MERCK SHARP & DOHME LTD v ONO PHARMACEUTICAL CO. LTD

[2016] R.P.C. 10 417 MERCK SHARP & DOHME LTD v ONO PHARMACEUTICAL CO. LTD PATENTS COURT Birss J.: 16, 17, 20 – 22, 27 and 28 July and 22 October 2015 [2015] EWHC 2973 (Pat), [2016] R.P.C. 10 H1 Patents – Validity – Construction – Immunotherapy cancer treatments – Swiss form claims – Purpose-limited product claims – Common general knowledge – Contradictory views – Added matter – Priority – Insufficiency – Agrevo obviousness – Lack of technical contribution – The role of the issue of plausibility in patent litigation – Novelty – Obviousness – Fair expectation of success. H2 Patents Act 1977, ss.1(1)(a), 1(1)(b), 2(3), 3 European Patent Convention (“EPC”), art.56 This report concerns the judgment delivered in two actions concerning European Patent (UK) 1,573,878 entitled “Immunopotentiating compositions” (“the Patent”) with a claimed priority date of 3 July 2002. The Patent related to the use of antiPD-1 antibodies for the treatment of cancer. The first action was brought by Merck Sharp & Dohme Ltd and was for the invalidation of the Patent. The second action was an action for infringement brought by Ono Pharmaceuticals and Prof Honjo as patentees and Bristol Myers Squibb Company as exclusive licensee (together referred to here as “Ono”) against both Merck Sharp & Dohme Ltd and Merck & Co Inc (together referred to as “Merck”). There were no distinct infringement issues. Both actions turned on the validity of the Patent. The relevant claims of the Patent were claims 1 and 3, which were in the following terms: H3 “1. Use of an anti-PD-1 antibody which inhibits the immunosuppressive signal of PD-1 for the manufacture of a medicament for cancer treatment.” “3. Anti-PD-1 antibody which inhibits the immunosuppressive signal of PD-1 for the use in cancer treatment.” H4 H5 Merck contended that the Patent was invalid on grounds of lack of novelty, obviousness, lack of entitlement to the claimed priority date, insufficiency/lack of technical contribution and added matter. Ono had applied to make conditional amendments to the claims to limit claims 1 and 3 to melanoma treatment. Merck accepted such amendments would be formally allowable but contended that the claims were obvious even in proposed amended form. Ono accepted that if priority was lost the claims were invalid over a paper published by the inventors themselves (referred to as “Iwai”). It was common ground that the Patent was addressed to a team including a cellular immunologist working with receptors and the function of T-cells in the immune system and that the skilled team would include members with experience in producing and modifying human antibodies or in working with transgenic mice. [2016] R.P.C., Issue 6 ß Crown Copyright 418 H6 H7 H8 H9 MERCK SHARP & DOHME LTD v ONO PHARMACEUTICAL CO. LTD However there was a question as to whether the knowledge of the skilled team would include knowledge of signal transduction pathways, being the mechanisms operating inside a cell whereby the signal caused by the activation of a receptor on the cell surface was acted upon. Merck summarised its case on common general knowledge in a series of 37 propositions, which are set out and addressed at [46] to [51] of the judgment. Many were either wholly, or at least largely, common ground (in some instances with qualifications). The main area of dispute concerned knowledge of the PD-1 pathway. It was Merck’s case that as at the priority date so far as the skilled team were concerned the binding of ligands PD-L1 or PD-L2 to the PD-1 T-cell membrane receptor generated an inhibitory signal. Although Merck accepted that there had been some co-stimulatory results relating to the ligands, it argued that the prevailing explanation was that there was probably another receptor for those ligands which was co-stimulatory (“the second receptor theory”). Merck also relied upon what was known about the CTLA-4 receptor, alleging that there was a close homology between CTLA-4 and PD-1. CTLA-4 was known to inhibit T-cell activation and CTLA-4 “knockout mice” (being mice in which the CTLA-4 gene had been disabled) suffered a lethal autoimmune disease. Further, anti-CTLA-4 antibodies were known to inhibit tumour growth in mice, were known to be in clinical trials in humans and, just before the claimed priority date of the Patent, successful clinical trials of Phase I studies had been published (in the “Tchekmedyian” and “Davis” abstracts). Merck contended that the step of testing anti-PD-1 antibodies to see if they too inhibited tumour growth in mice was obvious. The added matter objection was that the application as filed included wider disclosures than claim 1 and that the patentee had made a impermissible selection from these. Merck argued that the Patent could not be both valid over one of the prior art applications relied upon (“Dana Farber 557”) and overcome this objection. Merck’s arguments on priority, insufficiency and lack of technical contribution (“Agrevo obviousness”) all covered essentially similar territory. On the issue of priority, Merck contended (i) that there was no disclosure of an anti-PD-1 antibody being generated or tested in the priority document; (ii) that the claims were too wide to be supported by the narrower teaching of the priority document: the teaching of the priority document was limited to treating tumours which expressed PD-L1 or PD-1 ligands or which were immunogenic and the skilled person would not have been able to predict that all cancers or substantially all cancers would be susceptible to anti-PD-1 therapy; and (iii) the claims were too wide in that, to produce the unamended claim 1, there had been selection of the following: PD-1 from a disclosure of {PD-1 or PDL1}; an anti-PD-1 antibody from other therapeutic agents; cancer from a list including cancer, infection and other T-cell disorders; and (for the amended claims) melanoma from a list of cancers. As to insufficiency and lack of technical contribution, Merck contended (i) that the claims were excessively broad as they covered any and all cancers but the Patent did not render it plausible that all cancers could be treated by an anti-PD-1 inhibitory antibody (alternatively, rendered it plausible only in relation to cells expressing PD-L1 (or PD-L2) or which were otherwise known to be immunogenic); and (ii) that there were cancers which were not treated by the claimed antibodies such as colorectal cancer, prostate cancer and multiple myeloma. Ono contended, inter alia, that examples 4 and 5 of the priority document contained crucial in vivo mouse tumour models experiments in PD-1 knockout mice and expressly taught that anti-PD-1 inhibitory antibodies would be expected to have a similar effect. The fact that an anti-PD-1 antibody had not been made and tested Published by Oxford University Press for the Intellectual Property Office [2016] R.P.C. 10 H10 H11 H12 H13 419 did not matter. Moreover, the disclosure of the priority document wa (...truncated)