Neutral Citation Number: [2015] EWHC 2973 (Pat)
Case No: HP-2014-000038
Case No: HP14 A 02748
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Royal Courts of Justice, Rolls Building
Fetter Lane, London, EC4A 1NL
Date: 22/10/2015
Before:
THE HON. MR JUSTICE BIRSS
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Between:
Case No: HP-2014-000038
MERCK SHARP & DOHME LIMITED / Claimant- and -
(1) ONO PHARMACEUTICAL CO. LIMITED
(2) TASUKU HONJO / Defendants
and between:
Case No: HP14 A 02748
(1) BRISTOL MYERS SQUIBB COMPANY(2) ONO PHARMACEUTICAL CO. LIMITED
(3) TASUKU HONJO / Claimants
- and -
(1) MERCK & CO. INC.
(2) MERCK SHARP & DOHME LIMITED / Defendants
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Andrew Waugh QC , Tom Hinchliffe and Stuart Baran (instructed by Simmons & Simmons) for Merck
Henry Carr QC, Anna Edwards-Stuart (instructed by Freshfields) for Ono, Prof Honjo and Bristol Myers Squibb
Hearing dates: 16th, 17th, 20th, 21st, 22nd, 27th and 28th July 2015
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Approved Judgment
I direct that pursuant to CPR PD 39A para 6.1 no official shorthand note shall be taken of this Judgment and that copies of this version as handed down may be treated as authentic.
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Mr. Justice Birss
MR JUSTICE BIRSSApproved Judgment / Merck v Ono
Mr Justice Birss:
MR JUSTICE BIRSSApproved Judgment / Merck v Ono
Topic / Paragraph
Introduction / 1
The issues / 3
The witnesses / 13
The skilled person / 19
Common general knowledge / 22
The patent / 97
Claim construction / 115
Added matter / 118
Priority / insufficiency/ lack of technical contribution / 122
Novelty / 173
Dana Farber 557 / 176
Wyeth 499 / 204
Inventive step / 206
The Latchman paper / 209
Dana Farber 557 / 239
The Tchekmedyian and Davis abstracts / 242
Summary and Conclusion / 243
Annex 1 – bibliography
Annex 2 – Immune system diagram
Introduction
1. This is a patent case concerning EP (UK) 1 537 878 entitled “Immunopotentiating Compositions”. The patent claims a first priority date of 3rd July 2002 based on a Japanese filing JP 2002194491. The application was filed on 2nd July 2003 and the patent was granted on 22nd September 2010. The patentees are Ono Pharmaceutical Co. Ltd and Professor Tasuku Honjo. Prof Honjo is one of the inventors. Bristol Myers Squibb are the exclusive licensee. I will refer to the patentees and exclusive licensee together as Ono. The patents relate to the use of anti-PD-1 antibodies for the treatment of cancer. Anti-PD-1 antibodies are one type of a revolutionary new kind of cancer immunotherapy. Ono has developed an anti-PD-1 antibody called nivolumab (brand name Opdivo) and Merck has developed an anti-PD-1 antibody called pembrolizumab (brand name Keytruda). Both have obtained clinical approval for the treatment of some cancers and are in clinical trials in relation to many others. An article from the Financial Times on 5th June 2015 which was in evidence reports a figure of $35bn as the consensus on Wall Street for the annual revenues generated by immunotherapies.
2. Ono contends that Merck’s product infringes the patent and Merck contends that Ono’s patent is invalid. Ono also states that in this jurisdiction if its infringement claim is successful, given the life-saving nature of this therapy, it will not seek an injunction provided an appropriate royalty is agreed or awarded by the court for future infringement. The fact that Ono adopts this stance does not mean the patent is to be judged by a different standard from any other.
The issues
3. The relevant claims are claims 1 and 3, as follows:
Claim 1: Use of an anti-PD-1 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.
4. Claim 1 is in Swiss form while claim 3 is a purpose limited product claim (EPC 2000). For the purposes of this case there is no difference between them.
5. The issues which fall to be decided are:
i) Novelty in the light of:
a) PCT Application WO 01/14557 published on 1st March 2001 (“Dana Farber 557” );
b) PCT Application WO 02/079499 filed on 2nd April 2002 and published on 10th October 2002 (“Wyeth 499”).
ii) Obviousness in the light of:
a) Dana Farber 557;
b) “PD-L2 is a second ligand for PD-1 and inhibits T-cell activation” by Latchman et al (2001) Nature Immunology 2(3) pp261-268 (“the Latchman paper”);
c) “MDX-010 (human anti-CTLA4): a phase 1 trial in malignant melanoma” by Tchekmedyian et al (2002) Proc Am Soc Clin Oncol, 21 Abstract 56 (“the Tchekmedyian abstract”);
d) “MDX-010 (human anti-CTLA4): a phase 1 trial in hormone refractory prostate carcinoma (HRPC)” by Davis et al (2002) Proc Am Soc Clin Oncol, 21 Abstract 74 (“the Davis abstract”);
iii) Entitlement to the first priority date. This is challenged on the ground that the claim is not supported across its full width by the disclosure. It is admitted that if priority is lost, the claims are invalid over the Iwai paper (see below).
iv) Insufficiency / lack of technical contribution. This is really the same argument as arises in relation to priority.
v) Added matter.
6. Wyeth 499 is a citation under s2(3) of the 1977 Act and as such is available for anticipation only and not obviousness.
7. Merck also cites the paper “Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade” by Iwai et al (2002) PNAS Vol 99 no. 19 pp12293-12297 published on 17th September 2002. This Iwai paper was published before the second claimed priority date for the patent. Ono accepts that if the claims are not entitled to the first priority date then they are invalid in the light of Iwai.
8. There is no distinct issue of infringement. Pembrolizumab is a humanised monoclonal antibody that inhibits the immunosuppressive signal of PD-1 and Merck proposes to market it as a treatment for unresectable/metastatic melanoma. Merck accepts that if the patent is valid, its product falls within the ambit of the relevant claims.
9. Ono has applied to make a conditional amendment to the claims. The only amendment application live by the closing was to limit claims 1 and 3 to melanoma treatment. Such an amendment is formally allowable. Merck accepts that in the amended form those claims are novel, entitled to the first priority date and not insufficient. Merck maintains its obviousness case against them.
10. The parties prepared an agreed primer to explain the technical background and agreed aspects of common general knowledge. This was a very useful document. Important parts of it dealt with the adaptive immune system, T-cells, antibodies (polyclonal and monoclonal, structure, function and how they are made), transgenic mice, mouse models and the B7 family of molecules and their receptors.
11. This case is about a complex area of science. I wish to pay tribute to the parties’ efforts in educating the court and in particular to the time and effort put in to explaining things by all three expert witnesses. To attempt a full and accurate summary of the technical background for inclusion in the judgment would be a disproportionate task. An alternative would be to simply annex the primer but it runs to 68 pages with 113 paragraphs and annexing it does not assist. The approach I will take is to explain technical points as they arise if it seems necessary to do so.
12. A bibliography of the papers referred to in this judgment is in Annex 1.
The witnesses
13. Merck called Professor Vassiliki Boussiotis as an expert. Prof Boussiotis is a professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Centre and a member of the Dana-Farber/Harvard Cancer Centre. Since 1998 she has run a laboratory focussing on mechanisms and signalling pathways involved in the regulation of activating and inhibitory T-cell responses. She is also a clinical oncologist and treats patients with haematological cancers particularly lymphomas and leukaemias. She is therefore both an immunologist and an oncologist.
14. Ono called Professor Christopher Rudd as an expert. Prof Rudd is a professor of Molecular Immunology and head of the Cell Signalling Section at the University of Cambridge. He has held previous professorial positions at Harvard Medical School and Imperial College, London. He is an immunologist. A particular focus of his early work relates to T-cell activation and he has played a leading role in uncovering the mechanisms by which co-receptor signals function.
15. Ono also called Dr Renzo Canetta. He is Vice President of global R&D oncology policy at Bristol Myers Squibb and has worked in clinical oncology since 1974. In these proceedings Dr Canetta was originally called as a fact witness but his witness statements included expressions of his opinions on various topics. Merck objected to this course and Ono decided to designate Dr Canetta as an expert, with Dr Canetta filing a further short statement explaining that he understood his duties to the court as an expert witness and was giving his evidence on that basis. It is a pity that Dr Canetta’s evidence was produced in this way.
16. Each party criticised the witness(es) called by the other party. The criticisms were extensive and a number of them were serious. I have considered all of them carefully. I found none of them convincing. In my judgment all three of Prof Boussiotis, Prof Rudd and Dr Canetta were thoroughly honest and highly experienced experts in their respective fields who were seeking to explain to the court what they thought about the various issues to the best of their ability.
17. Perhaps aspects of the way in which Prof Boussiotis’s report was prepared could be criticised but even if those points are well founded, none of them persuaded me that I should discount the evidence of the professor. The way in which Prof Rudd answered the questions put in cross-examination involved him giving quite lengthy answers, to the evident frustration of the cross-examiner. In the course of doing so he mentioned points which Merck contended were new. In fact many of them were developments of points Prof Rudd had made in his report but it is quite true that his oral evidence placed emphasis on aspects which his reports had not and did raise new points of detail. That occurred because the witness was doing his level best to answer the questions put properly and fully. None of this persuaded me to discount Prof Rudd’s opinions. Nor was I persuaded that Prof Rudd’s expertise was not of direct bearing on the issues in this case, or was of lesser relevance than the expertise of Prof Boussiotis. As regards Dr Canetta, I have already mentioned the unfortunate way his evidence was produced.
18. All witnesses to a greater or lesser extent referred to post-published information and I have taken that into account. There are points of particular detail relating to all three witnesses but they are best dealt with when they arise.
The skilled person
19. Prof Boussiotis and Prof Rudd expressed their definitions of the skilled person in different words but subject to one point, it was common ground that they were equivalent. I will use Prof Rudd’s formulation. The patent is addressed to a team including a cellular immunologist working on receptors and the function of T-cells in the immune system. The team would include members with experience in producing and modifying antibodies, for example, a person skilled in preparing humanised antibodies or in working with transgenic mice. To this formulation I will add a couple of points mentioned by Prof Boussiotis. The team would have experience of animal cancer models. For certain aspects the team would additionally require the assistance of an oncologist familiar with the treatment of cancer with antibodies and conventional surgical care.
20. The debate was about signal transduction pathways. These are the mechanisms which operate inside a cell whereby the signal caused by a receptor on the cell surface being activated is acted upon. Prof Rudd’s view was that the knowledge of the skilled team would include knowledge of signal transduction pathways. Prof Boussiotis did not agree. Her evidence was that there was no need to have worked on signal transduction pathways and in support she explained that several leaders in the field at the time had not done so.
21. Much of Prof Rudd’s work has been concerned with signal transduction and he clearly regarded it as a vital element in the team’s consideration of issues relating to receptor function and T-cell activation. Prof Boussiotis personally had significant expertise in signal transduction but her point about other leaders in the field was that others did not. The debate is one of degree and in my judgment each side’s submission risks putting the matter too high. The team would include individuals with a working knowledge of signal transduction pathways. The skilled team would not ignore signal transduction but equally, while they are important in broad terms, detailed signal transduction pathways are not what the skilled team would be focussed upon.