Eli Lilly v Genentech: plausibility in practice

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In Eli Lilly v Genentech, Mr Justice Arnold applied Lord Sumption’s seven considerations in relation to plausibility from the UK Supreme Court’s Warner-Lambert decision, invalidating certain claims of Genentech’s patent in relation to psoriasis. Other claims in relation to rheumatoid arthritis were held to be obvious over prior art. Evidence presented by both parties’ experts and information in the patent were key in this decision. Despite holding the relevant claims of the patent to be invalid, Arnold made a reference to the Court of Justice of the European Union on whether a supplementary protection certificate may be granted on the basis of a third party marketing authorisation. The case highlights the dilemma faced by patentees of when they ought to file an application. File too early and risk a finding of insufficiency (implausibility), file too late and increase chances of a finding of anticipation or obviousness.

Eli Lilly sought revocation of a Genentech patent concerning an antibody which specifically binds to the IL-17A/F heterodimer for the treatment of rheumatoid arthritis and psoriasis, on the basis of novelty, obviousness and insufficiency (lack of plausibility).

Mr Justice Arnold held certain claims in dispute in Genentech's patent to be novel, but obvious in light of the prior art. Other claims were held to be obvious in relation to rheumatoid arthritis but these claims were found to be insufficient for lack of plausibility in relation to the treatment of psoriasis. As a result, all the disputed claims were held to be invalid.

In relation to Genetech's application for a supplementary protection certificate (SPC), despite holding that the patent was invalid, Arnold referred a question to the Court of Justice of the European Union (CJEU) on whether Genentech could rely on Eli Lilly's marketing authorisation (MA) to obtain an SPC.

Genentech is the proprietor of EP (UK) No 1 641 822, titled "IL-17A/F heterologous peptides and therapeutic uses thereof". While Genentech does not market a product covered by the patent, Eli Lilly markets an antibody called ixekizumab sold under the trade name Taltz for treatment of moderate to severe plaque psoriasis and psoriatic arthritis for adults.

The patent specification states that the invention "relates to identifying novel secreted polypeptides of the interleukin-17 (IL-17) family which have been shown to be related to immune-mediated and inflammatory disease." Interleukins are immune-modulating agents and also referred to as cytokines. The patent provides an overview of the IL-17 family of cytokines which are implicated in immune-related diseases. The patent further describes IL-17A and IL-17F members of the IL-17 family and discusses the identification of a new human cytokine that is comprised of a heterodimer consisting of IL-17A and IL-17F (IL-17A/F) stating that molecules which inhibit IL-17A/F activity would be expected to have practical utility when an inhibition of the immune response is desired. The claims of the patent cover an isolated antibody which specifically binds to the IL-17A/F heterodimer in the treatment of rheumatoid arthritis or psoriasis. Some claims are drafted as purpose-limited product claims, and others are drafted as purpose-limited process claims. Psoriasis and rheumatoid arthritis are included in a long list of examples of immune-related and inflammatory diseases in the specification of the Patent.

Eli Lilly filed a revocation action alleging that the claims of the patent are invalid on grounds of lack of novelty, obviousness and insufficiency. The company also sought a declaration that dealing in ixekizumab does not infringe the patent.

Ixekizumab was developed as an antibody against IL-17A for treatment of rheumatoid arthritis and asthma. Initial studies showed that ixekizumab did not interfere with the binding of IL-17A/F. In later development, psoriasis was suggested as a new indication following research relating to IL-17A. Eli Lilly then later obtained an MA for ixekizumab for the treatment of psoriasis for ixekizumab. Once the IL-17 A/F heterodimer became commercially available, Eli Lilly was able to determine that ixekizumab binds to both the IL-17A/A homodimer and the IL-17A/F heterodimer.

Arnold dismissed Eli Lilly's claims that the patent was anticipated but held that some claims were obvious over a US patent which disclosed recombinant production of a heterodimer between IL-17F and Il-17A. He also held that other claims were obvious as far as they were directed to rheumatoid arthritis.

Arnold considered the seven propositions made by Lord Sumption in Warner-Lambert in relation to plausibility (see Table 1).

The expert witness for Eli Lilly contended that the skilled person would note the broad list of conditions which the patent claims state can be treated with the anti-IL-17A/F antibodies and considered that it was 'highly unlikely' that the skilled person would consider targeting IL-17A/F to be beneficial in some of them and at best a guess for many. He also stated that there was no experimental evidence directed to the role or effect of IL-17 A/F in psoriasis. Further he stated that the skilled person would not consider IL-17A/F as a candidate to take forward to a clinical trial.

The expert witness for Genentech stated that the skilled person would regard it as plausible that IL-17A/F had a role in psoriasis and referred to other research papers referring to the mechanism by which IL-17 A/F played this role in psoriasis.

Based on the evidence, Arnold held that the skilled person would not regard it as plausible that an anti-IL-17A/F antibody would have a discernible therapeutic effect on psoriasis. He stated that the patent contained no experimental data on the role or effect of IL-17A/F in psoriasis, nor any discussion of the role or effect of IL-17 A/F in psoriasis. Pointing away from the idea that it would work, the patent showed that IL-17A/F is an order of magnitude less potent than the homodimer IL-17 A/A. Important in his finding was that the patent specification claimed efficacy against a broad list of conditions in relation to which the skilled person would not think it plausible that the antibody would be efficacious in relation to them all, and there was no specific singling out of psoriasis. Therefore, he found Genentech's claim of an efficacy against psoriasis not to have been plausibly disclosed by the patent.

Table 1: Seven plausibility propositions from Warner-Lambert

1) That the product is efficacious for the treatment of a given condition must be plausible.

2) A mere possibility that it will work or a bare assertion that it works is not enough.

3) The claimed therapeutic effect may be rendered plausible by a specification showing that something was worth trying for a reason and not just because there was an abstract possibility that it would work but because reasonable scientific grounds were disclosed for expecting that it might well work.

4) There is no need to prove that the product works, but there must be something that would cause the skilled person to think there was a reasonable prospect that the assertion would be true.

5) The reasonable prospect must be based on a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from prior art or demonstrated in the patent per se.

6) In the context of experimental data, the effect on the disease process need not necessarily be demonstrated by experimental data. It can be demonstrated by a priori reasoning. For example the specification may point to some property of the product which would lead the skilled person to expect that it might well produce the claimed therapeutic effect.

7) The disclosure may be supplemented or explained by the common general knowledge of the skilled person. However it is not enough that the patentee can prove that the product can reasonably be expected to work for the designated use, if the skilled person would not derive this from the teaching of the patent.

Given that it is now known that ixekizumab is known to bind to both IL-17A/A and Il-17A/F together with more recent research that shows that IL-17A/F plays a role in psoriasis, Arnold, applying the Supreme Court test for infringement from Actavis v Eli Lilly (pemetrexed), which takes into account doctrine of equivalents, held that if the patent claims were valid, that Eli Lilly would have infringed them.

An SPC aims to compensate patent owners for some types of regulatory delay and can be granted if:

• The product is protected by a basic patent in force.

• A valid authorisation has been granted to place the product on the market.

• The product has not been the subject of a previous SPC.

• The authorisation is the first to place the product on the market.

Although Genentech does not have a product covered by the patent on the market, it filed an application for an SPC based on its patent and on Eli Lilly's Taltz MA.

Eli Lilly argued that, assuming the patent is valid, Genentech's SPC application does not comply with the SPC Regulation because: 1) Taltz is not protected by the patent and 2) the Taltz MA is not a relevant authorisation since it is a third party MA relied on without the consent of the third party (Eli Lilly).

Arnold held that ixekizumab was covered by claim 1 of the patent but not covered by claim 12 because it was not permissible to take into account research on the efficacy of ixekizumab on psoriasis carried out after the date of the priority or filing date of the patent.

Ely Lilly argued that the object of the SPC Regulation is to compensate a research organisation for the delay to market entry as a result of the regulatory processes to obtain an MA, and that a company which has not suffered lost time because it was not the company that obtained the MA ought not to have any compensation.

Genentech referred to evidence that it is consistent practice at the national offices of EU member states to grant SPCs on the basis of third party MAs. Genentech also referred to case law that the basic patent and the MA may be held by different and unconnected parties, and that the wording of the SPC Regulation makes it clear that SPCs may be granted on third party MAs.

Arnold held that the law in this area is not clear and considered that the following question ought to be referred to the CJEU:

"Does the SPC Regulation preclude the grant of an SPC to the proprietor of a basic patent in respect of a product which is the subject of a marketing authorisation held by a third party without that party's consent?"

Arnold noted that if he was correct to hold the patent invalid, Genentech's SPC application must fail. Genentech indicated that it wished to appeal the judgment on the validity of the patent and that if the company were successful, the question on the SPC application would be relevant.

Eli Lilly argued that as any judgment of the Court of Appeal would take some time and that as the UK will shortly lose jurisdiction to make a reference to the CJEU due to Brexit, there were exceptional reasons to make a reference to the CJEU now. Further, the SPC dispute was not confined to the UK since Genentech had filed parallel SPC applications based on the Taltz MA, so an answer could be provided only by the CJEU.

Arnold accepted these arguments in these current exceptional circumstances and referred the question to the CJEU despite finding that the patent was invalid.

This case shows courts applying the principles established in Warner-Lambert in relation to plausibility. The dearth of experimental data or any other scientific reason in the patent showing why it would work made the patent open to an attack of insufficiency for lack of plausibility. In his findings, Arnold did accept that while Warner-Lambert was concerned with a second medical use, this case concerned a first medical use of a previously unknown antibody. Genentech has indicated its intention to appeal the decision.

The case highlights the dilemma faced by patentees of when they ought to file an application. File too early and risk a finding of insufficiency (implausibility), file too late and increase chances of a finding of anticipation or obviousness. It would be prudent to consider filing a patent application as soon as there is enough evidence to overcome the plausibility hurdle as set out in Lord Sumption's seven propositions. The findings of this case also give an opportunity to new market entrants wishing to 'clear the way'.

As set out by the parties in this case, it is current practice that an SPC applicant is granted an SPC based on another entity's MA. The question referred to the CJEU will be crucial in determining where the balance lies and whether the current practice will be prohibited taking into account the policy reasons for the SPC. Once the CJEU guidance is handed down, it will of course apply across all EU member states. The CJEU guidance provided will be crucial to current and future SPC applicants who base their SPC applications on a third party MA.

Varuni Paranavitane

Varuni Paranavitane is an IP litigation associate at AA Thornton in London.