Plausibility in immunotherapy – is PD-1 the way forward?


Ono is the proprietor of a patent for the use of anti-PD-1 antibodies which inhibit the immunosuppressive signal of PD-1 in the treatment of cancer. Ono developed such a monoclonal antibody, nivolumab, which it branded as Otivo. Merck has also developed a monoclonal antibody, known as pembrolizumab and branded as Keytruda.  It was common ground that Merck’s intended use of Keytruda would infringe Ono’s patent if the patent was valid.  Merck challenged the patent via lack of novelty, obviousness, lack of entitlement to priority, added matter and insufficiency attacks.  Birss J found Ono’s patent to be valid and infringed. However, several interesting issues came up along the way.

With regard to insufficiency, Merck alleged that the claims in Ono’s patent were not plausible because the patent does not enable an anti-PD-1 antibody that is suitable to treat all cancers. The claim was very broadly drafted in such terms. Despite acknowledging that certain cancers were unlikely to benefit from the treatment, Birss J confirmed that the claims were plausible because the correct test was whether the product has an effect on a disease process so as to make the claimed therapeutic effect plausible and that “success in this context does not mean success in every patient in all circumstances [because] no treatment will achieve that”.

On CGK, Birss J held that the CGK is capable of including contradictory ideas on a topic such that, while the skilled team regarded the PD-1 pathway as inhibitory, it was also within that team’s CGK that there was evidence of discrepancy in that the pathway might also involve a co-stimulatory response. Therefore, the skilled team would have been aware that the PD-1 receptor might not have an inhibitory effect in all circumstances. This finding had an important impact on obviousness.

Turning to obviousness, Merck alleged that it was obvious to carry out an experiment in which PD-1 was blocked using an anti-PD-1 antibody in a mouse tumour model because: (i) a suitable tumour cell line was readily available; (ii) a mouse model was readily available; and (iii) an anti-PD-1 antibody could be produced without difficulty.  Ono was forced into a squeeze between obviousness and insufficiency and had to accept that cell lines, mouse models and antibodies could be easily made or procured if the skilled person wanted to undertake the experiment.  Therefore, the point turned on the skilled person’s expectation of success.  On this point, Birss J was persuaded by Merck’s expert who conceded that she would have considered the test results in Ono’s patent to be “very, very exciting” because of the “mood of gloom” around using immunotherapy to treat cancer at the priority date (2002).  Accordingly, and bearing in mind the uncertainty in the CGK, Birss J held that, while the skilled person might have conceived of trying the invention, they would have done so in the hope that it would succeed rather than with an expectation of success and this was not enough to render Ono’s patent obvious.

An unusual point to note in this case is Ono’s stance that, if its patent was found valid and infringed, it would not seek an injunction in the UK against Merck because of the life-saving nature of Merck’s treatments (provided that it was awarded future damages on the basis of an appropriate royalty).  It is interesting to note the parallel between this voluntary stance on an injunction in the pharmaceutical industry and the mandatory stance on injunctions in relation to FRAND and essentiality in the telecommunications industry.

Emma Muncey