who seek to challenge the patents to clear the way for generic products. The relevant supplementary protection certificate (SPC) expires in November 2017, and the commercial stakes are high, with significant sales figures for the branded products in the UK and Europe.

Two patents are in issue: EP (UK) 1,173,181 ("the 181 patent") relating to dosing of tadalafil, and EP (UK) 1,200,092 ("the 092 patent") relating to drug formulation. The dispute involves issues of claim construction, infringement, priority entitlement, added matter, novelty, inventive step, and sufficiency. The litigation also involves consideration of prior art including WO 97/03675 (Daugan), WO 01/08688 (Anderson), WO 00/53148 (Stoner), and WO 01/08686 (Oren).

The case involves extensive expert evidence from medicinal chemists, clinical pharmacologists, clinicians, and pharmaceutical formulation experts, addressing both the technical and legal aspects of the patents and their validity and infringement.

Legal Issues Presented

1. Whether the claims of the 181 and 092 patents are entitled to priority from their respective priority documents.
2. Whether the claims of the patents include added matter beyond the original disclosures.
3. Whether the claims lack novelty over cited prior art, including Anderson, Stoner, and Oren.
4. Whether the claims involve an inventive step, particularly regarding the dosing regimen of tadalafil and its formulation.
5. Whether the claims are insufficient for lack of enablement or ambiguity.
6. Whether the claimants threaten to infringe the patents, justifying infringement counterclaims.
7. Issues of claim construction, including the interpretation of dosing limitations and particle size distributions.

Arguments of the Parties

Claimants' Arguments

• The claims are not entitled to priority because tadalafil is not clearly and unambiguously disclosed in the priority documents, especially due to chemical nomenclature issues.
• The dosing features relating to maximum daily doses are not supported by the priority documents.
• The claims lack novelty over prior art such as Anderson, Stoner, and Oren, especially if priority is lost.
• The dosing regimen of 5mg tadalafil is obvious as it would be routine to conduct dose-ranging studies starting from known compounds like sildenafil and tadalafil.
• Micronisation of tadalafil with surfactants is an obvious formulation approach given its poor solubility.
• The claims limited by pharmacokinetic parameters are too broad and insufficient, covering compositions beyond micronised tadalafil.
• There is no established threat of infringement merely by seeking revocation with contingent launch intentions.

Respondents' (Lilly's) Arguments

• Tadalafil is clearly disclosed in the priority documents, with the chemical name referring unambiguously to tadalafil based on expert evidence and application of chemical nomenclature rules.
• The dosing claims are supported by the priority documents, including sub-ranges such as 1-5 mg doses and maximum daily doses.
• The claims are novel and involve an inventive step, particularly the 5mg dosing regimen which was not obvious over the prior art and involved unexpected beneficial side effects.
• Micronised formulations are not obvious to work due to tadalafil's high dose number and pharmacokinetic challenges, and the skilled formulator would not dismiss these issues.
• The claims limited by pharmacokinetic parameters are supported and enabled by the patent disclosure and the skilled team would be able to produce formulations with the claimed properties.
• There is a real and strong probability of infringement by the claimants if they launch their generic products, justifying infringement counterclaims.

Table of Precedents Cited

Court's Reasoning and Analysis

The court undertook a detailed and technical analysis of the patents, the priority documents, and the prior art. The key points of the court’s reasoning are as follows:

• Priority: The court carefully analysed whether tadalafil was clearly and unambiguously disclosed in the priority documents, focusing on a disputed chemical name involving stereochemistry. The court preferred the expert evidence supporting that the chemical name referred to tadalafil, thus supporting priority. The court also considered the disclosure of dosing ranges and found that sub-ranges such as 1-5 mg and maximum daily doses of 5 mg were supported by the priority documents, except for specific claims to 2.5 mg doses which lacked priority.
• Added Matter: The court found no added matter in the claims compared to the application as filed, including for dosing ranges.
• Novelty: Claims lacking priority were found invalid for lack of novelty over Anderson and Oren. The court rejected anticipation by the Stoner prior art as it related to combination therapies and was not enabling for the claimed monotherapy. The court also found that certain claims of the 092 patent were anticipated by Oren due to inevitable result, as the formulations disclosed would, on the balance of probabilities, possess the claimed pharmacokinetic properties.
• Obviousness: The court applied the Pozzoli structured approach and considered the skilled team and common general knowledge. The prior art Daugan disclosed tadalafil and its use for erectile dysfunction but did not specifically disclose the 5 mg dosing regimen. The court found that while it was obvious to develop tadalafil and conduct routine clinical trials, including dose-ranging studies starting at higher doses (25, 50, 100 mg), it was not obvious to test or expect efficacy at 5 mg daily dosing. The existence of a plateau in dose response and a surprising low side effect profile at 5 mg supported inventive step. For the 092 patent, the court found that micronisation with surfactant was an obvious formulation approach, supported by expert evidence and common general knowledge, and thus the formulation claims lacked inventive step.
• Insufficiency: The court found no insufficiency for the 181 patent claims. For the 092 patent, claims limited only by pharmacokinetic parameters were insufficient as they covered compositions broader than the technical contribution of micronised tadalafil. The court rejected insufficiency challenges to claims limited by particle size distribution on the basis that the skilled formulator would construe the distribution as by volume (not number), resolving ambiguity.
• Claim Construction and Infringement: The court construed the dosing claims as covering administration up to a maximum total daily dose of 5 mg, meaning that use of 2.5 mg or 5 mg tablets as approved in product information leaflets and summaries of product characteristics (SmPC) would infringe. The court rejected the claimants’ contention that seeking revocation with contingent launch intentions did not constitute a threat of infringement, finding a sufficiently strong probability of infringement based on marketing authorisations and market conditions to justify infringement counterclaims.

Holding and Implications

The court’s final determinations are:

i) At least claim 7 of the 181 patent is valid and infringed. The court found that the 5 mg dosing regimen claim involves an inventive step and is supported by the priority documents and patent specification. The claimants’ generic products, if launched with the relevant marketing authorisations, would infringe the valid claims.

ii) All claims of the 092 patent are invalid. The court found the 092 patent claims to lack inventive step, particularly due to the obviousness of micronised tadalafil formulations with surfactant, and certain claims to be insufficient for lack of commensurateness with the technical contribution.

The decision means that the 181 patent remains enforceable against the claimants for the relevant dosing claims, while the 092 patent is revoked in full. The ruling does not establish any new legal precedent but applies settled principles to the complex technical facts of this case. The court’s reasoning clarifies the application of priority, obviousness, and sufficiency principles in the context of pharmaceutical patents involving dosing regimens and formulations.