Plausibility Put to the Test

Anna Hatt & Sarah-Jane Crawford | May 2019

Eli Lilly and Company (and 7 other Lilly companies) v Genentech, Inc.

This decision from the UK High Court relates to Genentech’s EP (UK) patent for an anti-IL-17 antibody and its use use in treatment of rheumatoid arthritis (RA) and psoriasis. Lilly had a product, ixekizumab, and sought revocation of the patent and a declaration of non-infringement. Genentech counterclaimed for infringement.

The decision runs to 618 paragraphs and Arnold J commented that “this is one of the most complex patent cases I have ever tried”. Notably, this is the first time that the High Court has applied the new plausibility test that was established by the Supreme Court in Warner-Lambert v Generics.

The Decision

The patent was found invalid, but would have been infringed if valid. The judge’s conclusions were summarised as follows:

For the reasons given above, I conclude that:

i)    Genentech’s unconditional amendments to the claims are allowable, with the minor exception of “comprises” in new claims 1 and 14, but the conditional amendment to “consists of” is allowable.

ii)    Claims 1, 2, 13, 14 and 15 are obvious over US344, as are claims 12, 20 and 22 in so far as those claims are directed to RA.

iii)   Claims 1, 2, 13, 14 and 15 are novel but obvious over the IL-17A/A prior art, as are claims 12, 20 and 22 in so far as those claims are directed to RA.

iv)   Claims 12, 20 and 22 are insufficient for lack of plausibility in so far as they are directed to psoriasis. Lilly’s other insufficiency objections are rejected.

v)    If (contrary to my conclusions) the claims are valid, they have been infringed by Eli Lilly & Co Ltd and Eli Lilly & Co.     

Construction

The claims required an antibody “which specifically binds to” a heterodimeric peptide complex, IL-17A/F. Lilly argued that this excluded antibodies which were also capable of binding to the homodimeric peptide complexes IL-17A/A and IL-17F/F. Genentech argued that all that was required was binding as an antibody. The judge adopted Genentech’s construction, noting that no negative screening step for binding was used in the patent.

The judge also construed the terms “inhibits the activity of…IL-17A/F… to induce production of IL-8 and IL-6” and “for” the treatment of RA or psoriasis.

Amendment

Genentech had made an unconditional request for amendment, with a further conditional request. Lilly opposed the amendment on the grounds of introduction of lack of clarity, extension of protection and added subject-matter.

With regard to clarity, the judge held that “which specifically binds to” and “induce protection of IL-6 and IL-8” were contained in the granted claims so could not be objected to; the former was clear in any case. “Comprises” was also clear.

With regard to extension of protection, the amendment changed a requirement for the peptide complex to “consist of” particular sequences to a requirement for it to “comprise” such sequences. The judge agreed that this extended protection, but granted the conditional request to amend the wording back to “consists of”.

With regard to added subject-matter, the judge noted that the EPO Opposition Division had revoked the patent on this ground, and that the Comptroller of the IPO had also objected to the proposed amendments. Nonetheless, the judge held that there was no added subject-matter on each of five points raised by Lilly.

The judge applied the test of Vector Corp v Glatt Air Techniques Ltd [2007] EWCA Civ 805, that is, whether a skilled person would, upon looking at the amended specification, learn anything about the invention which he could not learn from the unamended specification. The judge referred also to the EPO “gold standard” (Case Law of the Boards of Appeal 8th Ed. p. 401). However, the judge was unsympathetic to Lilly’s EPO-style argument that there had been an impermissible selection from multiple lists, finding that the relevant amendments narrowed the claim to part of the original disclosure without teaching the skilled person anything new about the invention. He was also unsympathetic to an argument by Lilly that the amended claims required an undisclosed subset of an originally claimed range of binding strengths.

The judge commented that evidence is of minor significance in assessing added subject-matter, stating that:

the question of added matter is not one which falls to be resolved by reference to the burden of proof since it involves an objection comparison by the court of the two documents.

Novelty and Obviousness

Lilly contented that the claims were obvious over a prior art document US344 which disclosed the heterodimeric complex IL-17A/F, as it would be obvious to make and isolate antibodies to this complex and test them for use in treating RA with a good expectation of success. The judge agreed. He commented also that:

There is nothing in the Patent that would give the skilled person any greater reason to believe that an anti-IL-17A/F antibody would be efficacious against RA. (This means that, if the skilled person’s expectation of success based on the prior art was not sufficient for obviousness to try, the claims would fail for lack of plausibility applying the principles discussed below; which is not to imply that the legal tests are the same.)

In relation to claims with the broad purpose limitation “for use in a method of medical treatment”, the judge commented that:

Given that these claims extend to absolutely any form of medical treatment, I consider that these claims cannot be independently valid. Either they require no threshold of efficacy, in which case it would be obvious to try humanised anti-IL-17A/F antibodies for treating various inflammatory diseases to see what happened; or they do require a threshold of efficacy, in which case it was and remains utterly implausible that IL-17A/F antibodies are efficacious for all forms of medical treatment.

The judge then considered novelty and obviousness over prior art relating to the better-known homodimeric complex IL-17A/A.

With regard to novelty, Lilly argued that working this prior art would inevitably lead to antibodies which also bound to IL-17A/F, and that novelty could not be established by providing more information about the same invention. The judge disagreed.

With regard to obviousness, experiments had been conducted by Lilly and criticised by Genentech, and the judge considered these matters at length. He held that the claims were obvious because, whilst it was not inevitable that anti-IL-17A/A antibodies produced in implementing the prior art by obvious methods would bind to IL-17A/F, this was highly probable.

Insufficiency

This aspect of the case related to the psoriasis-directed claims. The judge considered whether it would have been plausible to the skilled dermatologist reading the patent that an anti-IL-17A/F antibody would be effective against psoriasis, applying the recent decision of the Supreme Court in Warner-Lambert Co LLC v Generics (UK) Ltd [2018] UKSC 56. He noted that the Supreme Court guidance related to second medical use claims, but was also applicable to the first medical use claims here.

The judge held that the plausibility test was not met, so the patent was insufficient:

In my judgment the skilled person would not regard it as plausible that an anti-IL-17A/F antibody would have a discernible therapeutic effect on psoriasis for the reasons given by Prof Krueger. I would emphasise five points. First, the absence from the Patent of any experimental data concerning the role or effect of IL-17A/F, let alone an anti-IL-17A/F antibody, in psoriasis. Secondly, the absence of any discussion of the role or effect of IL-17A/F in psoriasis. Thirdly, the limited support for IL-17A/A (let alone IL-17A/F) having a pathogenic role in psoriasis provided by the papers cited in the Patent, particularly given the common general knowledge as to all the other cytokines which were implicated in psoriasis. Fourthly, the fact that the Patent shows that IL-17A/F is an order of magnitude less potent than IL-17A/A. Fifthly, the fact that the specification claims efficacy against a broad list of conditions which it is wholly implausible that an anti-IL-17A/F antibody (or any form of IL-17A/F therapy) would be effective against. Moreover, there is no emphasis on psoriasis in the specification. Such emphasis as there is concerns RA, which the skilled dermatologist would appreciate raised different considerations to psoriasis. In short, the claim of efficacy against psoriasis is speculative.

Lilly had also argued on insufficiency that the claims were ambiguous, and that it would be an undue burden to make anti-IL-17A/F-only antibodies. The judge did not accept these points.

Infringement

Although in his view the patent was invalid, the judge went on to consider infringement.

He considered that the patent, if valid, would have been infringed by Lilly’s use of ixekizumab.

In case his construction of “which specifically binds to” was wrong, he considered whether the alternative construction would have led to a finding of infringement under the doctrine of equivalents set out in Actavis v Lilly [2017] UKSC 48. He considered that there would still have been infringement (noting in passing that there are likely to be few cases in which the second question is answered in the negative).