In Merck Sharp & Dohme v Ono Pharmaceutical & Anr, Birss J found that Ono's cancer immunotherapy patent was valid. He applied the Court of Appeal's guidance on the 'obvious to try' doctrine; and his analysis on 'plausibility' underpinned his findings on all aspects of validity.

In Merck Sharp & Dohme v Ono Pharmaceutical & Anr [2015] EWHC 2973 (Pat) (22 October 2015), Birss J has found that Ono's patent, with Swiss form and EPC 2000 claims to anti-PD-1 antibodies which inhibit the immunosuppressive signal of PD-1 for cancer treatment, is valid. There was no distinct issue of infringement, which was conceded by Merck (in the event the patent was found valid).

In concluding that the patent was valid, Birss J steered a tight course between the disclosures of the prior art and the support for the claimed invention provided in the priority document (and the patent). He explored the role of the concept of 'plausibility', finding that mouse models for cancer supported the claimed invention. On the other hand, mouse models for autoimmune disease did not enable a prior art 'disclosure' of the claimed invention, with the result that the claimed invention was novel.

The judge also put into practice guidance on the 'obvious to try' doctrine given by the Court of Appeal in its recent decision in Teva v Leo [2015] EWCA Civ 780. Although it would not have been inventive to conduct tests by which the skilled person would have led to the invention, the skilled person would not have had a sufficient expectation that the outcome would be successful to render the claimed invention obvious.

Background

Merck sought revocation of the patent. Bristol Myers Squibb is the exclusive licensee of Ono's patent.

Both Merck and BMS have developed anti-PD-1 antibodies and obtained approval for their use for the treatment of some cancers; both parties' antibodies remain in clinical trials in relation to other cancer indications.

Merck did not defend the infringement claim beyond its assertion that the patent was invalid.

Ono's position was that in this jurisdiction, if its infringement claim was successful, given the life-saving nature of the therapy it would not seek an injunction provided an appropriate royalty was agreed or awarded by the court for future infringement. Birss J noted that Ono's stance did not mean that the patent was to be judged by a different standard to any other.

The claimed invention

The patent included two key claims:

Claim 1: Use of an anti-PD antibody which inhibits the immunosuppressive signal of PD-1 for the manufacture of a medicament for cancer treatment

Claim 3: Anti-PD-1 antibody which inhibits the immunosuppressive signal of PD-1 for the use in cancer treatment

Construction

There was a dispute as to whether "cancer treatment" meant that no cancer was excluded or whether it would be understood as limited in some way. Birss J stated that it was plainly not limited; the use of an anti-PD-1 antibody to treat any cancer would be within claim 1. The judge explained:

"This question is of most significance in the context of sufficiency of disclosure, priority and plausibility. With an eye on these arguments, it is worth noting that cancers can be divided up in numerous ways. There is no simple list of types of cancer. For example although in some contexts one can refer simply to lung cancer, in other contexts one distinguishes between non-small cell lung cancer and other kinds of lung cancer. The fact that the skilled reader knows and understands this does not alter the conclusion on construction. The claim is as wide as possible.

Very few drugs work in every single patient to whom they are administered, for a variety of reasons. The fact that no skilled reader of the patent would expect this drug to work in every patient does not alter the point on claim construction either."

Priority and sufficiency

Birss J noted that the question of whether a patent or priority document makes something plausible has come up in the cases in the context of industrial application, sufficiency, priority and obviousness. (In the present case it was argued to play a part in novelty too). In HGS v Eli Lilly [2011] UKSC 51, the Supreme Court said that the sense that the word 'plausible' conveys is that there must be some real reason for supposing that the statement is true, but the standard is not any higher than that.

However, said Birss J, plausibility is not a term found in the relevant parts of the European Patent Convention (EPC) or the 1977 Patents Act and there is no law of plausibility as such. So while it has proved to be a useful concept in various factual situations, that does not mean that everything said in one context applies in a different context:

"Whenever one is considering plausibility it must be done in the context of the invention determined by properly construing the claim and one must keep in mind the particular legal objection which is under consideration."

Birss J stated that second medical use claims "include the achievement of a therapeutic effect as a functional technical feature, and, to be satisfied, require someone ... to possess an appropriate state of mind". Birss J referred to his commentary in Hospira v Genentech (I) [2014] EWHC 1094 (Pat), [57]-[64], where he said:

"59…. such claims are generally regarded as novel over a mere proposal to administer the drug to patients in the manner claimed. That is because the mere proposal does not disclose that the treatment is indeed efficacious. If it was obvious that the treatment would be efficacious, or at least it was obvious to conduct a trial of the treatment which would involve treating patients, then the claim is likely to lack inventive step but that is another matter.

60. One might say therefore that the patent specification must contain the results of a clinical trial in order to prove efficacy, since the claims contain this element as a feature. But to require that at least in all circumstances may cause another problem. Finding new treatments for disease is highly desirable. Clinical trials are a necessary but very expensive and complex part of that process. The existence of a patent (or application) may facilitate investment in the clinical trial which might not otherwise take place but that means that the patent has to be applied for before the results are known. So a rule which demanded clinical results could cause real difficulties.

61. On the other hand, if all the patent contains is a mere proposal, then it has not made a contribution to the art in this example. One has now come full circle. A mere proposal is not a disclosure of the claim, properly construed. But the patentee can hardly argue, and the Court or Patent Office is unlikely to accept, that a mere prior proposal is not enough to invalidate the claim if all that is present in the specification of the patent is a mere proposal followed by a use claim.

62. Moreover it would be a recipe for abuse if all that was required in order to obtain a patent in this field was a proposal, without any basis, to use drug A to treat disease B.

63. Patent law seeks to address these factors balancing the requirements for sufficiency of disclosure against the rules of novelty and inventive step. But the conventional sufficiency test of asking whether the claimed invention works, does not help. The treatment does work but what if the patent does not say so?

64. For these reasons the idea of "plausibility" as part of the law of sufficiency of disclosure has been developed both in the EPO (T609/02 Salk Institute) and the UK (Regeneron). The term "plausibility" has been coined to characterise what it is that a patent specification must provide in order to be sufficient, short of full clinical proof of efficacy."

Birss J noted that sometimes there is difficulty because the material relied upon for sufficiency/plausibility does not relate with sufficient specificity to the agent claimed. This was the case for example in Idenix v Gilead [2014] EWHC 3916 (Pat) and Eli Lilly v Janssen Alzheimer Immunotherapy [2013] EWHC 177 (Pat).

On the other hand, the material relied on must make the particular use, whatever it is, plausible. On this Birss J said:

"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 focused 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."

In the present case, Merck contended that Ono's patent was not entitled to the first priority claimed, and was insufficient, for several inter-related reasons. In rejecting the challenges, the following points were key to the judge's reasoning:

  1. There was no disclosure in the priority document of an anti-PD-1 antibody being generated or tested. However, in view of the data provided - in mouse models for two types of cancer - it was nevertheless plausible that an anti-PD-1 antibody would treat cancer.
  2. Anti-PD-1 antibodies target a part of the immune system rather than the cancer directly. Therefore the skilled person would not understand the disclosure of the priority document, or the support in the patent, as limited to tumours which expressed a ligand to the PD-1 receptor, even though the relevant experiments only used cells that expressed such ligands.
  3. In support of sufficiency, Ono was entitled to rely on the results of work done many years after the priority date. Extended tumour stabilisation counted as 'treatment' because the result was a better survival for the patient. There were clinical approvals for non-small cell lung cancer, melanoma and renal cancer. There remained ongoing investigations for small cell lung cancer, bladder cancer, head and neck cancer, oesophageal cancer, gastric cancer, pancreatic cancer, hepatocellular cancer, breast cancer, ovarian cancer, cervical cancer, glioblastoma, acute leukaemia, chronic myeloid leukaemia, Hodgkin's disease and Non-Hodgkin's lymphoma. 'Cancer', therefore, was and remained a fair level of generality at which to describe the invention, even though the anti-PD-1 antibodies appeared not to work in prostate and colorectal cancers. The law "does not require perfection", said Birss J, and the skilled person would not expect 100% success across the board.
  4. Following the teaching of the priority document or the patent, there was no undue burden involved for the skilled person in creating and finding a suitable anti-PD-1 antibody which is useful in cancer. The steps involved in doing so all involved very substantial work and very substantial cost, but they were not of a quality which undermined the sufficiency of the patent's disclosure. Ten years was not a long time in the context of this sort of clinical research.
  5. The priority document disclosed the treatment of cancer with an inhibitory anti-PD-antibody, clearly and unambiguously. The fact that other things were disclosed too did not take away from the individualised nature of the relevant disclosure. (Merck's added matter challenge failed for the same reason).

Novelty

Ono submitted that plausibility was an aspect of the law of novelty. Birss J said:

"In my judgment, there is no distinct requirement for plausibility in the law of novelty, over and above disclosure and enablement, but in a proper case plausibility is an aspect of enablement. In order to amount to an enabling disclosure of a medical use claim and thereby deprive the claim of novelty, the prior art has to make the therapeutic effect plausible."

Merck alleged that Ono's patent was anticipated by two prior art documents:

  1. "Dana Farber 557"

Dana Farber 557 was a PCT application titled "PD-1, a receptor for B7-4 and uses therefore".

Birss J was satisfied that as a matter of disclosure (rather than enablement), Dana Farber 557 disclosed the idea of manipulating the PD-1 pathway. This included the idea of using an anti-PD-1 agent, which could be an anti-PD-1 antibody, for the treatment of cancer. There was an individualised disclosure of that combination in Dana Farber 557.

However, the judge agreed with Ono that Dana Farber 557 did not contain a clear and unambiguous teaching of how to do these things. In particular:

  • The document included evidence of both the inhibitory effect of the PD-1 receptor and the co-stimulatory effect of the PD ligands. Merck's argument involved putting to one side the co-stimulatory effect of ligand PD-L1 as being relevant to the behaviour of the receptor PD-1 (which would not have been in keeping with the skilled person's deemed CGK), but the document did not unambiguously enable that approach.
  • Due to the nature of the experiment in Example 18 of Dana Farber 557, it was not possible to tell whether the results in Example 18 were due to interaction with only a PD-1 receptor or with another receptor. Further, the example used a model for multiple sclerosis rather than cancer. It showed the immune system could be upregulated in vivo but it was not concerned with whether that upregulation could have an effect on cancer. Dana Farber 557 did not contain a cancer model studied using an agent which could be unambiguously identified as an anti-PD-1 agent.

Birss J concluded that:

"Overall in my judgment the content of Dana Farber 557 is not specific enough in one way and not broad enough in another. It is not specific enough to render plausible the use of an anti-PD-1 agent for the relevant disease. On the other hand, while the content may be sufficiently broad to render plausible the idea of using an agent which acts on the PD-1 pathway in medicine generally, and in that sense is similar to the situation in HGS; the content is not broad enough in its application or, looked at another way, not specific enough for cancer, to render plausible the use of that agent in the treatment of cancer.

I find that Dana Farber 557 does not amount to an enabling disclosure of the use of an anti-PD-1 agent for the treatment of cancer. "

  1. Wyeth 499

Wyeth 499 was described as a document that was "closely related" to Dana Farber 557. The only in vivo results in Wyeth 499 were the same as in Dana Farber.

The significant difference between the two, said Birss J, was a somewhat clearer reference to an anti-PD-1 antibody to be used to treat cancer. However this went to disclosure, rather than enablement, and so did not turn Wyeth 499 into an enabling disclosure if Dana Farber 557 itself was not.

Inventive step

Merck alleged that the patent was invalid for 'Agrevo' obviousness: the point being that a technical effect which is not rendered plausible across the breadth of the claim cannot be taken into account when assessing obviousness. This challenge failed for the same reasons that Merck's challenges to priority and sufficiency failed.

Merck also alleged that Ono's patent was invalid in light of four pieces of prior art.

The 'Latchman paper' highlighted the idea that expression of PD-1 ligands on tumours may attenuate anti-tumour responses, suggested that the PD-1 pathway may be an attractive therapeutic target and proposed blockade of the PD-1 pathway as a way of enhancing anti-tumour immunity.

The key difference between the disclosure of the Latchman paper and the claimed invention was that there was no description in the paper, explicitly or implicitly, of the use of an anti-PD-1 antibody which inhibits the immunosuppressive signal of PD-1 of PD-1 for the manufacture of a medicament for cancer treatment.

Merck contended 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: the results would be analogous to the experimental results in the first priority document and would tell the skilled person the same thing i.e. that anti-PD-1 antibodies are useful to treat cancer.

Ono "rightly" did not dispute that suitable tumour cell lines, mouse models and anti-PD-1 antibodies could be made or procured if the skilled person wanted to undertake this test. But Ono contended that the skilled person would not have a sufficient expectation of success to make the invention obvious.

The question of whether the skilled person would have a sufficient expectation of success became a battle of the experts, and in cross-examination, Merck's expert made a crucial slip.

Merck's expert, Prof Boussiotis, agreed that if she had seen the priority document data (Examples 4 and 5 of the patent) at the relevant time, she would have considered it "very, very exciting". Birss J said that this was an "unguarded and authentic expression of the thinking of someone working in this field" at the time. He gave this comment more weight than her evidence on the predictability of success that the skilled person would have had - the latter, "while entirely genuine, was an opinion advanced for the purposes of this case".

Birss J's conclusion on the Latchman paper was as follows:

"A skilled person reading the Latchman paper in the light of their common general knowledge, might conceive of carrying out a mouse tumour model test of PD-1 blockade. However if they did think about performing the test, they would be doing so hoping that the test might succeed, not expecting that it would. There would not be a sufficient expectation that the outcome would be successful to render the invention obvious. I find that the invention involved an inventive step over the Latchman paper."

Similarly, Birss J was not satisfied that the skilled person given Dana Farber 557 would have had a sufficient expectation of success testing an anti-PD-1 antibody in a mouse tumour model to render the invention obvious.

Merck also relied on two abstracts, one by "Tchekmedyian" and the other by "Davis", concerning the results of phase 1 clinical trials into an anti-CTLA-4 antibody for the treatment of cancer. (CTLA-4 is another cell surface receptor that was known, at the priority date, to have an inhibitory effect on the immune system. The pathway in which CTLA-4 was known to be involved was better understood than the PD-1 pathway).

Birss J found though that despite the analogy between CLTA-4 and PD-1, this did not render the claimed invention obvious:

"The way forward for a team given either abstract is to develop an anti-CTLA-4 antibody. The argument that a skilled team given the abstracts would change tack and embark on testing anti-PD-1 antibodies instead is tainted with hindsight."

Conclusion

So the patent was valid and infringed.

Comment

The 'battle of the experts'

This is a case in which the evidence of the expert witnesses proved crucial to the judge's determination of what was common general knowledge. This fed into the outcome of the case on priority, sufficiency, novelty, inventive step and added matter. On the 'obvious to try' challenge, the cross-examination of the experts was particularly crucial to the outcome - an "unguarded and authentic expression" trumping the evidence prepared for the purpose of case.

Plausibility

Merck v Ono is also a case in which the English Patents Court has recognised the novelty, invention and support underpinning a second medical use patent based, effectively, on two distinguishing points:

  • In the patent, (i) in vivo data from mouse models (x2) for cancer, combined with (ii) a selective presentation of information that was within, but not a comprehensive reflection of, the common general knowledge, ensured that the claim to priority was sound, the claims were sufficient, and the patent was not anticipated or rendered obvious by the prior art.
  • In contrast, prior art comprising (i) in vivo data from a mouse model for autoimmune disease, combined with (ii) a representative discussion of the common general knowledge, was not enough to 'enable' the disclosure of the invention claimed in the patent or to render it obvious - nor would it support a hypothetical claim equivalent to Ono's patent claims.

Underpinning all this was the judge's analysis on plausibility. Birss J took an opportunity to note that the creeping use of the concept of 'plausibility' does not make it a 'law' as such. Further, the analysis in each case is highly fact-specific.

For second medical use claims, the judge explained that this means that the material relied upon 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 agent claimed to have an effect, and in terms of the effect claimed.

It is worth comparing Birss J's reasoning on plausibility with recent reasoning from Arnold J in litigation between Warner-Lambert and Actavis and Mylan.

In the Warner-Lambert case, Arnold J's decision on validity and infringement was handed down on 10 September 2015. On sufficiency, Arnold J referred to guidance from Kitchin LJ in Regeneron:

"It must therefore be possible to make a reasonable prediction that the intention will work with substantially everything falling within the scope of the claim, or, put another way, the assertion that the invention will work across the scope of the claim must be plausible or credible...

...On the other hand, if it is not possible to make such a prediction or if it is shown the prediction is wrong and the invention does not work with substantially all the products or methods falling within the scope of the claim then the scope of the monopoly will exceed the technical contribution the patentee has made to the art and the claim will be insufficient."

Arnold J appeared to consider Kitchin LJ's guidance to amount to a two-stage test. In consequence, although there was no dispute in the Warner-Lambert case that the invention could, in fact, be performed acorss the scope of (Swiss form) claim 3 (to pregabalin for use in neuropathic pain), the judge found the claim invalid for insufficiency because the data contained in the specification, combined with the common general knowledge, did not render it plausible that pregabalin would be effective to treat 'central' neuropathic pain (a subset of the scope of the claimed indication).

Birss J, in contrast, in his Merck v Ono decision, appears to have stepped away from this sort of approach. Noting that there is no law of plausibility as such and noting the importance of considering the context of any particular invention, he indicated that there was no need for the court to apply previous wording incorporating a 'requirement' for plausibility as a test to be met in later cases. This suggests a potential inconsistency of approach between the English Patents Court judges on the assessment of sufficiency/priority.

In the Warner-Lambert case, Arnold J has given the parties permission to appeal his findings on sufficiency, so the law in this area looks likely to be reviewed by the Court of Appeal before long. In the meantime, practitioners should perhaps be cautious not to apply previous fact-specific guidance too literally.

Obvious to try

Birss J acknowledged that the Court of Appeal had told him, in its recent Teva v Leo decision, that he had got the 'obvious to try' test "wrong" in that case. In the Merck v Ono decision, he appears to have applied the Court of Appeal's guidance on the test.

In doing so, he found that while it would not have been inventive to conduct tests by which the skilled person would have led to the invention, the skilled person would not have had a sufficient expectation that the outcome would be successful to render the claimed invention obvious.

This is a positive development for innovators in all industries.