Patents - Eli Lilly v Genentech
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Jane Lambert
Patents Court (Mr Justice Arnold) Eli Lilly and Co. and others v Genentech Inc. [2019] EWHC 387 (Pat) (1 March 2019)
This was a claim for the revocation of Genentech Inc.'s European patent EP1641822 for heterologous polypeptides and therapeutic uses thereof on grounds of want of novelty, obviousness and insufficiency and a declaration of non-infringement of the patent; Genentech counterclaimed for infringement alleging that Lilly's product Ixekizumab marketed under the trade mark Taltz infringed its patent. The action and counterclaim came on before Mr Justice Arnold as he then was. The judge also had to decide whether Genentech was entitled to a supplemental protection certificate in relation to the patent. His lordship dealt with that issue in a separate judgment (see Eli Lilly And Company v Genentech, Inc No. 2 [2019] EWHC 388 (Pat) (1 March 2019) which I discussed in Supplemental Protection Certificates - Eli Lilly and Co. v Genentech Inc. 18 July 2019).
Complexity of the Case
His lordship described the case as one of the most complex that he had ever tried noting that he had considerable experience of trying complex patent cases. He observed that there were a large number of issues, and a formidable body of material addressing them. Lilly’s written closing submissions ran to 607 paragraphs and Genentech’s to 423, Both documents incorporated by reference additional sections from the parties’ respective opening skeleton arguments. There were 24 reports from nine expert witnesses running to 676 pages (including annexes, but excluding exhibits). The experts were efficiently cross-examined over seven and a half days. There were over 300 scientific papers (including a few abstracts) in the trial bundles plus extracts from two books.
Amendment of the Claims
Before the trial started, Genentech applied for the deletion of its first 26 claims, the amendment of the 27th which was renumbered as "1", the insertion of a new claim 2, the deletion of much of the renumbered claim 12, the deletion of the old claim 41, and substantial amendments of renumbered claims 13, 14, 15, 20 and 22. Those amendments appear at paragraph [180] of Mr Justice Arnold's judgment. Eli Lilly opposed the application on grounds of added matter, extension of protection and lack of clarity. The judge considered all those objections and rejected them except for the substitution of the words "consist of" for "comprise" in new claims 1 and 14.
Anticipation
At paragraph [411] of his judgment. Mr Justice Arnold summarized the case for want of novelty:
"First, Lilly contend that it is an inevitable result of working the IL-17A/A prior art that antibodies which also bind to IL-17A/F are produced. Secondly, Lilly rely upon case law of the Boards of Appeal to the effect that a claimed class of compounds lacks novelty if it overlaps with a class of compounds disclosed in the prior art. Thirdly, Lilly rely upon the principle that novelty cannot be established by just providing more information about the same invention."
The judge dealt with those arguments peremptorily at [412]:
"Without intending any disrespect to the lengthy submissions I received on these issues, I do not propose to discuss them in any detail. For reasons that will become apparent when I consider obviousness, I have concluded that it is not inevitable (or at least has not been proved to be inevitable) that anti-IL-17A/A antibodies produced in accordance with the prior art will bind to IL-17A/F as well. In those circumstances, I do not consider that it can be said that the Patent merely provides more information about the prior inventions. Nor do I consider that this is a case of overlapping classes of compounds: compare Dr Reddy’s Laboratories (UK) Ltd v Eli Lilly and Co Ltd [2009] EWCA Civ 1362, [2010] RPC 9."
Obviousness
His lordship noted at [397] that there was no dispute as to the relevant principles of law, which were very familiar, and so there was no need for him to set them out. The prior art upon which Eli Lilly relied included US patent number 6,043,344 entitled Human CTLA-8 and uses of CTLA-8-related proteins which disclosed:
"Polynucleotides encoding human CTLA-8 and related proteins are disclosed. Human CTLA-8 proteins and methods for their production are also disclosed. Methods of treatment using human CTLA-8 proteins, rat CTLA-8 proteins and herpesvirus herpes CTLA-8 proteins are also provided."
Between paragraphs [400] and [402] Mr Justice Arnold disposed of claims 1, 2, 13, 14 and 15:
"[400] Claim 1. Lilly contend that, given the disclosure of IL-17A/F in US344, it was obvious to make and isolate antibodies to IL-17A/F since it was a routine procedure in July 2003 and there is nothing unexpected about the properties of the anti-IL-17A/F antibodies disclosed and claimed in the Patent. Lilly contend that such antibodies will inherently inhibit production of IL-6 and IL-8, but in any event rely upon the evidence of Prof Kamradt that it was common practice by July 2003 to test IL-17 family members for inducing IL-6 and IL-8 production as showing that it was obvious to raise antibodies which inhibited this. Lilly further rely upon the evidence of Prof Martin that the effect on IL-6 and IL-8 was what the skilled person would be looking for as confirming this. In any event, Example 6 of US344 itself would make it obvious to do this. Finally, Lilly rely upon the evidence of Prof Martin that humanised antibodies were desired not only for use in therapy, but also for use in diagnostics, as showing that it was obvious to make humanised antibodies. I accept all of these points. Accordingly, I conclude that claim 1 is obvious over US344.
[401] Claims 2 and 15. It is clear from the evidence that the skilled team would aim to make antibodies with as high an affinity (as low a Kd) as possible, and would aim for a Kd of lower than 10 -8M. It follows that claim 2 is also obvious and that claim 15 is obvious if claims 13 and 14 are.
[402] Claims 13 and 14 . Claims 13 and 14 add the purpose limitation “for use in a method of medical treatment”. 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."
"[400] Claim 1. Lilly contend that, given the disclosure of IL-17A/F in US344, it was obvious to make and isolate antibodies to IL-17A/F since it was a routine procedure in July 2003 and there is nothing unexpected about the properties of the anti-IL-17A/F antibodies disclosed and claimed in the Patent. Lilly contend that such antibodies will inherently inhibit production of IL-6 and IL-8, but in any event rely upon the evidence of Prof Kamradt that it was common practice by July 2003 to test IL-17 family members for inducing IL-6 and IL-8 production as showing that it was obvious to raise antibodies which inhibited this. Lilly further rely upon the evidence of Prof Martin that the effect on IL-6 and IL-8 was what the skilled person would be looking for as confirming this. In any event, Example 6 of US344 itself would make it obvious to do this. Finally, Lilly rely upon the evidence of Prof Martin that humanised antibodies were desired not only for use in therapy, but also for use in diagnostics, as showing that it was obvious to make humanised antibodies. I accept all of these points. Accordingly, I conclude that claim 1 is obvious over US344.
[401] Claims 2 and 15. It is clear from the evidence that the skilled team would aim to make antibodies with as high an affinity (as low a Kd) as possible, and would aim for a Kd of lower than 10 -8M. It follows that claim 2 is also obvious and that claim 15 is obvious if claims 13 and 14 are.
[402] Claims 13 and 14 . Claims 13 and 14 add the purpose limitation “for use in a method of medical treatment”. 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."
At paragraph [409] he dealt with claims 12, 20 and 22:
"The conclusion I draw from the evidence is that the skilled person would consider it reasonably likely that IL-17A/F existed in nature and would consider it a promising target for RA therapy. Given that less was known about IL-17F than IL-17A, the skilled person would not have a positive expectation that targeting IL-17A/F would be efficacious, but would consider that success was sufficiently likely to warrant studies of the kind described by Dr Lubberts, leading to tests in animal models and then to trials in humans. I do not understand it to be in dispute that such tests and trials would be likely to be successful. Furthermore, 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.) "
Eli Lilly also relied on International Patent Application No WO 02/0587717, US Patent No 6,274,711 and Japanese Patent Application N JP2000-186046A. After referring to those citations, the learned judge concluded at paragraph [521] that claims 1, 2, 13, 14 and 15, and claims 12, 20 and 22 in so far as they were directed to the treatment of rheumatoid arthritis were obvious over that prior art.
"The conclusion I draw from the evidence is that the skilled person would consider it reasonably likely that IL-17A/F existed in nature and would consider it a promising target for RA therapy. Given that less was known about IL-17F than IL-17A, the skilled person would not have a positive expectation that targeting IL-17A/F would be efficacious, but would consider that success was sufficiently likely to warrant studies of the kind described by Dr Lubberts, leading to tests in animal models and then to trials in humans. I do not understand it to be in dispute that such tests and trials would be likely to be successful. Furthermore, 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.) "
Eli Lilly also relied on International Patent Application No WO 02/0587717, US Patent No 6,274,711 and Japanese Patent Application N JP2000-186046A. After referring to those citations, the learned judge concluded at paragraph [521] that claims 1, 2, 13, 14 and 15, and claims 12, 20 and 22 in so far as they were directed to the treatment of rheumatoid arthritis were obvious over that prior art.
Insufficiency
Regarding the use of the invention in the treatment of psoriasis, the judge noted at paragraph [522] that it was common ground that it must have been plausible to the skilled dermatologist reading the Patent in July 2003 in the light of the common general knowledge that an anti-IL-17A/F antibody would have some therapeutic efficacy for treating that disease. If not, he added, the claims will be insufficient.
Mr Justce Arnold noted that the Supreme Court had considered the law relating to insufficiency in Warner-Lambert Company LLC v Generics (UK) Ltd (t/a Mylan) and another (rev 1) [2018] UKSC 56, [2019] Bus LR 360 (14 Nov 2018) which I discussed in The Supreme Court's Judgment in Pregabalin 6 Dec 2018. He referred to Lord Sumption's judgment where he said that “the extent of the patent monopoly, as defined by the claims, should correspond to the technical contribution to the art”, that is to say, “the patent monopoly should be justified by the actual technical contribution to the art”. Mr Justice Arnold added, "the requirements of novelty, inventive step, industrial applicability and sufficiency are all, in one way or another, directed to ensuring that this principle is satisfied." He also quoted paragraph [37] of Lord Sumption's judgment on plausibility.
Regarding the use of the invention in the treatment of psoriasis, the judge noted at paragraph [522] that it was common ground that it must have been plausible to the skilled dermatologist reading the Patent in July 2003 in the light of the common general knowledge that an anti-IL-17A/F antibody would have some therapeutic efficacy for treating that disease. If not, he added, the claims will be insufficient.
Mr Justce Arnold noted that the Supreme Court had considered the law relating to insufficiency in Warner-Lambert Company LLC v Generics (UK) Ltd (t/a Mylan) and another (rev 1) [2018] UKSC 56, [2019] Bus LR 360 (14 Nov 2018) which I discussed in The Supreme Court's Judgment in Pregabalin 6 Dec 2018. He referred to Lord Sumption's judgment where he said that “the extent of the patent monopoly, as defined by the claims, should correspond to the technical contribution to the art”, that is to say, “the patent monopoly should be justified by the actual technical contribution to the art”. Mr Justice Arnold added, "the requirements of novelty, inventive step, industrial applicability and sufficiency are all, in one way or another, directed to ensuring that this principle is satisfied." He also quoted paragraph [37] of Lord Sumption's judgment on plausibility.
Applying these principles the judge decided at [577] that the skilled addressee would not have regarded it as plausible that an anti-IL-17A/F antibody would have a discernible therapeutic effect on psoriasis in 2003.
Infringement
His lordship's findings on obviousness and insufficiency were enough to dispose of the case, but he considered whether Eli Lilly's ixekizumab would have infringed the patent had it been valid. At paragraph [294] that there was "no dispute as [to] the legal principles to be applied. The claim must be given a “normal” interpretation: Actavis UK Ltd v Eli Lilly & Co [2017] UKSC 48, [2017] RPC 21 at [54], [58] (Lord Neuberger) This means a “purposive” interpretation, that is to say, an interpretation which takes into account the purpose of the Patent, which is to describe and claim an invention to a person skilled in the art: Icescape Ltd v Ice-World International BV [2018] EWCA Civ 2219 at [60] (Kitchin LJ, as he then was) and [96] (Floyd LJ). As HHJ Hacon sitting as a High Court Judge pointed out in Regen Lab SA v Estar Medical Ltd [2019] EWHC 63 (Pat) at [202]-[207], it is no longer necessary to take equivalents into account in such an interpretation, because it is now possible for a patentee to contend that a patent has been infringed by virtue of the doctrine of equivalents even if it is not infringed when the claims are given a normal interpretation."
According to the confidential product description, ixekizumab had the following characteristics:
"i) ixekizumab binds to purified recombinant human IL-17A/A homodimer and to IL-17A/F heterodimer with the same measured affinity (Kd < 3 pM);
ii) ixekizumab neutralises IL-17A/A- and IL-17A/F-induced GROα secretion from the human colorectal adenocarcinoma epithelial cell line HT-29;
iii) ixekizumab can neutralise human IL-17A/A-induced secretion of IL-8 from the human foreskin fibroblast cell line Hs27;
iv) ixekizumab can block human IL-17A/A binding to the human IL-17RA subunit; and
v) the expression of genes in psoriasis lesions including the IL-8 gene was reduced in patients after two weeks of treatment with 150 mg of ixekizumab."
At [595] the judge noted that there was no dispute that Ixekizumab would fall within claims 1, 2, 14 and 15 as he had construed them under a normal construction or if necessary under the doctrine of equivalents.
"i) ixekizumab binds to purified recombinant human IL-17A/A homodimer and to IL-17A/F heterodimer with the same measured affinity (Kd < 3 pM);
ii) ixekizumab neutralises IL-17A/A- and IL-17A/F-induced GROα secretion from the human colorectal adenocarcinoma epithelial cell line HT-29;
iii) ixekizumab can neutralise human IL-17A/A-induced secretion of IL-8 from the human foreskin fibroblast cell line Hs27;
iv) ixekizumab can block human IL-17A/A binding to the human IL-17RA subunit; and
v) the expression of genes in psoriasis lesions including the IL-8 gene was reduced in patients after two weeks of treatment with 150 mg of ixekizumab."
At [595] the judge noted that there was no dispute that Ixekizumab would fall within claims 1, 2, 14 and 15 as he had construed them under a normal construction or if necessary under the doctrine of equivalents.
Conclusion
Mr Justice Arnold summarized his findings at [618]:
"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."
Comment
Mr Justice Arnold summarized his findings at [618]:
"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."
Comment
As the judge noted at paragraph [3] given the duration of the trial, the volume of evidence and the complexity of the arguments, it was inevitable that this would be a lengthy judgment. Having said that there was surprisingly very little discussion of the law. The case turned entirely on the technical evidence which was voluminous. The challenge for me as a commentator has been to decide how much to include without making this note indigestible and how much to exclude without making it incomprehensible. I have read this long judgment several times and although I believe that I understand the judicial reasoning I think it would have been necessary to have attended the trial and to have read all the documentation to understand the basis of that reasoning.
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