Merck v Ono Pharma: immunotherapy second medical use

Ono has developed an anti-PD-1 antibody called nivolumab (brand name Opdivo) and Ono alleged that Merck Sharpe and Dohme's (MSD) anti-PD-1 antibody called pembrolizumab (brand name Keytruda) infringed the patent. MSD alleged that the patent was invalid. Both antibodies have obtained clinical approval for the treatment of some cancers. The judge, Birss J, found that the patent was valid. In this article we will particularly review MSD's plausibility attack under priority, sufficiency, AgrEvo obviousness, and also novelty.

Claims 1 and 3 read:

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.
2. Anti-PD-1 antibody which inhibits the immunosuppressive signal of PD-1 for the use in cancer treatment.

Common general knowledge

The judge noted that, in the field of cancer immunotherapy in the mid-2000s, the concept of trying to use agents associated with the immune system to attack cancer is old, but that whether these ideas work in practice is another matter entirely.

Particularly in relation to PD-1, the judge noted that, before the patent, although the skilled team regarded the PD-1 pathway as an inhibitory pathway, they were aware of evidence of a discrepancy, in that its ligands PD-L1/L2 had been shown also to have a co-stimulatory effect.

Priority/insufficiency/lack of technical contribution

MSD's objections included arguments about insufficiency, AgrEvo obviousness (lack of a technical contribution) and loss of priority. These points are not identical although they all cover very similar territory. If priority was lost it was not in dispute that the claims were invalid in the light of an intervening paper.

There is no disclosure of an anti-PD-1 antibody being generated or tested in the priority document. Ono argued however that the priority document contained crucial in vivo mouse tumour model experiments in PD-1 knockout mice and expressly taught that anti-PD-1 inhibitory antibodies would be expected to have a similar effect. They argued that the experiments in the priority document were evidence that blockade of PD-1 inhibits tumour growth in two different types of cancer. The skilled person would recognise that these results have a broad application in the treatment of cancer because the blockade treats the immune system rather than being directed to an attribute of any particular cancer. This makes it plausible that the invention is effective for treating a wide range of cancers.

The question of plausibility was considered by the Supreme Court in HGS [see note 2 below] primarily in the context of Art 57 EPC (susceptible of industrial application) and sufficiency. The contrast drawn in that case was between "speculation" on one side and a "plausible" or "reasonably credible" claimed use on the other.

The judge noted that while a low standard might work to Ono's advantage in the context of arguments about priority and sufficiency, there was a tension in the context of novelty as one of Ono's submissions was that the lack of such in vivo tumour data in the prior art did not deprive the claims of novelty because the art did not make the treatment plausible.

In HGS it was found to be plausible that the product claimed would have some sort of therapeutic utility. At the level of individual diseases one could not say which might be treated but that did not matter because the claim was not so limited. For a purpose limited medical use claim, more specificity is likely to be required than was necessary in HGS but on the other hand, material which is too narrowly focussed may not support a wide claim. The principle applicable to purpose limited medical use claims must be that the material relied on to establish plausibility must be both sufficiently specific, and have a sufficient breadth of application, to fairly support the claim both in terms of the nature of the agent claimed to have an effect, and in terms of the effect claimed.

The judge went on to say he was satisfied that to a skilled person reading the patent application when it was filed in 2003 (or the priority document in 2002), the document makes a soundly based and reasonable prediction that the therapy will work to treat cancer in general. Success in this context does not mean success in every patient in all circumstances, no treatment will achieve that. Nevertheless given the patent described the invention at a fair level of generality, the claims were found to be entitled to priority, sufficiently disclosed and commensurate with the technical contribution of the patent.

Novelty

For anticipation to be established there must be disclosure of the invention by the prior art and that disclosure must be enabling [see note 3 below]. For medical use claims (Swiss style/EPC 2000) there must be an enabling disclosure of the same therapeutic effect in the prior art, since those claims derive their novelty from the intended medical use.

The judge found that as a matter of disclosure (rather than enablement), the main prior art citation discloses the idea of using an anti-PD-1 agent, which could be an anti-PD-1 antibody, for the treatment of cancer. An anti-PD-1 agent is not the only agent disclosed and cancer is not the only disease proposed to be treated but nevertheless there is an individualised disclosure of that combination in the citation. The issue was therefore enablement.

The citation was not only long, it hedged its bets. Overall the judge decided that the content of the citation while sufficiently broad to render plausible the idea of using an agent which acts on the PD-1 pathway in medicine generally; the content was not specific enough for cancer, to render plausible the use of that agent in the treatment of cancer. The citation was not enabling and therefore the claims were novel.

Although not discussed here, the judge went on to find in favour of Ono on inventive step. Interestingly, the patent was also found valid by the Opposition Division in parallel proceedings and is now under appeal at the EPO.

The judge noted this case is complex and summarised some of his reasons for reaching the conclusion that the patent is valid as follows:

• At the priority date the common general knowledge of the person skilled in the art included the idea that the PD-1 pathway was an important aspect of the immune system with a role in self-tolerance. It could be a target for therapeutic manipulation. This knowledge included the concept that PD-1 was an inhibitory receptor. However it also included knowledge of a debate about the PD-1 pathway. It was known that ligands to PD-1 also had a co-stimulatory effect and it was known that a proven explanation had not emerged.
• The in vivo mouse data contained in the first priority document, in which two different kinds of tumour are transferred to PD-1 knockout mice, represent an important advance. The data make plausible the idea that an agent which blocks the PD-1 receptor can manipulate the immune system in such a way as to treat cancers in general, not only those tumours which express PD-1 ligands. Nevertheless, while the reasonable prediction which the priority document supports is a wide one, it does not purport to promise that every cancer patient in all circumstances can be treated. Claims 1 and 3 are plausible and are entitled to priority.
• The patent enables the skilled person to make and use anti-PD-1 antibodies as anti-cancer medicines. Moreover, and crucially, the evidence today shows that anti-PD-1 antibodies have been approved to treat a number of different cancers and are worth investigating in a very wide range of cancers. The evidence today also shows that anti-PD-1 monotherapy probably does not treat prostate cancer and most colorectal cancers, but this does not demonstrate a lack of technical contribution or undue burden. The law does not require perfection.
• The prior art document discloses the idea of manipulating the PD-1 pathway and includes the idea of an anti-PD-1 agent as a therapeutic agent to be used to treat a number of diseases including cancer. That agent could be an anti-PD-1 antibody. However the document includes evidence of both the inhibitory effect of the PD-1 receptor and the co-stimulatory effect of PD ligands. While its disclosure may be enough to support the general idea of using an agent which acts somehow on the PD-1 pathway in medicine, it does not make plausible the specific idea of an anti-PD-1 agent to treat cancer. Therefore claims 1 and 3 are novel.
• The claims involve an inventive step because the common general knowledge includes knowledge of the existence of the debate about the cause of the co-stimulatory role of PD-1 ligands. Although it was known that the PD-1 receptor was inhibitory, the existence of the debate meant that a skilled person who conducted a test of PD-1 blockade against a tumour in a mouse, would not have a fair expectation of success. The mouse tumour results in the patent were exciting and were not predictable from the prior art. Claims 1 and 3 are not obvious.

Notes

1. Full decision of Merck Sharp & Dohme Ltd v Ono Pharmaceutical Co Ltd & Anor [2015] EWHC 2973 (Pat) (22 October 2015): http://dycip.com/msdvonopharma
2. Human Genome Sciences Inc v Eli Lilly and Company [2011] UKSC 51 (2 November 2011): http://dycip.com/hgs11dec
3. Synthon BV v. Smithkline Beecham plc [2005] UKHL 59 (20 October 2005): http://dycip.com/synthonvsb