Mammoth judgment on IL-17A/F antibodies leads to patent revocation and brief SPC excursion to the CJEU

10.05.2020

On 1 March 2019, Mr Justice Arnold (as he then was) handed down judgment following a 12 day trial in the Patents Court involving Eli Lilly and Genentech. The litigation related to anti-IL-17 antibodies, which can be used to treat auto-immune diseases such as psoriasis and ankylosing spondylitis. In addition to the patent dispute, the case gave rise to interesting SPC issues, in particular third party MA SPC applications. In the judge’s own words, it was “one of the most complex patent cases” he had ever tried and had potentially far-reaching consequences for the pharmaceutical industry.

The action concerned Genentech’s European Patent (UK) No. 1 641 822 (“EP822”). EP822 claimed an antibody “which specifically binds to an isolated IL-17A/F heterodimeric complex…”, and the use of that antibody to treat psoriasis and rheumatoid arthritis (RA) via EPC 2000 and Swiss-type claims. IL-17A/F is a dimer of IL-17A and IL-17F monomers. It is now known that various forms of the dimer (IL-17A/A, IL-17A/F and IL-17F/F) have been seen to be elevated at different stages of autoimmune disease and inflammation. Their precise roles, however, have not yet been elucidated. Notably, Genentech has not commercialised an anti-IL-17A/F antibody.

Eli Lilly (“Lilly”) had independently developed ixekizumab (trade name: Taltz®). Ixekizumab is an antibody that binds to the IL-17A/A homodimer and the IL-17A/F heterodimer with equal affinity and is marketed for the treatment of psoriasis and psoriatic arthritis. In July 2017, Lilly sought a declaration of non-infringement in respect of ixekizumab and EP822, as well applying to revoke the patent. Genentech counterclaimed for infringement.

In addition to the patent dispute, Genentech had filed an SPC application based on EP822 and Lilly’s MA for Taltz®. Lilly objected to this application and sought a declaration that such an SPC would be contrary to Article 3(a) of Regulation (EC) No 469/2009 (the “SPC Regulation”), as Taltz® was not a product protected by EP822, nor was the Taltz® MA a valid authorisation for the purposes of Articles 3(b) or 3(d) of the SPC Regulation on the basis that Lilly had not consented to Genentech applying for an SPC based on the Taltz® MA.

Patent decision[1]

Construction

A fundamental issue in the case related to the construction of claim 1 which, as proposed to be amended, claimed:

“An isolated antibody which specifically binds to an isolated IL-17A/F heterodimeric complex and which inhibits the activity of the IL-17A/F heterodimeric complex to induce the production of IL-8 and IL-6, wherein the isolated IL-17A/F heterodimeric complex comprises SEQ ID NO:3 and SEQ ID NO:4, without their associated signal peptides, and further comprises two interchain disulphide linkages between SEQ ID NO:3 and SEQ ID NO:4; and wherein the antibody is either man or humanized.”

In particular, there was disagreement over what “specifically binds” means. Lilly argued that an antibody that “specifically binds” to IL-17A/F should do so to the exclusion of all other targets (including, for example, the IL-17A/A homodimer). Genentech maintained that such an antibody should bind to IL-17A/F in a manner that was not non-specific (i.e. by “sticky” adherence alone). The judge found in favour of Genentech’s broader construction.

Added matter

Prior to the UK litigation, EP822 had been revoked by the Opposition Division for added matter grounds (the decision of which was still, at the time of writing, under appeal before the EPO’s Technical Board of Appeal). During the course of the UK proceedings, Genentech applied to amend its claims and similar added matter objections were raised by Lilly. Arnold J respectfully disagreed with the approach adopted by the Opposition Division and allowed the amendments, demonstrating perhaps the English courts’ more lenient and less rigid approach when it comes to added matter. The Technical Board of Appeal has since upheld the decision of the Opposition Division on added matter.

Obviousness and novelty

On novelty and obviousness, Lilly focussed their efforts on two streams of prior art: (i) IL-17A/F prior art; and (ii) IL-17A/A prior art. In the former category, US patent 6,043,344 was found to be an enabling disclosure of an IL-17A/F heterodimer. At the priority date, Arnold J held that it would have been obvious to the skilled person to produce a humanised antibody to IL-17A/F, rendering the antibody per se claims obvious. Furthermore, at that time, IL-17A/A was known to be a key factor in the pathogenesis of RA. On the back of the US patent, the skilled person would have considered it reasonably likely that IL-17A/F existed in nature and thus it would be a promising target for RA, which would lead them to conduct tests and trials in humans. The medical use claims, insofar as they related to RA, were thus also obvious.

Turning to the IL-17A/A prior art, it was common ground that IL-17A/A itself and IL-17A/A antibodies were known at the priority date. Lilly argued that working the IL-17A/A prior art would inevitably result in antibodies that bind to IL-17A/F, providing evidence that no such IL-17A/A-only antibody existed in reality, nor could it in theory. To support its invalidity case, Lilly also carried out experiments to characterise murine antibodies to IL-17A/A (murine antibodies having been described in the prior article), humanise them and characterise the results. One of the experimental protocols proposed by Lilly’s expert required the use of active recombinant human IL-17A/A to immunise mice to generate hybridomas. However, section 5C of the Animals (Scientific Procedures) Act 1986 does not permit experiments on animals for the purposes of patent litigation. Lilly thus relied on three particular murine antibodies to IL-17A/A that had already been generated in the 90s for the purposes of its experiments, instead of generating its own panel of antibodies for humanisation. Whilst Arnold J held that it was not proven to be inevitable that all IL-17A/A antibodies would bind to IL-17A/F, he accepted the premise of the experiments and found it to be highly probable that they would and thus the antibody claims, and medical use claims directed towards RA, were obvious.

Lack of plausibility insufficiency

Applying the test set out by the Supreme Court in Warner-Lambert [2], Arnold J stated that the correct question to ask was whether the skilled person would consider it plausible that an IL-17A/F antibody would have a discernible therapeutic effect on psoriasis. It would not be enough that IL-17A/F was a potential target for psoriasis therapy and deserving of further research to determine the efficacy of an IL-17A/F antibody.

Arnold J found that the claim to psoriasis was speculative and not plausible. He based this decision on the following factors: (i) the absence of experimental data regarding IL-17A/F and psoriasis in the patent; (ii) the lack of discussion regarding IL-17A/F in psoriasis in the prior art; (iii) the limited support for IL-17A/A (let alone IL-17A/F) having a pathogenic role in psoriasis; (iv) the patent indicated that IL-17A/F was less potent than IL-17A/A; and (v) the specification claimed efficacy against a broad list of conditions (for which it was implausible that an anti-IL-17A/F antibody would be effective against all of them).

Infringement

In light of the broad construction of “specifically binds”, Arnold J found that ixekizumab, which binds to IL-17A/F and IL-17A/A with equal affinity, infringed the antibody per se claims. Arnold J also considered infringement of the claims on the basis of the narrower proposed construction, which he had rejected. Applying the doctrine of equivalents, he found that the variant (an antibody that inhibited IL-17A/A as well as IL-17A/F) would achieve substantially the same result in substantially the same way, as both IL-17A/A and IL-17A/F were pro-inflammatory cytokines involved in psoriasis. He held that this would be obvious to the skilled person at the priority date and there was nothing in the patent to indicate that it was essential for antibodies to bind to IL-17A/F only. Thus, even on a narrow construction, ixekizumab would infringe the antibody claims, had they been valid.

Looking next to the medical use claims, Arnold J held that ixekizumab was essential for putting the invention into effect and Lilly would be supplying the product knowing that the users would intend to treat psoriasis with ixekizumab. These claims (to the extent they covered use for treatment of psoriasis) would thus be infringed, save for the invalidity findings.

In summary, the antibody claims were found to be obvious over both the IL-17A/F and IL-17A/A prior art, as were the RA medical use claims. The psoriasis medical use claims were insufficient for lack of plausibility. Had they claims been valid however, they would have been infringed by ixekizumab.

SPC decision [3]

As noted above, Lilly challenged Genentech’s SPC application on two grounds: (1) ixekizumab was not protected by EP822 for the purposes of Article 3(a) of the SPC Regulation; and (2) Lilly’s MA for Taltz® was not the correct MA pursuant to Articles 3(b) and/or 3(d) of the SPC Regulation (the “Third Party MA Issue”).

Article 3(a)

Applying the test as described by the CJEU in Teva v Gilead Sciences[4], Arnold J found that ixekizumab necessarily falls under the invention of the patent, as it is an antibody as claimed in claim 1 and embodies the technical contribution of the claim. Turning to the second limb of the test, he held that ixekizumab would be specifically identifiable by the skilled person at the priority date by reference to the functions in claim 1, i.e. it specifically binds to IL-17A/F.

Notably, Arnold J stated that it was irrelevant for the purpose of both limbs of the test that ixekizumab was not created until after the priority date. Had the patent been valid, it would have protected ixekizumab.

Third party MA issue

Lilly relied on comments from the Court of Justice of the European Union (CJEU) and national case law to support its argument that the SPC Regulation was intended to compensate innovators for the erosion of their patent term caused by delays incurred by the regulatory approval process. Genentech countered that it was implicit from the case law (namely Biogen v SmithKline Beecham Biologicals[5]) that the basic patent and MA may be held by unconnected parties. It alleged that Lilly was attempting to read words into the SPC Regulation and it further noted that Regulation No 1610/96/EC (the equivalent SPC Regulation governing plant protection products) demonstrated that third party MA SPCs are permissible.

Whilst Arnold J saw the merit of Lilly’s policy arguments, he could not dismiss Genentech’s contentions. He therefore found that the law was not acte clair and referred the following question 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?”

It was notable that Arnold J referred this question despite finding that EP822 was invalid, thus rendering the SPC dispute academic, at least pending the outcome of any appeal. He justified the referral on three grounds. First, it was likely that Genentech would appeal the decision and, given that the UK’s departure from the EU (‘Brexit’) was due to occur on 29 March 2019 (at the time of judgment), it was possible that the Court of Appeal would no longer have jurisdiction to make referrals. Second, Genentech had filed SPC applications based on EP822 and Lilly’s MA in other EU Member States. An EU-wide answer would thus assist the parties. Third, it was in the interests of the wider pharmaceutical industry to settle the Third Party MA Issue. This topic had been hotly debated for years and its resolution would be welcomed.

The CJEU decision

After Arnold J made the reference to the CJEU by Order on 4 March 2019, the UK’s exit from the European Union on 29 March 2019 was postponed. Nevertheless, Arnold J’s reference was in the queue for the CJEU’s consideration, much to the interest of pharmaceutical companies and SPC enthusiasts throughout Europe.

On 5 September 2019, the CJEU issued an Order declaring that the reference was manifestly inadmissible[6]. The CJEU noted that a reference is to be rejected where the problem is hypothetical, which includes the circumstance where the basic patent had been held to be invalid. Notwithstanding the hypothetical nature of the dispute, the CJEU considered that the grounds put forward by Arnold J were not capable of justifying the reference. First, the grounds were based on several hypothetical premises: (i) that Genentech would file the appeal; (ii) that the Court of Appeal would overturn the first instance decision; and (iii) that the Court of Appeal would feel it necessary to make a referral. In relation to the then-impending Brexit date of 31 October 2019 (which was again extended), the CJEU remarked that the UK’s notice of intention to withdraw from the European Union was just that: a mere notification. It is not an actual withdrawal. Until that date, EU law applies and any Court of a Member State may refer a question to the CJEU. In the CJEU’s view, the fact that there were parallel disputes in other Member States, and that the wider pharmaceutical industry had an interest in seeing the issue resolved, was irrelevant to the question of admissibility.

To be continued

This case has been interesting for IP practitioners to follow, not least for Arnold J’s application of the relatively newly-minted Warner Lambert insufficiency test and the subject matter of the litigation itself – biologics. Another fascinating aspect of this litigation has been its foray into the world of SPCs and the murky arena of Brexit. The UK Court’s attempt to resolve the Third Party MA Issue was welcomed by practitioners, and the CJEU’s reluctance to engage on the topic has certainly disappointed some, although of course others will be pleased with the outcome. As a wider takeaway, it is apparent that the CJEU will not be influenced by the time-pressures of Brexit when it comes to considering referrals, although this may now change with the subsequent confirmation that the UK has indeed left the EU on 31 January 2020.

Whilst the Third Party MA Issue has been seemingly extinguished by the CJEU, the UK litigation rumbles on. Genentech appealed Arnold J’s judgment which, at the time of writing, had been listed to be heard in January 2021. Following on from the CJEU’s dismissal of the referral on the Third Party MA Issue, Lilly applied to the UK Patents Court seeking a reasoned judgment on the issue as no decision had been given in the SPC action. The court refused to provide judgment as the patent had been held invalid – if the judge were to provide a reasoned decision, it would only be obiter. Further, the judge noted that Lilly had other opportunities to raise the Third Party MA Issue, for example in the main appeal, as it is only a point of law, as well as in further proceedings between the parties concerning a divisional patent which are currently pending before the Patents Court.

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[1] Eli Lilly and Company & Ors v Genentech Inc [2019] EWHC 387 (Pat)
[2] Warner-Lamber v Generics (UK) (t/a Mylan) [2018] UKSC 56
[3] Eli Lilly v Genentech [2019] EWHC 388 (Pat)
[4] Case C-121/17 Teva v Gilead EU:C:2018:585
[5] Case C-181/95 Biogen v SmithKline Beecham Biologicals EU:C:1997:32
[6] Case C-239/19 Eli Lilly & Co v Genentech EU:C:2019:68

Kate O’Sullivan

Author