Merck Sharp & Dohme Ltd v Ono Pharmaceutical Co Ltd & Anor

For purpose-limited medical-use claims, plausibility is not a free-standing statutory requirement. It is relevant to whether the disclosure is enabling and, in appropriate cases, to novelty, priority, sufficiency and obviousness.

A patent may plausibly support a broad cancer-treatment claim where the evidence establishes a general therapeutic principle, even though the treatment will not work for every cancer or patient. Prior art which discloses the general idea of manipulating a biological pathway may nevertheless fail to anticipate where it does not make the claimed therapeutic effect plausible.

An experiment may be obvious to try without the invention being obvious. The question is whether the skilled person had a fair or reasonable expectation of success, assessed against the whole state of the art and the uncertainties in the field.

Ono owned a patent concerning the use of inhibitory anti-PD-1 antibodies for cancer treatment and Bristol Myers Squibb was its exclusive licensee. Merck challenged the validity of claims 1 and 3 on grounds including added matter, lack of priority, insufficiency, lack of technical contribution, lack of novelty and obviousness.

The principal prior art was Dana Farber 557, Wyeth 499, the Latchman paper and two abstracts concerning anti-CTLA-4 antibodies. Merck accepted that its pembrolizumab product fell within the claims if the patent was valid. Ono proposed a conditional amendment limited to melanoma, but the live dispute concerned the unamended claims. The central questions were whether the broad claims were adequately supported and enabled, and whether the prior art disclosed or made obvious the claimed anti-PD-1 cancer treatment.

1. Construction and support. The unamended claims covered cancer generally. They were not limited to particular cancers, cancers previously regarded as immunogenic, or universal success in every patient. The priority document individually disclosed the idea of using an inhibitory anti-PD-1 antibody to treat cancer. The mouse tumour experiments, together with the teaching that antibodies would be expected to produce a similar effect, made that use plausible.
2. Common general knowledge. The skilled team understood that PD-1 was an inhibitory receptor, but also knew of contradictory evidence concerning co-stimulatory effects associated with PD-L1 and PD-L2. The explanation for the discrepancy was unresolved. It was therefore wrong to treat the common general knowledge as establishing an exclusively inhibitory net effect in every circumstance.
3. Priority, sufficiency and technical contribution. The evidence supported a sound prediction that anti-PD-1 therapy could treat cancer generally, whether or not PD-L1 or PD-L2 was expressed on tumour cells. The fact that the treatment was less effective or ineffective for some cancers did not destroy the generality of the teaching. The claims were sufficiently disclosed and did not impose an undue burden. They were entitled to the first priority date.
4. Novelty. Following Synthon v SmithKline Beecham [2006] RPC 10, anticipation required disclosure and enablement. A medical-use claim required an enabling disclosure of the same therapeutic effect. Dana Farber 557 and Wyeth 499 disclosed the idea of an anti-PD-1 agent for cancer treatment, but their contradictory disclosures and absence of an unambiguous anti-PD-1 cancer model did not make the claimed effect plausible. Claims 1 and 3 were novel.
5. Inventive step. The Latchman paper and Dana Farber 557 would have suggested testing PD-1 blockade in a tumour model. The necessary materials and methods were available. However, because of the unresolved scientific debate, the history of limited success in cancer immunotherapy and the excitement generated by the later tumour-model results, the skilled person would have hoped for success rather than reasonably expected it. The claims were not obvious. The anti-CTLA-4 abstracts did not make a switch to anti-PD-1 therapy obvious and reliance on them involved hindsight.
6. Disposition. The patent was valid. Judgment was given in favour of Ono.