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You are here: BAILII >> Databases >> England and Wales High Court (Patents Court) Decisions >> Eli Lilly And Company & Ors v Genentech, Inc [2019] EWHC 387 (Pat) (01 March 2019) URL: http://www.bailii.org/ew/cases/EWHC/Patents/2019/387.html Cite as: [2019] EWHC 387 (Pat) |
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Neutral Citation Number: [2019] EWHC 387 (Pat)
Case No: HP-2017-000041
IN THE HIGH COURT OF JUSTICE
BUSINESS AND PROPERTY COURTS
INTELLECTUAL PROPERTY LIST (CHANCERY DIVISION)
PATENTS COURT
Rolls Building
Fetter Lane, London, EC4A 1NL
Date: 1 March 2019
Before :
MR JUSTICE ARNOLD
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Between :
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(2) (3) (5) (7) |
Claimants |
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Defendant |
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Andrew Waugh QC , Thomas Mitcheson QC and Stuart Baran (instructed by Allen & Overy LLP ) for the Claimants
Michael Tappin QC , Justin Turner QC, Mark Chacksfield and William Duncan (instructed by Marks & Clerk Solicitors LLP ) for the Defendant
Hearing dates: 16-19, 21-25, 30-31 January, 1 February 2019
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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.
.............................
MR JUSTICE ARNOLD
MR JUSTICE ARNOLD:
Contents
Topic Paragraphs
Introduction 1
The witnesses 4-38
Fact witnesses 4-6
Expert witnesses 7-38
The dermatologists 8-18
The rheumatologists 19-25
The antibody experts 26-38
General technical background 39-133
Nucleic acids 40-41
Proteins 42-52
Recombinant expression of proteins 53-55
Innate vs adaptive immunity 56-64
Antigen-presenting cells 65-67
B cells 68-70
Antibody expression 68-69
B cell differentiation 70
T cells 71-77
Interaction with APCs 71
CD4 + /CD8 + Cells 72-73
T H 1/T H 2 cells 74-76
Memory T cells 77
Inflammation 78-79
Cytokines 80-83
Tumour necrosis factor alpha 84-85
Interferon gamma 86
Interleukin-6 87-88
Interleukin-8 88
The interleukin-17 family 89-92
Antibody structure 93-98
Antibody classes 99-102
Antigen binding 103-110
Epitopes 103-104
Binding affinity 105-107
Measuring antibody binding affinity 108-110
X-ray crystallography 111-112
Generating antibodies by immunising animals 113-117
Generating antibodies using phage display 118
Immunocytochemistry/immunohistochemistry 125-126
Neutralisation assay 127-129
Fc fusion proteins 130
Therapeutic antibodies 131-133
The Patent 134-178
Field of the invention 135
Background of the invention 136-143
Summary of the invention 144-148
A. Embodiments 144-147
B. Additional embodiments 148
Brief description of the drawings 149
Detailed description of the preferred embodiments 150-160
I. Definitions 150-152
II. Compositions and methods of the invention 153-159
Examples 160-178
Example 1 161-167
Example 2 168-170
Examples 3 to 11 171-178
The claims 179-181
The skilled team 182-187
Common general knowledge 188-292
The CGK of the rheumatologist 189-208
RA and its immuno-pathophysiology 190-191
Animal models 192
IL-6 and IL-8 193
IL-17A 194-196
IL-17 family 197-199
IL-17A and RA 200-206
Use of IL-17A for treating RA 207-208
The CGK of the antibody engineer 209
The CGK of the dermatologist 210-292
Psoriasis 211
Psoriatic arthritis 212
PASI 213
PGA 214
The immunological basis for psoriasis 215-216
Models of psoriasis 217-218
Treatment options for psoriasis 219-220
Relationship with RA 222-224
Cytokines involved in psoriasis 225-229
TNFα 230-231
IFNγ 232
IL-12 and IL-23 233-234
IL-6 235-253
IL-8: general 254-255
IL-8: Abgenix’s antibody 256-257
IL-8: Prof Krueger’s evidence 258-260
IL-8: Prof Prens’ evidence 261-276
IL-8: PPP 277-279
IL-8: Other later evidence 280-281
IL-8: conclusion 282-284
IL-17 285
IL-1 286-287
NF-kB 288
ICAM-1 289
GM-CSF 290
MIP/CCL20 291
Overall 292
Construction 293-314
The law 294
Which specifically binds to 295-312
Inhibits the activity of …IL-17A/F…to induce the production 313
of IL-8 and L-6
Use of an antagonist anti-IL A/F antibody … for 314
Genentech’s
amendment applications 315
Clarity 316-318
Extension of protection 319-321
Added matter 322-351
The law 324-328
The absence of specific evidence 329-330
The “complex” point 331-334
The “IL-8 and IL-6” point 335-349
The “combination” point 340-344
The “Kd” point 345-347
The “conditions” point 348-351
Conclusion in relation to Genentech’s
amendment applications 352
The prior art 353-396
The IL-17A/F prior art: US344 354-358
The IL-17A prior art: W0717, US711, JP046 and Lubberts 2001 359-396
W0717 360-369
US711 370-384
JP046 385-396
Obviousness over US344 397-410
The disclosure of US344 398-399
Obviousness of claims 1,2,13,14 and 15 400-403
Claim 1 400
Claims 2 and 15 401
Claims 13 and 14 402
Obviousness of claims 12, 20 and 20 in so far as directed to RA 403-410
Novelty over the IL-17A/A prior art 411-412
Obviousness over the IL-17A/A prior art 413-521
An outline of the issues 416-418
The use of mAbs 5, 16 and 25 as a starting point 419-430
Taking mAbs 5, 16 and 25 forward 431-435
The humanisation work 436
Use of IMGT definitions of CDRs 437-440
Use of germline sequences 441-444
Choice of residues to back mutate 445-472
Adair 453-457
Carter 458-460
Queen 461-471
Conclusion 472
The affinities of the humanised antibodies 473-481
Inevitability of binding to and inhibition of IL-17A/F 482-485
as well as IL-17A/A
Structures of IL-17A, IL-17 F/F IL-17A/F and 486-497
binding to receptors
Antibodies that bind to and inhibit IL-17 A/A 498-503
Immunodominance 504-506
Immune self-tolerance 507-508
Epitope clustering 509
The known antibodies 510-517
Conclusion on obviousness 518-521
Insufficiency: plausibility of the psoriasis claims 522-578
The law 523-531
Assessment 532-577
Fossiez 533
Chabaud 534-535
Jovanovic 536
Teunissen 537-542
Albanesi 543-548
Homey 549-550
Aggarwal 2002 551
Aggarwal 2003 552
The skilled person’s perception of the potency and 553
range of effects of IL-17A
Examples 1 and 2 of the Patent 554-556
Prof Krueger’s evidence 557-571
Prof Prens’ evidence 572-574
Prof Kamradt’s evidence 575
Conclusion 576-578
Insufficiency: other grounds 579-581
Ambiguity 579
Undue burden 580-581
The development of ixekizumab 582-593
Infringement 594-617
Ixekizumab 594
Which specifically binds to 595-599
Use … for: contribution of inhibition of IL-17A/F 600-606
Infringement of claims 1 and 2 607
Infringement of claims 13, 14, 15 and 22 608-613
Infringement of claims 12 and 20 614-615
Infringement of claims 13, 14 and 20 if conditionally 617
amended
Summary of principal conclusions 618
Introduction
1. The Defendant (“Genentech”)
is the proprietor of European Patent (UK) No. 1 641 822 entitled “IL-17A/F heterologous peptides and therapeutic uses thereof” (“the Patent”).
Genentech
does not itself have a product covered by the Patent at present. The Claimants (“
Lilly”)
market a formulation of an antibody called ixekizumab as a treatment for moderate to severe plaque psoriasis and psoriatic arthritis in adults under the trade mark Taltz. Ixekizumab is an antibody to interleukin-17A (“IL-17A”) which also binds to interleukin-17A/F (“IL-17A/F”).
Genentech
contends that this falls within the scope of protection of the Patent.
2. Lilly
seek revocation of the Patent, alleging that all of the claims are invalid on grounds of lack of novelty, obviousness and insufficiency, and a declaration that dealings in ixekizumab do not infringe the Patent in any event. There is no challenge to the earliest claimed priority date of 8 July 2003.
Genentech
counterclaims for infringement.
Genentech
has also applied to amend the Patent both unconditionally and conditionally.
Lilly
opposes the amendments on grounds of added matter, extension of protection and lack of clarity as well as contending that they do not cure the invalidity of the claims. Although both the application for the Patent and the Patent as granted contained claims directed to the treatment of any immune-related disorder,
Genentech
only maintains claims directed to rheumatoid arthritis (“RA”) and psoriasis. Claims directed to inflammatory diseases generally and asthma specifically were abandoned as recently as 4 January 2019.
3. It is pertinent to observe at the outset that this is one of the most complex patent cases I have ever tried (and I have considerable experience of trying complex patent cases). There are a large number of issues, and a formidable body of material addressing them. Some indication of this is provided by the following metrics. Lilly’s
written closing submissions run to 607 paragraphs and
Genentech’s
to 423 paragraphs, and both documents incorporate by reference additional sections from the parties’ respective opening skeleton arguments. There are 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 are over 300 scientific papers (including a few abstracts) in the trial bundles (although I estimate that only about half were referred to), plus extracts from two books. I have done my best to take all this material into account; but I cannot possibly refer to all of it in this judgment. As will appear, I have been able to deal quite briefly with some of the issues. Even so, it cannot avoid being a lengthy judgment.
The witnesses
4. Lilly
adduced evidence from three factual witnesses. Dr Kristine Kikly is a former Senior Research Fellow at
Lilly.
After obtaining a Batchelor’s degree in Medical Technology, a Master’s degree in Biological Sciences and a PhD in cellular immunology, she carried out post-doctoral research in cellular immunology. After being employed for some time by SmithKline Beecham, she joined
Lilly
in 2000. She was the Group Leader for its Therapeutic Antibody Group between 2000 and 2003, and from 2008 to 2017 she was Lead Biologist in the development project that led to ixekizumab. She is now retired. Dr Kikly gave evidence about the development of ixekizumab which was not challenged in cross-examination. She also verified
Lilly’s
Product Description.
5. Dr Jean-Jacques Pin is a founder and President of Dendritics SAS (“Dendritics”), a position he has occupied since 2005. While working for Schering-Plough in 1993-1994, he was the scientist primarily responsible for the preparation of the mAb5, mAb16 and mAb25 monoclonal antibodies that Lilly
relies on as representative of prior art murine antibodies raised to IL-17A/A.
Genentech
did not require Dr Pin to attend for cross-examination.
6. Dr Ian Wilkinson has been the Chief Scientific Officer of Absolute Antibody Ltd (“Absolute”) since 2012. Absolute carried out the humanisation of the mAb5, mAb16 and mAb25 antibodies as part of Lilly’s
experiments.
Genentech
did not require Dr Wilkinson to attend for cross-examination.
7. Lilly
called five experts and
Genentech
called four. Both parties called a dermatologist, a rheumatologist and two or more witnesses to address topics relating to antibody engineering.
8. The dermatologists . Lilly’s
dermatology expert was Professor James Krueger, who is D. Martin Carter Professor in Clinical Investigation in the Laboratory for Investigative Dermatology at the Rockefeller University in New York and a Senior Physician, Co-Director of the Center for Clinical and Translational Science and Chief Executive Officer of the Rockefeller University Hospital. He obtained an AB in Biochemistry from Princeton University in 1979 and a PhD in Virology-Cell Biology from the Rockefeller University in 1984. He undertook medical training at Cornell University Medical College, obtaining his MD in 1985, followed by residencies in the Department of Internal Medicine and Division of Dermatology at the same institution. He joined the Laboratory for Investigative Dermatology at the Rockefeller University as a Guest Investigator in 1985. He became an Assistant Professor in the Laboratory in 1990, Associate Professor and the head of the Laboratory in 1995 and Professor with tenure in 2003. Subsequently, he was awarded an endowed chair. From 1996 to 2008, he was the Medical Director of the Rockefeller University Hospital. He has been the Hospital’s CEO since 2008. From 1996 to 2006, he was also Program Director of the General Clinical Research Center of the Rockefeller University Hospital. In 2006, the General Clinical Research Center was superseded by the Center for Clinical and Translational Science, of which Prof Krueger has been the Co-director since its inception. In 2003, about half of his time was dedicated to clinical practice and research and about half dedicated to laboratory studies.
9. The main focus of Prof Krueger’s research since the early 1990s has been on skin inflammation, and in particular psoriasis. In addition to psoriasis, he has carried out research in relation to skin cancers and he has collaborated with investigators of other inflammatory skin diseases such as atopic dermatitis and psoriatic arthritis. He has participated in over 50 clinical trials, many involving psoriasis treatments, including ones that selectively deplete activated T cells, block early T cell activation signals, block T cell mitogenic receptors, alter T cell differentiation toward regulatory cells, and antagonise specific inflammatory cytokines. Prof Krueger has published over 300 peer-reviewed publications, primarily in relation to psoriasis biology and treatment. Since 1995 he has been a member of advisory boards for a number of pharmaceutical companies and he has been consulted by a number of companies that have being developing treatments for psoriasis, including both Lilly
(in relation to ixekizumab) and
Genentech
(in relation to efalizumab, an anti-CD11 antibody which received approval from the US Food and Drug Administration in October 2003, but was withdrawn from the market in 2009 due to adverse reactions). He has received a number of awards and honours, including the Distinguished Achievement Award and the Psoriasis Research Achievement Award from the American Skin Association in 2001.
10. Counsel for Genentech
accepted that Prof Krueger was an eminent psoriasis expert, but submitted that his expertise significantly exceeded that of the relevant skilled person. I accept that, but this is a common attribute of expert witnesses in patent litigation in this country. Counsel also submitted that Prof Krueger had occasionally found difficulty in answering questions from the perspective of the person skilled in the art rather than from his own personal perspective. I also accept this, but again it is a common problem. I found Prof Krueger to be an impressive witness, and in general I have no hesitation in preferring his evidence to that of Prof Prens where they conflict. As always, however, it remains necessary to consider the evidence on each issue as a whole.
11. Prof Krueger was well placed to speak to the common general knowledge of the skilled person in July 2003 since he had written a review for the continuing medical education of dermatologists which was published in January 2002 (Krueger, “The immunologic basis for the treatment of psoriasis with new biologic agents”, J Am Acad Dermatol , 46, 1-23, “Krueger 2002”) and had co-authored two reviews published in 2004 (Lowes et al , “Current concepts in the immunopathogenesis of psoriasis”, Dermatol Clin , 349-369, “Lowes” and Lew et al , “Psoriasis vulgaris: cutaneous lymphoid tissue supports T-cell activation and ‘Type 1’ inflammatory gene expression”, Trends in Immunol , 25, 295-305, “Lew”) which were probably written in around July 2003. He also gave a presentation entitled “IL-17 Family Cytokines and Psoriasis” at a Psoriasis: Gene to Clinic meeting in December 2017 in which he reviewed the history of discoveries relating to the IL-17 family and its role in psoriasis. Counsel for Genentech
criticised Prof Krueger for not re-reading Kreuger 2002 when writing his reports even though he had referred to it, but Prof Krueger explained that he remembered it very well. In any event, as Prof Krueger also explained, the field had moved on by July 2003. Thus I do not accept counsel for
Genentech’s
submission that Prof Krueger’s evidence was inconsistent with Krueger 2002.
12. Counsel for Genentech
submitted that some of Prof Krueger’s evidence was wrong, but the principal example he relied upon was what Prof Krueger had said about allergic contact dermatitis in his first report. As discussed below, Prof Krueger modified his position in cross-examination, but maintained the thrust of the point he was making. Counsel for
Genentech
also submitted that Prof Krueger had adopted an unduly negative attitude to some of the prior publications in the field, but I consider that Prof Krueger was simply giving his opinion as a scientist.
13. Finally, counsel for Genentech
submitted that Prof Krueger’s evidence was coloured by the fact he personally had not considered IL-17A to be a target for psoriasis in 2003, but had considered IFN-γ to be an important target. I accept that the view of the skilled person in July 2003 would not necessarily have coincided with that of Prof Krueger, and that it is necessary to take this into account when considering the evidence as a whole.
14. Genentech’s
dermatologist is Professor Errol Prens, who is a Professor of Experimental Dermatology at the Erasmus University Medical Centre in Rotterdam (“Erasmus MC”), where he also practices clinically as a dermatologist. He obtained a medical degree from the University of Groningen in 1981. Following training at the Erasmus University, he became a certified dermatologist in 1985. He joined the Department of Immunology at Erasmus MC in 1986 where he completed a PhD on the immunopathophysiology of psoriasis in 1992. In 1993 he became a Researcher and group leader. In 2005 he was appointed to his current position.
16. Counsel for Lilly
submitted that Prof Prens’ evidence was unsatisfactory, but accepted that, in some respects, this appeared to be due to the way in which he had been instructed, and his reports prepared, by
Genentech’s
legal team. Counsel gave three examples of this. The first was the exhibition of a selective extract from Freedberg et al (eds), Fitzpatrick’s Dermatology in General Medicine (6th ed, 2003). Prof Prens explained that the particular pages had been selected by the legal team, and he had not seen the selection at the time he signed his report. I regard this as unfortunate, but of no further significance.
17. The second example was the reliance upon a paper on cyclosporine Prof Prens had published in 1995 (Prens et al , “Effects of cyclosporine on cytokines and cytokine receptors in psoriasis”, J Am Acad Dermatol , 33, 947-953) rather than a review he had published in the same year (Prens et al , “T lymphocytes in psoriasis”, Clinics in Dermatol , 13, 115-129). This in itself does not strike me as significant, particularly given the age of the review. What is more significant is, as counsel for Lilly
submitted, the brevity and superficiality of Prof Prens’ exposition of the common general knowledge of the skilled person in his first report compared to that of Prof Krueger, something which I noted when I first read the reports. For example, there was little discussion of the complexity of the cytokine network, and no mention at all of the phenomenon of redundancy.
18. The third example was Prof Prens’ evidence concerning Abcream. I shall deal with this topic in context below. As this stage, it is sufficient to record that I do not accept that the cross-examination of Prof Prens on this matter was, as counsel for Genentech
submitted, “bizarre”, “inappropriate”, “aggressive” or “bullying”, although it is fair to say that some of the questions were mis-directed. I found Prof Prens’ evidence on the topic deeply unsatisfactory for the reasons I shall explain. While it may be said to be an isolated and somewhat peripheral topic which does not necessarily affect Prof Prens’ evidence on the other issues in the case, I am bound to say that it did reduce my confidence in Prof Prens’ evidence and thus the weight which I am able to give it.
19. The rheumatologists . Lilly’s
expert on RA was Dr Erik Lubberts, who is Head of the Research Laboratory of Immune Mediated Inflammatory Diseases and an Associate Professor in the Department of Rheumatology at Erasmus MC. He obtained a Master’s in Biology and Medical Biotechnology from the University of Groningen in 1994 and a PhD on the role of interleukin (IL)-4 and IL-10 in the regulation of experimental arthritis from the University of Nijmegen in 1999. From 1999 to 2002 he was a post-doctoral fellow in Prof van den Berg’s group in the Department of Rheumatology working on two projects on the role of IL-17 in arthritis. From November 2002 to August 2003 he carried out research as a visiting scientist in three US laboratories, including work on IL-17. From September 2003 to March 2005 he was a post-doctoral researcher in the Department of Rheumatology at the University of Nijmegen. He then moved to the Department of Rheumatology at Erasmus MC as an Assistant Professor and became an Associate Professor in 2009.
21. Much of Dr Lubberts’ evidence was unchallenged in cross-examination. Consistently with that, counsel for Genentech
accepted that Dr Lubberts was well qualified to give the evidence he had given and made no criticism of that evidence.
22. Genentech’s
expert on RA was Professor Thomas Kamradt, who is Professor of Immunology at the Institute of Immunology at Jena University Hospital in Germany. He undertook his medical training at the Universities of Cologne, Vienna and Berlin, obtaining his medical licence in 1984. From 1984 to 1989 he was a resident in internal medicine at the Medical School of the University of Bonn. During that period, he obtained a Dr. med degree at the Free University of Berlin in 1987. From 1989 to 1991 he was a post-doctoral associate in the Department of Biology at the Massachusetts Institute of Technology, where he researched T-cell immunology. From 1991 to 1994 he was an Assistant Professor of Medicine in the Department of Rheumatology/Clinical Immunology at Tufts Medical School in Boston. During this period, his research focus was Lyme disease, in particular Lyme arthritis. From 1994 to 2004 he was the Group Leader of T-cell Immunology at the Deutsches RheumaForschungszentrum (German Rheumatism Research Centre, “DRFZ”) in Berlin. In 1998, his group became interested in IL-17-producing Th cells through their work on Lyme disease. In parallel with his work at the DRFZ, from 1995 to 2003 he was a practising clinician at the rheumatology outpatients clinic at Charité University Hospital in Berlin. He has been head of the Institute of Immunology at Jena University Hospital since 2004. He has collaborated with pharmaceutical companies on a number of occasions.
23. In the area of autoimmunity, Prof Kamradt’s research group primarily investigates the induction, chronification and modulation of pathological immune responses in (models of) arthritis and autoimmune encephalitis. In the area of immunoregulation, they primarily investigate the induction, function and stability of Th17 cells, and how cytokine receptors (in particular IL-33R) interact with other cellular receptors. He has published over 130 articles on immunology and rheumatic diseases, including RA. In addition, he has written chapters in about 10 textbooks, including the Oxford Textbook of Rheumatology .
24. Counsel for Lilly
submitted that Prof Kamradt had been wrongly instructed with respect to his consideration of the prior art, and in particular WO717. I think there is some force in this, and that it explains a statement made by Prof Kamradt in his first report which counsel criticised as being wrong. Prof Kamradt’s evidence was clarified in cross-examination, however.
25. Counsel for Lilly
also criticised Prof Kamradt’s oral evidence with respect to US344. As counsel himself submitted, however, Prof Kamradt’s final position was essentially the same as that set out in his first report.
26. The antibody experts . Lilly’s
principal expert on antibody engineering was Dr John Tite. Dr Tite is a director of Pannier Consulting Ltd, a biotechnology consultancy company, part-time Scientific Advisor at Touchlight Genetics Ltd, a biopharmaceutical company developing synthetic DNA manufacturing technology, and a non-executive director of Iquar Ltd, a biopharmaceutical company developing a vaccine platform. He obtained a degree in Zoology from University College London in 1974 and a PhD in Immunology from the Department of Immunology of the Middlesex Hospital Medical School, University of London in 1977. From 1977 to 1980 he was a post-doctoral researcher in the Medical Research Council (MRC) Immunobiology Unit, Department of Pathology at the University of Bristol Medical School. From 1980 to 1985 he held a position in the Division of Immunobiology, Department of Pathology at Yale University School of Medicine. In 1986 he joined the Wellcome Foundation as a postdoctoral Research Associate. Prior to the merger of Wellcome plc with Glaxo plc, he managed the Wellcome Therapeutic Antibody programme. After the formation of GlaxoWellcome in 1995 he held the positions of Unit Head of the Immunology Research Unit overseeing the early Discovery Portfolio (1995-1999), Head of the Immunology and Virology Department (1999-2001) and Acting Director of Biological Sciences Division (2000-2001). After the merger of GlaxoWellcome and SmithKline Beecham to form GlaxoSmithKline plc, he was Vice-President, Gene and Protein Therapeutics, Discovery Research (2001-2003) and Vice-President for Discovery Biology within the Biopharm Centre of Excellence for Drug Discovery (2003-2008). During the latter period he was also Chair of the Board of Trustees of the Edward Jenner Institute for Vaccine Research. From 2009 to 2012 he was the founding Chief Executive Officer of Bicycle Therapeutics Ltd, which had a proprietary technology for the development of highly stable bicyclic peptides as novel biopharmaceutical agents. He established Pannier Consulting Ltd in 2012.
27. Counsel for Genentech
made no criticism of Dr Tite as a witness. Counsel submitted that it was regrettable that certain points made by Dr Tite in his oral evidence had not been included in Dr Tite’s written reports, but accepted that this may have been the fault of
Lilly’s
legal team. More importantly, counsel pointed out that Dr Tite was an immunologist, not an expert in structural biology, and that he had had no experience of working with IL-17 cytokines or antibodies to them. Accordingly, Dr Tite accepted that he was not in a position to question Prof Carr’s structural analysis of what antibodies would be expected to be raised against IL17A and how they would be expected to interact with IL-17A/F. As counsel for
Lilly
pointed out, however, Dr Tite emphasised that he was in a position to consider the question from the perspective of an immunologist.
28. Dr Lutz Riechmann was Lilly’s
expert on antibody humanisation. He is now a consultant in antibody engineering. He obtained a degree in biology from the University of Bremen in 1984 and a PhD in biology from the same institution in 1986. From 1986 to 1988 he was a post-doctoral researcher in the laboratory of Professor Sir Gregory Winter CBE FRS (as he now is). During this period, Dr Riechmann produced the first ever fully humanised antibody, CAMPATH-1H. Following work at the Scripps Institute in La Jolla in 1988 to 1989, he was employed by MRC Laboratory of Molecular Biology as a Group Leader (1989-1997) and then Senior Scientific Officer (1997-20008 and 2009-2011). He was Director of Antibody Display Technology at F-star Cambridge from 2008 to 2009. He has been a consultant since 2011. He has published over 40 articles and patents.
29. Counsel for Genentech
advanced no real criticism of Dr Riechmann as a witness, as opposed to the substance of certain points that he made.
30. Finally, Lilly
called Professor Arthur Lesk as an expert in computational biology. He is a Professor in the Department of Biochemistry and Molecular Biology at the Pennsylvania State University, where he also holds an honorary appointment in the Department of Computer Science and Engineering. He obtained an AB in Biochemical Sciences from Harvard University in 1961 and a PhD in Physics and Physical Chemistry from Princeton University in 1966. Following this, he held positions including Professor of Chemistry at Fairleigh Dickinson University (1971-1987); a Visiting Scientist at the MRC Laboratory of Molecular Biology (1977-1979 and 1981-1990); Group Leader of the Biocomputing Programme at the European Molecular Biology Laboratory in Heidelberg (1987-1990); and Senior Research Associate in the Department of Haematology at the University of Cambridge (1990-2003). He has held his current position since 2003.
32. As counsel for Genentech
pointed out, Prof Lesk had one main task in this case (although he also produced some 3D images for Dr Tite). His main task was to produce models that reflected those which a skilled person in 2003 would have produced if humanising mAbs 5, 16 and 25 so that Dr Riechmann could use the inter-atomic distances to apply his 3.5 Å distance criterion. In that task he singularly failed, for the reasons explained below. Counsel for
Genentech
submitted that the sequence of events discussed there did not reflect well on Prof Lesk. I have to say that I agree with this.
33. Genentech’s
principal expert on antibody engineering was Professor Andrew Martin, who is Professor of Bioinformatics and Computational Biology in the Department of Structural and Molecular Biology, Division of Biosciences at University College London (“UCL”). He obtained a degree in Biochemistry from the University of Oxford in 1986 and a DPhil in the molecular modelling of antibody combining sites from the same institution from 1986 to 1990. From 1990 to 1994, he was self-employed doing contract work for Oxford Molecular Ltd. and The National Grid Company as well as independently developing scientific software. In 1994 he joined UCL as a post-doctoral Research Fellow and in 1998-1999 he was seconded four days a week to Inpharmatica Ltd, a spin-off from UCL, where he held the position of Technical Director. From 1999 to 2003, he was Lecturer in Bioinformatics at the University of Reading. In 2004 he took the same position at UCL, becoming Senior Lecturer in Bioinformatics in 2005 and Reader in Bioinformatics and Computational Biology in 2014. He was appointed to his current position in 2018.
35. Counsel for Lilly
made no real criticism of Prof Martin as a witness, but pointed out that Prof Martin’s expertise was in computational biology rather than immunology and that he had done no “wet” laboratory work since part-way through his undergraduate degree. Counsel for
Lilly
submitted that Prof Martin had strayed into a field in he did not have expertise, namely SPR. As Prof Martin explained, however, although he did not have experience of performing SPR, he did have experience in interpreting SPR results. More generally, he had experience of working as part of teams dealing with antibody engineering.
36. In addition, Genentech
called Professor Mark Carr , an expert in structural biology. He is Professor of Biochemistry in the Department of Molecular and Cell Biology at the University of Leicester, and has a leadership role in the Leicester Institute of Structural and Chemical Biology. He obtained a degree in Biochemistry from the University of Birmingham in 1983 and a D.Phil. in Biochemistry from the University of Oxford in 1987. From 1987 to 1989 he held Post-doctoral Fellowships at the Max Planck for Medical Research and the Max Planck Society in Heidelberg. From 1989 to 2003 he held a post-doctoral research position in the Laboratory of Molecular Structure at the National Institute for Medical Research. From 1993 to 1997 he was a Group Leader in the Laboratory of Molecular Structure at the National Institute for Biological Standards and Control. From 1997 to 2001 he was Lecturer in Structural Biology in the Department of Biosciences at the University of Kent. From 2001 to 2009 he was Reader in Biological NMR Spectroscopy in the Department of Biochemistry at the University of Leicester. He was appointed to his present position in 2009. From 2011 to 2015, he was also Director of Enterprise for the College of Life Sciences at the University of Leicester. In addition to his roles at the University of Leicester, he has acted as a senior scientific advisor to UCB since 2002.
37. Prof Carr’s research focuses on determining the structures, functions, interactions and mechanisms of action of proteins and protein complexes involved in key biological processes of significant medical importance, including the characterisation of interactions with potential new therapeutics. He has published over 60 articles covering structural and functional studies of a diverse range of proteins and protein complexes. Importantly, he was very familiar with the IL-17 cytokines, having worked with them as part of a two-to-three year project carried out by his group in collaboration with UCB. He was thus well qualified to opine on what would be expected in terms of antibodies binding to these molecules from a structural perspective. He also had experience of working with collaborators in therapeutic antibody projects. As counsel for Lilly
pointed out, however, Prof Carr was not an immunologist and he accepted that he was not as well qualified as Dr Tite to speak about such matters as B-cell recognition, maturation and somatic hypermutation.
38. Counsel for Lilly
pointed out that it had emerged from Prof Carr’s oral evidence that he had received some help in the preparation of his first report from his research assistant Dr Lorna Waters which was not fully or properly acknowledged. I agree that this should have been fully disclosed in the report, but Prof Carr was candid about the assistance he had received in cross-examination and was clear that the evidence he gave was his own.
General technical background
Nucleic acids
Proteins
Recombinant expression of proteins
54. This process involves the following steps:
i) Identification and DNA sequencing of the gene encoding the particular protein or fragment which is to be produced.
ii) Generating DNA encoding the protein/fragment of interest – usually by amplification of the DNA sequence encoding the protein of interest.
iii) Insertion of the DNA into a “vector” that is able to carry the DNA sequence into the host cell and cause the protein(s) encoded by the DNA sequence to be expressed by the host cell.
iv) Introducing the vector into the host cell by transfection, transduction, or transformation.
v) Expression of the protein by the host cell, followed by collection and purification of the resultant protein or fragment.
Innate vs adaptive immunity
Phagocytes
Antigen-presenting cells
B cells
T cells
Inflammation
Cytokines
Tumour necrosis factor alpha
Interferon gamma
Interleukin-6
Interleukin-8
The interleukin-17 family
Antibody structure
Antibody classes
Antigen binding
i) A continuous epitope (also referred to as consecutive or linear), in which the epitope is formed by a stretch of neighbouring amino acid residues along the primary sequence of the antigen.
ii) A discontinuous epitope (also referred to as non-consecutive or conformational), in which the amino acid residues forming the epitope are discontinuously arranged along separate parts of the primary sequence of the antigen, but are brought into close proximity through the native folding of the polypeptide chains and/or arrangement of the polypeptide chains that form the protein (see Figure 11).
X-ray crystallography
Generating antibodies by immunising animals
113. Antibodies against an antigen of interest may be generated by immunising an animal. The antigen of interest may act as an immunogen (a foreign protein eliciting
an adaptive immune response).
Generating antibodies using phage display
119. An enzyme-linked immunosorbent assay (ELISA)
is a high throughput solid phase immunoassay, meaning that one of the components (i.e. antigen or antibody) is fixed to a solid surface. There are three types of
ELISA:
direct, indirect and sandwich.
120. In a direct ELISA,
an antigen (Ag, shown as a green circle in Figure 13) is immobilised on the surface of a well in a microtitre plate and then incubated with the antibody of interest which has been linked (conjugated) to an enzyme (the primary antibody conjugate in panel A of Figure 13 below) after which the plate is washed to remove any antibody that has not bound to the antigen. The enzyme is able to produce a detectable response by catalysing a reaction in a substrate. Common enzymes used for this purpose include horseradish peroxidase (HRP) or alkaline phosphatase (AP).
122. An indirect ELISA
involves coating the antigen of interest onto a microtitre plate but the detectable response is provided by a secondary antibody which recognises any portion of the primary antibody bound to the antigen (see panel B of Figure 13 above). The secondary antibody is applied after washing away any unbound antibody and is conjugated to an enzyme. The enzyme attached to the secondary antibody catalyses a reaction leading to a detectable change in the substrate and the amount of binding can be measured, for example, as a change in colour (see Figure 14).
123. A sandwich ELISA
employs two antibodies, or three for an indirect assay (see panel C of Figure 13 above). The first antibody for the antigen is attached to the bottom of the wells of a microtitre plate; this is referred to as the capture antibody. The test solution containing the antigen of interest is then introduced. The antigen is captured by the fixed antibody and any unbound proteins are washed away. An antibody which recognises the antigen via a different epitope is then added and the binding of this second antibody, referred to as a detection antibody, will be used to detect that the antigen has been captured. Figure 14 shows this being performed using an indirect method, but a direct method using an enzyme conjugated to the detection antibody is possible. The signal is developed and the detectable response is measured as outlined above.
124. A competitive ELISA
can be performed, amongst other ways, by coating the antigen of interest on to the microtitre plate and incubating with a primary antibody conjugated to an enzyme. The level of binding of the primary antibody is then measured. A second antibody which is not conjugated is then introduced step-wise in increasing concentrations. The amount of primary antibody bound is detected at each concentration of the unlabelled antibody. If the antibodies bind to the same or an overlapping epitope the signal from the primary antibody will be reduced.
Neutralisation assay
127. A neutralisation assay can be used to measure the ability of an antibody to inhibit the activation of a downstream signal which is elicited
when a ligand binds to a receptor. The ligand is applied to cells or a tissue in which it is known to
elicit
a response, such as the release of a cytokine or other messenger. The reduction in the defined response in the presence of increasing concentrations of the test antibody is measured.
Fc fusion proteins
Therapeutic antibodies
The Patent
Field of the invention
135. The specification states at [0001] that the invention “relates generally to the identification and isolation of a novel human cytokine designated as interleukin-17A/F (IL-17A/F)”.
Background of the invention
138. At [0009] the specification states (emphasis added):
“Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis , immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis , and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, etc.”
140. From [0015] to [0019] the specification provides a detailed overview of IL-17A and the other members of the IL-17 family (i.e. IL-17B-F). Since this passage is central to Genentech’s
case on plausibility, it is necessary to quote it in full. It can be divided into three parts. I shall highlight references to certain articles which featured prominently in the evidence and which are referred to below. I shall also highlight references to RA and psoriasis.
141. The first part discusses IL-17 i.e. IL-17A:
“[0015] lnterleukin-17 (IL-17) is a T-cell derived pro-inflammatory molecule that stimulates epithelial, endothelial and fibroblastic cells to produce other inflammatory cytokines and chemokines including IL-6, IL-8, G-CSF, and MCP-1 [ see , Yao, Z. et al., J. Immunol., 122(12):5483-5486 (1995); Yao, Z. et al., Immunity, 3(6):811-821 (1995); Fossiez, F., et al., 30 J. Exp. Med., 183(6): 2593-2603 (1996) ; Kennedy, J., et al., J. Interferon Cytokine Res., 16(8):611-7 (1996); Cai, X. Y., et al., Immunol. Lett, 62(1):51-8 (1998); Jovanovic, D.V., et al., J. Immunol. 160(7):3513-21 (1998) ; Laan, M., et al., J. Immunol., 162(4):2347-52 (1999); Linden, A., et al., Eur Respir J, 15(5):973-7 (2000); and Aggarwal, S. and Gurney, A.L., J Leukoc Biol, 71(1):1-8 (2002) ]. IL-17 also synergizes with other cytokines including TNF-a and IL-1β to further induce chemokine expression ( Chabaud, M., et al., J. Immunol. 161 (1):409-14 (1998) ). Interleukin 17 (IL-17) exhibits plei[o]tropic biological activities on various types of cells. IL-17 also has the ability to induce ICAM-1 surface expression, proliferation of T cells, and growth and differentiation of CD34 + human progenitors into neutrophils. IL-17 has also been implicated in bone metabolism, and has been suggested to play an important role in pathological conditions characterized by the presence of activated T cells and TNF-α production such as rheumatoid arthritis and loosening of bone implants (Van Bezooijen et al., J. Bone Miner. Res., 14: 1513-1521 [1999]). Activated T cells of synovial tissue derived from rheumatoid arthritis patients were found to secrete higher amounts of IL-17 than those derived from normal individuals or osteoarthritis patients (Chabaud et al., Arthritis Rheum., 42: 963-970 [1999]). It was suggested that this proinflammatory cytokine actively contributes to synovial inflammation in rheumatoid arthritis . Apart from its proinflammatory role, IL-17 seems to contribute to the pathology of rheumatoid arthritis by yet another mechanism. For example, IL-17 has been shown to induce the expression of osteoclast differentiation factor (ODF) mRNA in osteoblasts (Kotake et al., J. Clin. Invest., 103: 1345-1352 [1999]). ODF stimulates differentiation of progenitor cells into osteoclasts, the cells involved in bone resorption. Since the level of IL-17 is significantly increased in synovial fluid of rheumatoid arthritis patients, it appears that IL-17 induced osteoclast formation plays a crucial role in bone resorption in rheumatoid arthritis . IL-17 is also believed to play a key role in certain other autoimmune disorders such as multiple sclerosis (Matusevicius et al., Mult. Scler., 5: 101-104 (1999); Kurasawa, K., et al., Arthritis Rheu 43(11):2455-63 (2000)) and psoriasis ( Teunissen, M.B., et al., J Invest Dermatol 111 (4):645-9 (1998) ; Albanesi, C., et al., J Invest Dermatol 115(1):81-7 (2000) ; and Homey, B., et al., J. Immunol. 164(12:6621-32 (2000) ).
[0016] IL-17 has further been shown, by intracellular signalling, to stimulate Ca 2+ influx and a reduction in [cAMP] in human macrophages ( Jovanovic et al., J. Immunol., 160:3513 [1998] ). Fibroblasts treated with IL-17 induce the activation of NF-κB, [Yao et al., Immunity, 3:811 (1995), Jovanovic et al., supra], while macrophages treated with it activate NF-κB and mitogen-activated protein kinases (Shalom-Barek et al., J. Biol. Chem., 273:27 467 [1998]). Additionally, IL-17 also shares sequence similarity with mammalian cytokine-like factor 7 that is involved in bone and cartilage growth. Other proteins with which IL-17 polypeptides share sequence similarity are human embryo-derived interleukin-related factor (EDIRF) and interleukin-20.
[0017] Consistent with IL-17's wide-range of effects, the cell surface receptor for IL-17 has been found to be widely expressed in many tissues and cell types (Yao et al., Cytokine, 9:794 [1997]). While the amino acid sequence of the human IL-17 receptor (IL-R) (866 amino acids) predicts a protein with a single transmembrane domain and a long, 525 amino acid intracellular domain, the receptor sequence is unique and is not similar to that of any of the receptors from the cytokine/growth factor receptor family. This coupled with the lack of similarity of IL-17 itself to other known proteins indicates that IL-17 and its receptor may be part of a novel family of signaling proteins and receptors. It has been demonstrated that IL-17 activity is mediated through binding to its unique cell surface receptor (designated herein as human IL-17R), wherein previous studies have shown that contacting T cells with a soluble form of the IL-17 receptor polypeptide inhibited T cell proliferation and IL-2 production induced by PHA, concanavalin A and anti-TCR monoclonal antibody (Yao et al., J. Immunol., 155:5483-5486 [1995]). As such, there is significant interest in identifying and characterizing novel polypeptides having homology to the known cytokine receptors, specifically IL-17 receptors.”
142. The second part discusses IL-17B to F, and in particular IL-17F:
“[0018] Interleukin 17 is now recognized as the prototype member of an emerging family of cytokines. The large scale sequencing of the human and other vertebrate genomes has revealed the presence of additional genes encoding proteins clearly related to IL-17, thus defining a new family of cytokines. There are at least 6 members of the IL-17 family in humans and mice including IL-17B, IL-17C, IL-17D, IL-17E and IL-17F as well as novel receptors IL-17RH1, IL-17RH2, IL-17RH3 and IL-17RH4 (see W001/46420 published June 28, 2001). One such IL-17 member (designated as IL-17F) has been demonstrated to bind to the human IL-17 receptor (IL-17R) (Yao et al., Cytokine, 9(11):794-800 (1997)). Initial characterization suggests that, like IL-17, several of these newly identified molecules have the ability to modulate immune function. The potent inflammatory actions that have been identified for several of these factors and the emerging associations with major human diseases suggest that these proteins may have significant roles in inflammatory processes and may offer opportunities for therapeutic intervention.
[0019] The gene encoding human IL-17F is located adjacent to IL-17 (Hymowitz, S.G., et al., Embo J, 20(19):5332-41 (2001)). IL-17 and IL-17F share 44% amino acid identity whereas the other members of the IL-17 family share a more limited 15-27% amino acid identity suggesting that IL-17 and IL-17F form a distinct subgroup within the IL-17 family (Starnes, T., et al., J Immunol, 167(8):4137-40 (2001); Aggarwal, S. and Gurney, A.L., J. Leukoc Biol, 71 (1):1-8 (2002) ). IL-17F appears to have similar biological actions as IL-17, and is able to promote the production of IL-6, IL-8, and GCSF from a wide variety of cells. Similar to IL-17, it is able to induce cartilage matrix release and inhibit new cartilage matrix synthesis (see US-2002-0177188-A1 published November 28, 2002). Thus, like IL-17, IL-17F may potentially contribute to the pathology of inflammatory disorders. Recently, these authors have observed that both IL-17 and IL-17F are induced in T cells by the action of interleukin 23 (IL-23) ( Aggarwal, S., et al., J. Biol. Chem., 278(3):1910-4 (2003) ).”
“The observation that IL-17 and IL-17F share similar chromosomal localization and significant sequence similarity [as] well as the observation that IL-17 and IL-17F appear to be induced with the same cell population in response to a specific stimuli has lead to the identification of a new human cytokine that is comprised of a covalent heterodimer of IL- 17 and IL-17F (herein designated IL-17A/F). Human IL-17A/F is a distinctly new cytokine, distinguishable from human IL-17 and 1L-17F in both protein structure and in cell-based activity assays. Through the use of purified recombinant human IL-17 A/F as a standard, a human IL-17AF-specific ELISA
has been developed. Through the use of this specific
ELISA,
the induced expression of human IL-17A/F was detected, confirming that IL-17A/F is naturally produced from activated human T cells in culture. Hence, IL-17A/F is a distinctly new cytokine, detectable as a natural product of isolated activated human T cells, whose recombinant form has been characterized, in both protein structure and cell-based assays, as to be different and distinguishable from related cytokines. Thus, these studies provide and identify a novel immune stimulant (i.e. IL-17 A/F) that can boost the immune system to respond to a particular antigen that may not have been immunologically active previously. As such, the newly identified immune stimulant has important clinical applications. This novel IL-17A/F cytokine or agonists thereof, would therefore find practical utility as an immune stimulant, whereas molecules which inhibit IL-17A/F activity (antagonists) would be expected to find practical utility when an inhibition of the immune response is desired, such as in autoimmune diseases. Specifically, antibodies to this new cytokine which either mimic (agonist antibodies) or inhibit (antagonist antibodies) the immunological activities of IL-17 A/F would possess therapeutic qualities. Small molecules which act to inhibit the activity of this novel cytokine would also have potential therapeutic uses.”
It can be seen that no specific clinical applications or therapeutic uses are identified in this passage. The nearest one gets is the reference to auto-immune diseases.
Summary of the invention
145. At [0023] the specification states (emphases added):
“In another embodiment, the invention relates to a method of treating an immune related disorder in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of an IL-17A/F polypeptide, an agonist thereof, or an antagonist thereto. In a preferred aspect, the immune related disorder is selected form the group consisting of: systemic lupus erythematosis, rheumatoid arthritis , osteoarthritis, juvenile chronic arthritis, spondyloarthropathies, systemic sclerosis, idiopathic inflammatory myopathies, Sjögren's syndrome, systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, thyroiditis, diabetes mellitus, immune-mediated renal disease, demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy, hepatobiliary diseases such as infectious, autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis, inflammatory bowel disease, gluten-sensitive enteropathy, and Whipple's disease, autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis , allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria, immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis, transplantation associated diseases including graft rejection and graft-versus-host-disease.”
147. The specification goes on to describe a series of diagnostic embodiments:
“[0028] Described herein is a method of diagnosing an immune related disease in a mammal, comprising detecting the level of expression of a gene encoding an IL-17A/F polypeptide …
[0029] In another embodiment, the present invention concerns a method of diagnosing an immune disease in a mammal, comprising (a) contacting an anti-IL-17A/F antibody with a test sample of tissue cells obtained from the mammal, 15 and (b) detecting the formation of a complex between the antibody and an IL-17A/F polypeptide, in the test sample; wherein the formation of said complex is indicative of the presence or absence of said disease. …
[0030] In another embodiment, the invention provides a method for determining the presence of an IL-17A/F polypeptide in a sample comprising exposing a test sample of cells suspected of containing the IL-17A/F polypeptide to an anti-IL-17A/F antibody and determining the binding of said antibody to said cell sample …
[0031] In another embodiment, the present invention may concern an immune-related disease diagnostic kit, comprising an anti-IL-17A/F antibody and a carrier in suitable packaging. The kit preferably contains instructions for using the antibody to detect the presence of the IL-17 A/F polypeptide. …
[0032] In another embodiment, the present invention may concern[] a diagnostic kit, containing an anti-IL-17A/F antibody in suitable packaging. The kit preferably contains instructions for using the antibody to detect the IL-17A/F polypeptide.”
Brief description of the drawings
Detailed description of the preferred embodiments:
“[0115] A ‘species-dependent antibody,’ e.g., a mammalian anti-human lgE antibody, is an antibody which has a stronger binding affinity for an antigen from a first mammalian species than it has for a homologue of that antigen from a second mammalian species. Normally, the species-dependent antibody ‘bind[s] specifically’ to a human antigen (i.e., has a binding affinity (Kd) value of no more than about 1 x 10 -7 M, preferably no more than about 1 x 10 -8 and most preferably no more than about 1 x 10 -9 M) but has a binding affinity for a homologue of the antigen from a second non-human mammalian species which is at least about 50 fold, or at least about 500 fold, or at least about 1000 fold, weaker than its binding affinity for the human antigen. The species-dependent antibody can be of any of the various types of antibodies as defined above, but preferably is a humanized or human antibody.
[0118] [A] An antibody, oligopeptide or other organic molecule ‘which binds’ an antigen of interest, e.g. a tumor-associated polypeptide antigen target, is one that binds the antigen with sufficient affinity such that the antibody, oligopeptide or other organic molecule is useful as a diagnostic and/or therapeutic agent in targeting a cell or tissue expressing the antigen, and does not significantly cross-react with other proteins. In such embodiments, the extent of binding of the antibody, oligopeptide or other organic molecule to a ‘non-target’ protein will be less than about 10% of the binding of the antibody, oligopeptide or other organic molecule to its particular target protein as determined by fluorescence activated cell sorting (FACS) analysis or radioimmunoprecipitation (RIA).
[B] With regard to the binding of an antibody, oligopeptide or other organic molecule to a target molecule, the term ‘specific binding’ or ‘specifically binds to’ or is ‘specific for’ a particular polypeptide or an epitope on a particular polypeptide target means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the blinding of the labeled target to a probe is competitively inhibited by excess unlabeled target.
[C] The term ‘specific binding’ or ‘specifically binds to’ or is ‘specific for’ a particular polypeptide or an epitope on a particular polypeptide target as used herein can be exhibited, for example, by a molecule having a Kd for the target of at least about 10 [-]4 M, alternatively at least about 10 -5 M, alternatively at least about 10 -6 M, alternatively at least about 10 -7 M, alternatively at least about 10 -8 M, alternatively at least about 10 -9 M, alternatively at least about 10 -10 M, alternatively at least about 10 -11 M, alternatively at least about 10 -12 M, or greater.
[D] In one embodiment, the term ‘specific binding’ refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.
[0131] ‘Active’ or ‘activity’ for the purposes herein refers to form(s) of an IL-17A/F polypeptide which retain a biological and/or an immunological activity of native or naturally-occurring IL-17A/F polypeptides, wherein ‘biological’ activity refers to a biological function (either inhibitory or stimulatory) caused by a native or naturally-occurring IL-17A/F polypeptide other than the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring IL-17A/F polypeptide and an ‘immunological’ activity refers to the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring IL-17A/F polypeptide. One preferred biological activity includes inducing activation of NF-[κB] and stimulation of the production of the pro inflammatory chemokines IL-8 and IL-6. Another preferred biological activity includes stimulation of peripheral blood mononuclear cells or CD4 + cells. Another preferred biological activity includes stimulation of the proliferation of T-lymphocytes. Another preferred biological activity includes, for example, the release of TNF-α from THP1 cells. Another activity includes an enhancement of matrix synthesis in articular cartilage. Alternatively, another activity includes promoting breakdown of articular cartilage matrix as well as inhibiting matrix synthesis. Another preferred biological activity includes modulating the level of the interleukin-17 signalling pathway during mild to severe stages of inflammatory bowel disease or during stroke.”
151. Although it is not strictly a definition, the specification states at [0136] (emphases added):
“ Examples of immune-related and inflammatory disease, some of which are immune or T cell mediated, which can be treated according to the invention, include systemic lupus erythematosis, rheumatoid arthritis , juvenile chronic arthritis, osteoarthritis, spondyloarthropathies, systemic sclerosis (scleroderma), idiopathic inflammatory myopathies (dermatomyositis, polymyositis), Sjögren's syndrome, systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia), thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis), diabetes mellitus, immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis), demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy, hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis, inflammatory bowel disease (ulcerative colitis: Crohn's disease), gluten-sensitive enteropathy, and Whipple's disease, autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis , allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria, immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis, transplantation associated diseases including graft rejection and graft versus-host-disease.”
A. Full-length IL-17A/F polypeptides: [0141];
B. IL-17A/F polypeptide variants: [0142]-[0150];
C. Modifications of IL-17A/F: [0151]-[0161];
D. Preparation of IL-17A/F: [0162]-[0188];
E. Uses for IL-17A/F: [0189]-[0232];
F. Tissue distribution: [0233]-[0235];
G. Antibody binding studies: [0236]-[0239];
H. Cell-based assays: [0240]-[0250];
I. Animal models: [0251]-[0264];
J. Immunoadjuvant therapy: [0265];
K. Screening assays for drug candidates: [0266]-[0269];
L. Compositions and methods for the treatment of immune related diseases: [0270]-[0274];
M. Anti-IL-A/F antibodies: [0275]-[0332];
N. IL-17A/F binding oligopeptides: [0333]-[0337];
O. IL-17A/F binding organic molecules: [0338];
P. Screening for anti-IL-17A/F antibodies, oligopeptides and organic molecules having the desired properties: [0339]-[0342];
Q. Pharmaceutical compositions: [0343]-[0349];
R. Methods of treatment: [0350]-[0378];
S. Articles of manufacture: [0379];
T. Diagnosis and prognosis of immune related disease: [0380]-[0383].
154. In the sub-section concerning tissue distribution (F), the specification states at [0235]:
“Gene expression in various tissues, alternatively, may be measured by immunological methods, such as immunohistochemical staining of tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product. Antibodies useful for immunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal. Conveniently, the antibodies may be prepared against a native sequence of an IL-17 A/F polypeptide or against a synthetic peptide based on the DNA sequences encoding the IL-17A/F polypeptide or against an exogenous sequence fused to a DNA encoding an IL-17 A/F polypeptide and encoding a specific antibody epitope. General techniques for generating antibodies, and special protocols for Northern blotting and in situ hybridization are provided below”
“Additionally, the compounds of the invention can be tested on animal models for psoriasis like diseases. Evidence suggests a T cell pathogenesis for psoriasis. The compounds of the invention can be tested in the scid/scid mouse model described by Schon, M. P. et al., Nat. Med., 3:183 (1997), in which the mice demonstrate histopathologic skin lesions resembling psoriasis. Another suitable model is the human skin/scid mouse chimera prepared as described by Nickoloff, B. J. et al., Am. J. Path., 146:580 (1995).”
“It is further important that antibodies be humanized with retention of high binding affinity for the antigen and other favourable biological properties. To achieve this goal, according to a preferred method, humanized antibodies are prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from the recipient and import sequences so that the desired antibody characteristic, such as increased affinity/or the target antigen(s), is achieved.”
“Psoriasis is a T lymphocyte-mediated inflammatory disease. Lesions contain infiltrates of T lymphocytes, macrophages and antigen processing cells, and some neutrophils”
“[0372] Other diseases in which intervention of the immune and/or inflammatory response have benefit are infectious disease including but not limited to viral infection (including but not limited to AIDS, hepatitis A, B, C, D, E and herpes) bacterial infection, fungal infections, and protozoal and parasitic infections (molecules (or derivatives/agonists) which stimulate the MLR can be utilized therapeutically to enhance the immune response to infectious agents), diseases of 55 immunodeficiency (molecules/derivatives/agonists) which stimulate the MLR can be utilized therapeutically to enhance the immune response for conditions of inherited, acquired, infectious induced (as in HIV infection), or iatrogenic (i.e., as from chemotherapy) immunodeficiency, and neoplasia.
[0373] It has been demonstrated that some human cancer patients develop an antibody and/or T lymphocyte response to antigens on neoplastic cells. It has also been shown in animal models of neoplasia that enhancement of the immune response can result in rejection or regression of that particular neoplasm. Molecules that enhance the T lymphocyte response in the MLR have utility in vivo in enhancing the immune response against neoplasia. Molecules which enhance the T lymphocyte proliferative response in the MLR (or small molecule agonists or antibodies that affected the same receptor in an agonistic fashion) can be used therapeutically to treat cancer. Molecules that inhibit the lymphocyte response in the MLR also function in vivo during neoplasia to suppress the immune response to a neoplasm; such molecules can either be expressed by the neoplastic cells themselves or their expression can be induced by the neoplasm in other cells. Antagonism of such inhibitory molecules (either with antibody, small molecule antagonists or other means) enhances immune-mediated tumor rejection.
[0374] Additionally, inhibition of molecules with proinflammatory properties may have therapeutic benefit in reperfusion injury; stroke; myocardial infarction; atherosclerosis; acute lung injury; hemorrhagic shock; burn; sepsis/septic shock; acute tubular necrosis; endometriosis; degenerative joint disease and pancreatitis. …”
Examples
“Western Blot analysis indicated that this novel protein species is also able to interact both with an antibody that is able to bind to IL-17 and with an antibody that is able to bind to IL-17F. Each of these observations and the distinct molecular mass of the novel isolated protein species suggest that the isolated protein IL-17A/F is a novel protein species comprised of a covalent association of IL-17 and IL-17F.”
“Thus, specific antibodies which bind selectively to the novel heterodimeric complex of IL-17A/F have been identified which may serve to modulate the activity of this novel cytokine”.
165. The final part of Example 1 describes how the authors used the TK-10 human kidney carcinoma cell line to analyse the ability of purified IL-17A/F to induce the production of IL-6 and IL-8 using ELISAs.
Dose response curves comparing IL-6 and IL-8 induction by IL-17A/F, IL-17A/A, and IL-17F/F are set out in Figures 5A and 5B. These show that IL-17A/F, IL-17A/A and IL-17F/F all induce the production of IL-6 and IL-8 in TK-10 cells in a dose-dependent fashion.
166. The specification comments on these results in [0399] as follows:
“Interestingly, IL-17 A/F was observed to have a unique potency that differs from that of either IL-17 or IL-17F. The difference in activity differs from IL-17 and IL-17F by roughly an order of magnitude in each case. The substantially greater activity of IL-17 A/F than IL-17F in this assay suggests that IL-17A/F may comprise a critical component of the cytokine activity resulting from the IL-17F gene product. This unique potency may enable the molecule to possess distinct range of actions in vivo. IL-17A/F also induced production of IL-6 from this cell line (Figure 5B). Additionally, it is likely that IL-17A/F may possess additional characteristics not present in either IL-17 or IL-17F as a result of its novel heterodimeric composition that may alter the kinetics and utilization of receptor subunits in vivo, resulting in unique biological consequences.”
168. Example 2 ([0400]-[0407]). Example 2, headed “Identification of a novel IL-17 cytokine produced in activated human T cells”, demonstrates that IL-17A/F is naturally produced in activated human T-cells. Human blood was first extracted from a healthy donor. Human T-lymphocytes were then isolated from the blood and activated using anti-CD3 and anti-CD28 antibodies. Samples of media were collected at various time points following plating and assayed for IL-17A/F by a sandwich ELISA.
An anti-human IL-17A antibody was coated onto a microtitre plate, and after the test sample had been added a biotinylated anti-human IL-17F antibody as a detection antibody diluted in assay buffer. A positive signal would only be detected in response to the IL-17A/F heterodimer – the anti-human IL-17A coat antibody first binds to the IL-17A chain and immobilises the molecule, and the anti-human IL-17F antibody binds to the IL-17F chain to visualise it. IL-17A and IL-17F were used as positive controls to demonstrate that the assay was specific for IL-17A/F.
169. The results, which are set out in Figures 11 and 12, show that IL-17A/F was produced by the activated human T-cells, but that no production of IL-17A/F was detected from the non-activated T-cells (as expected from the negative control). This confirms that the ELISA
was able to selectively and reproducibly detect IL-17A/F (but not IL-17A/A or IL-17F/F).
170. The specification comments on these results as follows:
“[0404] … Hence, IL-17A/F is a distinctly new cytokine, detectable as a natural product of isolated activated human T cells, whose recombinant form has been characterized, in both protein structure and cell-based assays, as to be different and distinguishable from related cytokines.
[0405] This new cytokine can act to modulate the activity of IL-17 in vivo , acting as a competitive inhibitor to binding sites for IL-17 or other related cytokines. IL-17A/F can also modulate the activity of other related cytokines by down regulation of binding sites for itself and/or binding sites for other related cytokines. IL-17A/F can exhibit activity through intracellular adapters or signaling molecules which act to affect its own signaling activity or that of other related cytokines. IL-17A/F has the ability to affect the pairing of receptors and co-receptors found at the surface of cells or within the intracellular compartment.
[0406] Thus, these studies provide and identify a novel immune stimulant (i.e. IL-17A/F) that can boost the immune system to respond to a particular antigen that may not have been immunologically active previously. As such, the newly identified immune stimulant has important clinical applications. …
[0407] Thus, antibodies to this new cytokine which either mimic (agonist antibodies) or inhibit (antagonist antibodies) the immunological activities of IL-17A/F would possess therapeutic qualities. …”
174. Example 8 ([0444]-[0449]) is said at [0444] to illustrate “preparation of monoclonal antibodies which can specifically bind IL-17A/F”. It describes a method for producing murine antibodies to IL-17A/F, and then screening for them by ELISA.
No such antibodies are disclosed by the Patent. The example does not propose to demonstrate that any such antibodies inhibit the production of IL-6 or IL-8.
176. Example 10 ([0454]-[0457]) describes the use of IL-17A/F in drug screening techniques.
The claims
179. Genentech
does not seek to defend the validity of the claims as granted. It has applied to amend the claims both unconditionally and conditionally. The unconditional amendments include the deletion of granted claims 1-26, namely claims relating to isolated nucleic acids (1-11), vectors (12-13), host cells (14-15), a process for producing IL17A/F (16) and isolated polypeptides and/or complexes (17-26).
180. The proposed amended claims which Genentech
contends to be independently valid as are follows. The conditional amendments are shown in bold in square brackets
“ 27 1 . An isolated antibody which specifically binds to the an isolated IL-17A/F heterodimeric complex according to claim 23 or claim 24 and which inhibits the activity of the IL-17A/F heterodimeric complex to induce production of IL-8 and IL-6, wherein the isolated IL-17A/F heterodimeric complex comprises [consists of] SEQ ID NO:3 and SEQ ID NO:4, without their associated signal peptides, and further comprises two interchain disulfide linkages between SEQ ID NO:3 and SEQ ID NO:4; and wherein the antibody is either human or humanized .
2. The isolated antibody of Claim 1, wherein said antibody has a Kd for the IL-17A/F heterodimeric complex of at least about 10 -8 , 10 -9 , 10 -10 , 10 -11 or 10 -12 M .
40 12 . Use of an antagonist anti-IL-17A/F antibody as defined in Claim 27 1 or 2 in the preparation of a medicament for
(i) the treatment of an immune related disorder;
(ii) inhibiting the proliferation of T-lymphocytes; or
(iii) decreasing the infiltration of inflammatory cells into a tissue in a mammal in need thereof.
41. The use according to Claim 39 or Claim 40 wherein the immune related disorder is systemic lupus erythematosis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, a spondyloarthropathy, systemic sclerosis, an idiopathicinflammatory myopathy, Sjogren's syndrome, systemic vasculitis, sarcoidosis, autoimmune haemolytic anemia, autoimmune thrombocytopenia, thyroiditis, diabetes mellitus, immune-mediated renal disease, a demyelinating disease of the central or peripheral nervous system, idiopathic demyelinating polyneuropathy, Guillain-Barre syndrome, a chronic inflammatory demyelinating polyneuropathy, a hepatobiliary disease, infectious or autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, sclerosing cholangitis, inflammatory bowel disease, gluten-sensitive enteropathy, Whipple's disease, an autoimmune or immune-mediated skin disease, a bullous skin disease, erythema multiforme, contact dermatitis, psoriasis , an allergic disease, asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity, urticaria, an immunologic disease of the lung, eosinophilic pneumonia, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, a transplantation associated disease, graft rejection or graft-versus-host-disease .
13. The isolated antibody of Claim 1 or 2 for use [as an antagonist of the IL-17A/F heterodimeric complex in] a method of medical treatment.
14. 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 production of IL-8 and IL-6, wherein the isolated IL-17A/F heterodimeric complex comprises [consists of] SEQ ID NO:3 and SEQ ID NO:4, without their associated signal peptides, and further comprises two interchain disulfide linkages between SEQ ID NO:3 and SEQ ID NO:4; and wherein the antibody is for use [as an antagonist of the IL-17A/F heterodimeric complex] in a method of medical treatment.
15. The isolated antibody for use of Claim 14, wherein said antibody has a Kd for the IL-17A/F heterodimeric complex of at least about 10 -8 , 10 -9 , 10 -10 , 10 -11 or 10 -12 M.
20. Use of an antagonist anti-IL-17A/F antibody as defined in Claim 14, 15 or 16 in the preparation of a medicament for [antagonizing the IL-17A/F heterodimeric complex in] the treatment of rheumatoid arthritis or psoriasis.
22. The isolated antibody for use of Claim 14, 15 or 16 wherein the method of medical treatment is a treatment of rheumatoid arthritis or psoriasis. ”
181. The polypeptide sequences SEQ ID 3 and SEQ ID 4 referred to in claims 1 and 14 are the sequences of the prior art IL-17A and IL-17F polypeptide monomers . In relation to claims 2 and 15, Genentech
asserts independent validity for each Kd value. In relation to claims 12, 20 and 22,
Genentech
asserts independent validity for each of RA and psoriasis.
The skilled team
Common general knowledge
The CGK of the rheumatologist
190. RA and its immuno-pathophysiology. RA is a chronic inflammatory autoimmune disease that mainly affect the small joints. RA affects about 1% of the population worldwide. It causes disability and is associated with increased morbidity and mortality. Persistent joint inflammation, cartilage destruction and bone erosion are features of RA. Memory T cells which infiltrate the synovium (a thin cellular lining in joints) play a central role in the pathogenesis of RA.
191. TNFα and IL-1 were considered to be key cytokines in RA and had been shown to stimulate joint inflammation and damage. TNFα (etanercept sold as Enbrel and infliximab sold as Remicade) and IL-1 (anakinra sold as Kineret) inhibitors had been approved for the treatment of RA by July 2003 and were on the market. Whilst Remicade and Enbrel were known to be very effective, there was still a significant proportion of patients who did not respond. Kineret was less effective.
192. Animal models . Collagen-induced arthritis (CIA) is a well-accepted experimental animal model for RA in which mice are injected with collagen. CIA was used to test the efficacy of therapeutic agents for RA prior to clinical trials in humans. Another animal model that was used to evaluate treatments for RA was adjuvant-induced arthritis (AIA), in which rats are injected with an adjuvant containing mycobacterium.
193. IL-6 and IL-8 . IL-6 is a pro-inflammatory cytokine considered to be important in bone destruction and joint inflammation and to be a target for the treatment of RA. IL-8 is a chemokine involved in neutrophil recruitment which had been shown to be upregulated in RA.
194. IL-17A . IL-17A is secreted as a homodimer by activated memory T helper cells (CD4 + ). IL-17A binds to its receptor, IL-17R. IL-17R is ubiquitously expressed on almost all cell types .
195. IL-17A binds to IL-17R with low affinity. As a relatively low concentration of IL-17A was required to produce a biological response, however, it was suggested that IL-17A may interact with an unidentified additional receptor component present on IL-17A-responsive cells . Lack of IL-17R in mice results in increased susceptibility to lung bacterial infection.
200. IL-17A and RA. IL-17A is found in synovial fluid and tissue of patients with RA, and IL-17A-producing T cells are present in RA synovium.
202. IL-17A is less potent than TNFα and IL-1 based on in vitro studies. IL-17A has additive or synergistic effects with TNFα and IL-1 based on in vitro studies .
206. IL-17A induces receptor activator of NF-κB (RANKL, a key cytokine in osteoclast formation and activation) in in vitro studies. The addition of IL-17A leads to bone erosion in in vitro studies and in in vivo animal models of RA.
The CGK of the antibody engineer
209. The antibody engineer’s common general knowledge included:
i) the use of different cell systems for generating recombinant proteins;
ii) the need to use humanised or fully human antibodies in a therapeutic agent to avoid inducing an immune response to the antibody itself;
iii) methods for generation of murine antibodies;
iv) antibody characterisation methods including an understanding of ELISA
and SPR techniques;
v) the requirements for antagonistic activity, namely:
a) recognition of an epitope on the protein of interest so as to cause a steric (spatial blocking) effect, or a conformational change in that protein, so as to prevent the protein interacting with its receptor; and
b) a greater binding affinity for the protein than the protein-receptor binding affinity;
vi) bioassay methods to screen for antagonistic antibodies;
vii) criteria to select antibodies for humanisation, including based on affinity for their targets; and
viii) (with assistance from a humanisation expert as required) methods for humanising antibodies.
The CGK of the dermatologist
i) RA was considered to be a mixed T cell and B cell disease, whereas psoriasis was not considered to have a B cell component;
ii) RA involves tissue destruction, whereas psoriasis involved an increase in the number of keratinocytes resembling a healing response; and
iii) RA affects discrete and relatively small amounts of joint tissue, whereas psoriasis is a disease affecting the skin, the largest organ in the body.
236. Counsel for Genentech
put to Prof Krueger in cross-examination, and relied in closing submissions on, a review of IL-6 from 2011 (Jones et al , “Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling”, J Clin Invest , 121, 3375-3383). The passage relied on discusses how IL-6 was recognised as a major growth factor in multiple myeloma in the early 1990s. This led to clinical trials with neutralising anti-IL-6 antibodies, but it was found that this led to massive systemic elevation of IL-6. To overcome this problem, blockade of IL-6’s receptor, IL-6R, was targeted. This led to the development of tocilizumab, which inhibits the binding of IL-6 to IL-6R. This was the subject of clinical trials in a variety of conditions after 2003, and tocilizumab has been approved for the treatment of RA since 2010. There is no reference to psoriasis in this passage (or anywhere else in the review so far as I can see), and Prof Krueger said that he was not familiar with this work. Moreover, Prof Prens confirmed that information relating to tocilizumab was not publicly available before July 2003. As Prof Krueger had pointed out in his first report, it has recently been found that tocilizumab can lead to the onset of psoriasis in patients with no prior history of it.
238. Counsel for Genentech
asked Prof Krueger if he could point to any publications which said that IL-6 was not a target of interest for treating psoriasis in 2003. Unsurprisingly, Prof Krueger was unable to do so, but he said that one should consider the totality of the reviews and that at best the role of IL-6 was uncertain. As will appear, what the reviews do not say is more significant than what they do say. For reasons that will appear, it is relevant also to consider what they say about redundancy.
“In summary, the data presented here clearly illustrate that T cell-keratinocyte interactions in psoriasis are responsible for enhanced bidirectional cellular activation. Minute quantities of cytokines released during these interactions may trigger a cascade of intercellular cytokine signals which induce or boost cutaneous inflammation, or both. Therefore, the identification of the primary signal and its cellular source in psoriasis remains extremely difficult.”
When cross-examined on this passage, Prof Prens accepted that redundancy could be an issue in targeting a cytokine, but said that one did not know until an agent was tested.
“ … increases the local production of chemokines such as IL-8, monocyte chemoattractant protein-1 (MCP-1) and Gro-α, thereby promoting the recruitment of monocytes and neutrophils, and stimulates production of G-CSF and GM-CSF. … Other actions such as the stimulation of IL-6 and PGE2 production enhance the local inflammatory environment.”
“It has been shown that TNFα is capable of increasing production of interleukin (IL)-1, IL-6, IL-8 and nuclear transcription factor κB (NFκB). These proinflammatory cytokines can be synthesized by stimulated T lymphocytes and keratinocytes, exerting specific effects in the pathogenesis of psoriasis”.
It goes on to say that IL-6 is involved in proliferation of keratinocytes and that NFκB stimulates transcription of cytokines including TNFα, IL-6, IL-8 and various adhesion molecules. There is no discussion of targeting IL-6 for therapy (as the title suggests, the focus of the review is on TNFα).
“The authors’ belief of the importance of IFN-γ as a pivotal cytokine in the initiation or maintenance of psoriatic lesions has been supported with evidence throughout this article, while acknowledging that TNFα plays an important and probably synergistic role.”
Similarly, IL-6 is not mentioned in Lew (while IL-8 is mentioned in passing).
“According to the pathogenic model drawn in Fig 6, IL-8 is a chemokine that amplifies T-cell–‘driven’ inflammation by recruiting neutrophils into psoriasis lesions. Although this chemokine might also affect T-cell recruitment into lesions, there is no evidence for selectivity of its receptor (CCR1) in regulating type 1 T-cell responses. ABX–IL-8 (Abgenix, Inc, Fremont, Calif), [is] a fully human anti–IL-8 antibody that neutralizes this chemokine. Moderate clinical improvements observed in most patients with psoriasis treated with anti–IL-8 135 support the role of this chemokine as a part of an inflammatory cascade, but not as a sole mediator. There is also a difficult anatomic problem with respect to IL-8 neutralization in that upper spinous keratinocytes synthesize large amounts of this chemokine, whereas penetration of large proteins (anti-IL-8 antibodies) into the epidermis is likely to be quite limited. In addition, a general problem with antagonizing single chemokines is that considerable redundancy exists. For example, both IL-8 and Gro-α are neutrophil chemoattractants that bind to surface receptors CXCR1 or CXCR2. Gro-α is highly expressed in psoriatic lesions 85 and could still stimulate neutrophil trafficking even though IL-8 is fully neutralized by an antibody. The situation in T lymphocytes is similar in that multiple chemokines control T-cell migration responses. However, there is additional redundancy in that some receptors bind 2 or more chemokine ligands (Fig 5). Despite these problems, chemokines and chemokine receptors are attractive therapeutic targets because highly specific immune blockade can be obtained with[out] producing generalized immune suppression.”
257. The facts concerning the clinical trials of Abgenix’s anti-IL-8 antibody are as follows:
i) There was a Phase I trial in 26 patients in which 25% of patients achieved PASI75, but efficacy was only shown in a subgroup. The results were reported in an abstract, Lohner et al , “Clinical trials of a fully human anti-IL-8 antibody for the treatment of psoriasis, Br J Dermatol , 141, 989 (1999, “Lohner”). In addition to being mentioned in Krueger 2002 in the passage quoted above (reference 135 is Lohner), this trial is referred to in Cather (which does not mention the efficacy results), in Kirby and in Kanitakis. Both Krueger 2002 and Kanitakis describe the results as showing “moderate clinical improvements”.
ii) There was a Phase I/II trial in 45 patients in which 21% of patients achieved at least PASI50. Abgenix reported the results in a press release dated 30 November 1999 which stated that they were to be presented at the Psoriasis: From Gene to Clinic meeting in London on 2 December 1999. Asadullah states, however, that preliminary results presented at the American Academy of Dermatology meeting in 2001 suggested that the antibody had no significant effect on the PASI score of psoriasis patients.
iii) There was a Phase IIa trial in 94 patients in which 24% of patients achieved at least PASI75. The results were reported at the 63rd Annual Meeting of the Society of Investigative Dermatology in Los Angeles in May 2002 and published in an abstract, Horowitz et al , “ABX-IL8 in the treatment of psoriasis: clinical results”, J Invest Dermatol , 119, 239 (2002). They are mentioned in Kanitakis and in Prinz (although Prinz does not give the figures, simply saying “Reduction in PASI has been observed”, and the reference he gives is erroneous).
iv) There was a Phase IIb trial in 276 patients which failed. Abgenix announced this in a press release on 14 May 2002. The press release stated:
“ … treatment with ABX-IL8 did not result in a significant improvement in PASI scores, the primary efficacy end point of the trial. Based on these findings, Abgenix is discontinuing clinical development of ABX-IL8 in psoriasis. In addition, the company will not proceed with a previously planned clinical study of ABX-IL8 in melanoma and will wind down its ongoing Phase 2a study in chronic obstructive pulmonary disease (COPD). Abgenix currently has no plans to conduct further clinical studies involving ABX-IL8.”
The results were also presented at the 63 rd Annual Meeting. Although Kanitakis does not mention the Phase IIb trial or its failure, it does state that the results of the Phase IIa trial were “modest” and therefore “the sponsor decided to discontinue clinical trials with this product”.
264. By way of support for his second reason, Prof Prens stated in paragraph 25:
“I note that further research into anti-IL-8 therapy continued after the failed Abgenix trial. In particular, Anogen (a Canadian biopharmaceutical company) conducted studies on a topical anti-IL-8 therapy called Abcream. A phase 2/3, double blind, placebo-controlled trial involving 412 psoriasis patients demonstrated that efficacy was higher in the active treatment group than the control group (49% versus 14.9%). Subsequently, a phase 4 clinical trial of 1452 psoriasis patients showed that following Abcream treatment for 6 weeks, 62% of patients achieved PASI60, and 18% of patients achieved PASI90. Abcream has been approved in China for psoriasis treatment. 10 ”
“ Abcream (Enboke) . A phase II/III, double-blind, placebo-controlled trial enrolled 412 psoriasis patients to test the efficacy of Abcream, a topical IL-8 inhibitor. After 6 weeks, the efficacy was higher in the active treatment group than in the control group (49% versus 14.9%). The adverse reactions including irritation, pain, itch and edema were 5.9% in the Abcream group and 6.6% in the control group. The therapeutic effect of IL-8 monoclonal antibody is thought to be related to the decrease of neutrophil recruitment and angiogenesis. 85 Then, a phase IV clinical trial (n = 1452) showed that after Abcream treatment for 8 weeks, 62% and 18% of patients achieved PASI 60 and PASI 90, respectively. 86 Abcream has been approved by China for psoriasis treatment.
…
Although anti-IL-8 is approved as a topical treatment for psoriasis in China, it has not been accepted as an effective treatment for psoriasis elsewhere. The use of anti-IL-8 biologics is still under development for oncologic indication, but no further development was in progress for psoriasis.”
“I have checked the clinical paper. I have seen the results in the patients being treated before and after pictures. They are there. [Reference] 86”.
When I asked him if he read Chinese, he said no, but he could see the pictures and he had read the abstract which gave the patient numbers.
270. When he was recalled, counsel for Lilly
showed Prof Prens a copy of reference 86 and a machine translation of it. The authors match those credited by Tsai and Tsai. Just as the title to the reference as reproduced in Tsai and Tsai contains the Arabic numeral 172, so does the title of the actual paper. The same Arabic numeral appears repeatedly in the text. The number 1452 does not appear. The translation of the title is “Clinical observations on 172 cases of psoriasis vulgaris treated with Enboke cream”. The paper states that 172 patients were treated with the cream during the period from November 2001 to April 2002 and reference is made to “approval number S20010003”. After eight weeks the “cure rate” was 13.4% and the “total effective rate” was 48.3%. There was no placebo control. Accordingly, reference 86 does not support the statement made in Tsai and Tsai about a Phase IV clinical trial. I would add that the paper cites four references (three of which are given in English in the original and the fourth of which is cited using Arabic numerals for the date, volume and page numbers) which were all published in the period 1996 to 1998.
276. It is convenient to note that at this point that, although one of Genentech’s
counsel (Dr Turner QC) submitted that Prof Prens had not been giving an opinion on the efficacy of Abcream, even though some of the cross-examination was directed to that question, and that the efficacy of Abcream was not in issue, another (Mr Chacksfield) submitted that Abcream showed that IL-8 inhibition worked in psoriasis. In my judgment Dr Turner was correct on this point, and therefore Mr Chacksfield was wrong. In any event, I do not consider that there is any reliable evidence that Abcream, and therefore IL-8 inhibition, is efficacious against psoriasis. Mr Chacksfield relied upon the results of the Phase II/Phase III trial reported in the Anogen document, but that document has not been published in the scientific literature and there is no evidence that it has ever been peer-reviewed. Given the document is internally inconsistent as to the numbers of patients in the relevant groups, I do not consider it a reliable report of whatever trial was carried out. Moreover, the trial included an open-label arm, which, as Prof Prens agreed, is irregular. Finally, as noted above, there is no list of ingredients, and thus one cannot be sure that the cream did not include e.g. a corticosteroid. Reliance was also placed on the supposed fact that Abcream is on the market in China, but the only evidence of that is the statement in Tsai and Tsai which I do not regard as reliable. In any event, that would not demonstrate that it is effective.
277. IL-8: PPP . Counsel for Genentech
relied on a paper by Skov et al , “IL-8 as antibody therapeutic target in inflammatory diseases: reduction of clinical activity in palmoplanar pustulosis”, J Immunol , 181, 669-679 (2008) which reports a trial concerning a human anti-IL-8 antibody developed by Genmab and Medarex for the treatment of palmoplanar pustulosis (PPP, an inflammatory condition affecting the palms and soles). In this paper, which was submitted for publication on 14 December 2007, the authors state (at page 677):
“Previously, the efficacy of murine IL-8 Ab in acute inflammatory diseases has been demonstrated in a number of animal models, suggesting Ab-mediated neutralization of IL-8 can potentially be used for various human inflammatory disorders (21, 23, 24, 34– 38). Few studies have been performed in chronic inflammatory diseases. The anti-IL-8 activity of another human IL-8 mAb, ABX-IL-8 (IgG2/κ), was demonstrated in vitro and in animal models in vivo (30). The result of a placebo-controlled phase IIb clinical trial for treatment of moderate-to-severe psoriasis with this Ab, however, was disappointing (39). This failure might well have resulted from the low and infrequent dosing used in these studies, leading to insufficient Ab concentrations in situ. Additionally, heterogeneity in clearance rates of the human IgG2 Ab resulting from a polymorphism for FcγRIIa that is known to affect IgG2 serum concentrations (40) may have played a role.”
278. Their conclusion (at page 678) is:
“In conclusion, we show IL-8 to play a central role in PPP. Using an IL-8-neutralizing Ab, we demonstrate that targeting a single critical factor in this disease characterized by high IL-8 overexpression leads to clinically relevant reductions in disease activity. This observation bears promise for the treatment of other diseases characterized by IL-8 overexpression.”
280. IL-8: Other later evidence . More relevantly, to my mind, counsel for Genentech
also relied upon two other papers published after July 2003 concerning psoriasis as casting light backwards. The first is Arican et al , “Serum levels of TNFα, INF-γ, IL-6, IL-8, IL-12, IL-17 and IL-18 in patients with active psoriasis and correlation with disease severity”, Mediators Inflamm , 5, 273-279 (2005). This states (at page 276):
“Elevated amounts of IL-8 have been detected in psoriatic lesional skin [30]. Many studies indicate that IL-8 may be involved in the pathomechanism of psoriasis. In fact, data currently available suggest that this cytokine exerts a critical role as a potent chemoattractant for neutrophils and T lymphocytes, as well as a factor prompting keratinocyte proliferation [10].”
Reference 10 is Bonifati.
“A fully human anti IL-8 antibody (ABX-IL-8) has been developed and tested in a dose-escalation study for psoriasis.[21] At the highest dose (3 mg/kg intravenously), 30% of the patients had a >50% reduction in PASI scores, but this was on the edge of clinical significance and lower doses were ineffective. Drug-specific issues cannot be excluded as the reason for the failure of the anti-IL-8 therapy; for example, whether the antibody achieved sufficient levels in the skin has not been conclusively determined. However, a consensus is emerging that IL-8 is not a suitable target for the treatment of psoriasis.”
Reference 21 is Lohner.
285. IL-17 . It is common ground that, while the skilled dermatologist would probably be aware of its existence, IL-17 was not considered to be therapeutically relevant to psoriasis in July 2003. There was disagreement between Prof Krueger and Prof Prens as to how much the skilled person would have known about IL-17, with Prof Krueger opining that the skilled person would know more about it than Prof Prens considered they would. As counsel for Genentech
submitted, however, it is not necessary to resolve this dispute because, as explained below, it is common ground that the skilled person would obtain and read the relevant papers when considering the question of plausibility. Accordingly, what matters is what the perception of the skilled person would be after having read those papers. I will address that question below.
286. IL - 1 . IL-1 has two isoforms, IL-1α and IL-1β. IL-1 was important historically as it was one of the first cytokines to be measured in psoriasis lesions. It was known to be implicated in keratinocyte hyperplasia. It was also known to have direct mitogenic effects on keratinocytes. Prof Prens’ evidence in his first report was that IL-1 was considered to be one of the most important cytokines in the pathology of psoriasis. Prof Krueger disagreed with this in his second report, referring to several papers which reached differing conclusions as to the upregulation and bioactivity of IL-1α and IL-1β in psoriasis lesions. In cross-examination Prof Krueger convincingly explained that the picture was a complicated and confusing one. Counsel for Genentech
submitted that Bonifati undermined Prof Krueger’s evidence. In my view it does the opposite. Thus Bonafati states (at page 242):
“Although the assumption of a key role of IL-1 in the psoriatic cytokine network seemed very promising, many conflicting results have been reported by different authors on the relative amounts of IL-1alpha and IL-1beta in psoriatic skin and their roles in the pathomechanisms of the dermatosis. 10-18 ”
Construction
293. There are three issues as to the construction of the claims.
The law
294. There is no dispute as 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.
Which specifically binds to
295. It is a requirement of all the claims relied upon by Genentech
that the antibody “specifically binds to” IL-17A/F.
Lilly
contend that this phrase means that the antibody binds only to IL-17A/F and not to IL-17A/A or IL-17F/F (or any other cytokine).
Genentech
contends that it merely means that the antibody binds to IL-17A/F as an antibody rather than adhering non-specifically to it, and thus does not exclude binding to IL-17A/A (or IL-17F/F or any other cytokine).
296. Lilly’s
written closing submissions on this issue run to 36 paragraphs and
Genentech’s
to 28 paragraphs. I shall not set out all the rival submissions, although I have taken them all into consideration. Instead, I shall simply set out the reasons which have led me to the conclusion stated below.
298. Given that the meaning of the expression “which specifically binds to” depends on context, the crucial question is how the skilled team would understand the patentee to be using it in the context of the Patent. As is common ground, the interpretation of the wording of the claim is a matter for the court, but expert evidence as to the technical content of the specification which bears upon the question is both admissible and of assistance. Given the issue is one of antibody binding, this would fall within the province of the antibody engineer. Hence it was primarily addressed by Dr Tite for Lilly
and by Prof Martin for
Genentech.
Some of the other experts also gave relevant evidence on the point, however.
299. Given that the specification contains a series of definitions, I consider that the skilled person would turn first to the definition in [0118]. Lilly’s
case is that this paragraph either supports
Lilly’s
construction or is incoherent. Dr Tite’s evidence was that it is somewhat confusing. It was clear from his oral evidence, however, that the principal source of his confusion was the first sentence of section A, and in particular the statement that an antibody “which binds” is “one that binds the antigen with sufficient affinity …, and does not significantly cross-react with other proteins”. Dr Tite’s view was that the effect of this was to conflate the meaning of “binds” and “specifically binds”.
300. The first sentence of section [B] gives a definition of “specifically binds” which, as Dr Tite accepted, accords with the first meaning he identified. Thus this definition supports Genentech’s
case. Section [B] goes on to describe two example approaches. As the experts agreed, the first involves a control molecule which is similar to the molecule that is doing the binding (e.g. a control IgG antibody), whereas the second involves a control molecule which is similar to the target. Dr Tite accepted that this passage is consistent with the first sentence.
302. Section [D] states that “in one embodiment” the term “specific binding” refers to binding to a particular polypeptide or epitope without substantially binding to any other polypeptide or epitope (i.e. in accordance with Lilly’s
interpretation of the claim). Again, as the experts agreed, this is plainly not a general statement or a definition. Moreover, as I will discuss, there is indeed at least one embodiment in which specific binding in this more restricted sense is required.
305. Next, the skilled person would consider the teaching of the specification to see whether this confirmed or contradicted their reading of [0118]. Lilly
rely upon the fact that the focus of the invention is on what the specification repeatedly refers to as a “novel” or “new” cytokine, IL-17A/F: see [0001], [0019], [0396], [0399] and [0404]-[0407] and the headings to both Example 1 and 2. Moreover, the specification refers to this novel cytokine as having “unique potency” and “unique biological consequences”: see [0399]. None of this requires the skilled reader to interpret the words “specifically binds to” in a different manner to the way in which they are defined in section [B] of [0118], however.
306. The skilled reader would appreciate that the central core of the teaching of the specification is to be found in Examples 1 and 2. In Example 1, the Patent describes using phage display to prepare antibodies which bind to IL-17A/F. Although counsel for Lilly
relied upon the statement at [0396] that IL-17A/F is able to interact both with an antibody that binds to IL-17 and an antibody that binds to IL-17F, this is nothing in this statement to indicate that the claimed antibodies to IL-17A/F must not bind to IL-17A/A or IL-17F/F.
309. It is common ground that the specification describes embodiments in which the skilled person would understand that an antibody that bound to IL-17A/F but not to IL-17A/A or IL-17F/F was required, that is to say, embodiments which accord with the more restricted meaning of “specific binding” in section [D] of [0118]. Example 9 provides a specific instance of this. Lilly
rely on the fact that Example 9 does not describe a negative selection step either, and ask the rhetorical question why the skilled reader would understand that it was to be performed in Example 9 but had not been performed in Example 1. In my judgment the answer to this is supplied by the point which
Lilly
make that the skilled reader would appreciate that Example 9 is a prophetic example. Thus Example 9 merely sets out an outline of a proposed experiment. By contrast, Example 1 describes an actual experiment carried out by the inventors, reports the results obtained and analyses those results, which as I have already observed form part of the central core of the teaching of the Patent. In those circumstances, the skilled person would expect that, if an important step like negative selection had been carried out in Example 1, the inventors would have described it, but would consider that Example 9 fell into a different category. The same applies to the diagnostic applications referred to in [0028]-[0032] and [0235]. I should add that it is common ground that the skilled reader would know how to carry out a negative selection step from their common general knowledge.
310. As the skilled person would appreciate, there are other applications in which antibodies that bind to IL-17A/F, but not IL-17A/A or IL-17F/F, are not required. A specific instance of this is the drug screening process of Example 10.
311. Dr Tite accepted that there is nothing in the Patent to show that one must use an antibody that only binds IL-17A/F for a therapeutic application. In particular, there is nothing which requires the skilled person to identify actions of IL-17A/F which are distinct from those of IL-17A/A or IL-17F/F when using an antibody. This evidence is consistent with that of Prof Kamradt looking at the matter from the perspective of the rheumatologist. Prof Krueger’s opinion looking at the matter from the perspective of the dermatologist was different, but I do not find his reasoning persuasive so far as the interpretation of the expression “specifically binds” is concerned (its impact on other aspects of the case is another matter). As counsel for Genentech
submitted, given the significance of therapeutic applications, there is all the more reason not to limit the claims to antibodies that are required for applications such as that in Example 9.
312. For the reasons given above, I conclude that the expression “specifically binds” is to be interpreted in the manner contended for by Genentech.
Inhibits the activity of … IL-17A/F … to induce production of IL-8 and IL-6
313. Claims 1 and 14 both require the claimed antibody “inhibits the activity of … IL-17A/F … to induce production of IL-8 and IL-6”. Lilly
contend that the skilled team would understand that claims 12 and 20, which are dependent on claims 1 and 14 respectively, require the therapeutic effect to be mediated through the inhibition of IL-6 and IL-8. In support of this contention,
Lilly
point to
Genentech’s
reliance upon IL-6 and IL-8 inhibition as part of its case on plausibility.
Genentech
disputes this interpretation, and contends that the skilled team would understand that inhibition of IL-6 and IL-8 is part of the test used in claims 1 and 14 to identify the claimed antibodies, and is not a functional requirement of the therapeutic uses in claims 12 and 20. In my judgment
Genentech
is correct about this. Plausibility is a separate question which I will consider below.
Use of an antagonist anti-IL-17A/F antibody … for
314. Claims 12 and 20 require “use” of the claimed antibody “for” the treatment of RA or psoriasis. It is common ground that the skilled team would understand this to mean that the antibody must have a discernible therapeutic effect in some patients. Lilly
contend that the skilled team would understand inhibition of IL-17A/F must contribute to the therapeutic efficacy to a significant extent.
Genentech
accepts that inhibition of IL-17A/F has to make a contribution to the therapeutic effect of the antibody. In my judgment the skilled team would not regard an insignificant contribution as material for this purpose. The same goes for claim 22, which requires the antibody to be “for use in” the treatment of RA or psoriasis.
Genentech’s
amendment applications
315. As noted above, Genentech
seeks to amend the claims of the Patent and
Lilly
oppose the amendments on grounds of added matter, extension of protection and clarity. It is convenient to address these objections in reverse order. I shall consider the validity of the claims as proposed to be amended later.
Clarity
316. Lilly
contend that, if the words “which specifically binds to” in claims 1 and 14 are not construed in the manner contended for by
Lilly,
then they are unclear. I disagree. On
Genentech’s
interpretation, which I have accepted, the words have a clear meaning. In any event, as
Genentech
points out, these words were contained in the granted claims. Accordingly, no objection arises on the application to amend: see G3/14 Clarity [2015] EPOR 29.
317. Lilly
also contend that the word “comprises” in claims 1 and 14 is unclear. I disagree. As I see it,
Lilly’s
real objection is one of extension of protection.
318. Finally, Lilly
contend that the words “induce production of IL-6 and IL-8” are unclear. Counsel for
Genentech
pointed out that
Lilly
had not pleaded this objection, but sensibly did not object to
Lilly
advancing it on that ground. As he also pointed out, however, there is no evidence that this requirement is unclear. In any event, the relevant words were again contained in the granted claims and therefore no objection can be taken on the application to amend.
Extension of protection
319. Lilly
contend that the substitution of the word “comprises” in new claims 1 and 14 for the words “consists of” in granted claim 17 results in an extension of protection. Claim 17 was in the following terms:
“An isolated polypeptide or complex having at least 80% amino acid sequence identity to an IL-17A/F heterodimeric complex consisting of SEQ ID NO:3 …and SEQ ID NO:4 …with or without their associated signal peptides”
320. New claims 1 and 14 permit the complex to comprise not merely the sequences in SEQ ID NO:3 and SEQ ID NO:4, but also other material. Counsel for Genentech
relied upon the requirement of 80% amino acid sequence identity in granted claim 17, but this makes
Lilly’s
point, since no such limit appears in new claims 1 and 14.
321. As is common ground, however, this objection is easily fixed by Genentech’s
conditional application to re-instate the words “consists of”. I shall consider claims 1 and 14 on that basis.
Added matter
322. Lilly
advance five different added matter objections to the amendments. Although these objections require a comparison to be made between the application for the Patent as filed (“the Application”) and the Patent as proposed to be amended, in the present case the only material differences between the Application and the Patent lie in the claims: the substantive content of the documents is otherwise the same. For convenience, I shall therefore refer to the passages in the Patent which correspond to the passages in the Application which are relied upon by
Genentech
as providing support for the amended claims.
323. Although objections of added matter are sometimes lacking in substance, Lilly’s
objections must be taken seriously for two reasons. First, in opposition proceedings concerning the Patent in the European Patent Office, the Opposition Division held in a decision dated 24 November 2016 that
Genentech’s
main and auxiliary requests were all unallowable on this ground. That decision is presently under appeal, and I am informed that a decision of the Technical Board of Appeal is not expected before January 2020 at the earliest. (I am not aware that any request has been made for acceleration due to these proceedings. Certainly, the parties did not request this Court to support such a request, as they could have done. This is particularly unfortunate given that the Opposition Division did not determine any of the other grounds of opposition, and thus if
Genentech’s
appeal is allowed the case will need to be remitted to the Opposition Division with the potential for a further appeal to the Board of Appeal thereafter.) Secondly, the Comptroller-General of Patents has filed comments on
Genentech’s
amendment application in a letter dated 3 January 2019 stating that, in the Comptroller’s opinion, the proposed amendments are unallowable on this ground.
The law
324. Article 123(2) of the European Patent Convention provides:
“The European patent application or European patent may not be amended in such a way that it contains subject-matter which extends beyond the content of the application as filed.”
This provision is transposed into UK law by section 76(2) and (3)(a) of the Patents Act 1977.
“The ‘ gold standard ’ … for assessing compliance with Art. 123(2) EPC is the following: any amendment to the parts of a European patent application or European patent relating to the disclosure (the description, claims and drawings) is subject to the mandatory prohibition on extension laid down by Art. 123(2) EPC and can therefore, irrespective of the context of the amendment made, only be made within the limits of what a skilled person would derive directly and unambiguously, using common general knowledge, and seen objectively and relative to the date of filing, from the whole of these documents as filed …”
326. As it was put by Jacob LJ in Vector Corp v Glatt Air Techniques Ltd [2007] EWCA Civ 805, [2008] RPC 10 at [4] approving his own earlier statement as Jacob J in Richardson-Vicks Inc’s Patent [1995] RPC 568 at 576:
“I think the test of added matter 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.”
327. Two points must be noted about the way in which the English courts apply these principles. First, the English courts consider it important to distinguish between what a claim covers and what it discloses . As Birss J explained in IPCom GmbH & Co KG v. HTC Europe Co Ltd [2015] EWHC 1034 (Pat) at [125]:
“… as the line of cases leading from AC Edwards to AP Racing … explains, English patent law draws a distinction between coverage and disclosure. To amount to added matter, the intermediate generalisation must be a generalisation in terms of disclosure, not coverage. In other words, to characterise a claim as an intermediate generalisation is not sufficient to establish the presence of added matter. Proving that a claim is an intermediate generalisation in terms of coverage does not establish added matter.”
328. Secondly, there is a line of cases in the Boards of Appeal of the EPO concerning the addition of matter by selections from multiple lists. The English courts recognise that matter may be added in this way, just as a selection from multiple lists may be novel over the disclosure of those lists. As Henry Carr J said in GlaxoSmithKline UK Ltd v Wyeth Holdings LLC [2016] EWHC 1045 (Ch) at [119], however:
The absence of specific evidence
329. As is common ground, the court must compare the disclosure of the Application with the disclosure of the Patent as proposed to be amended. It must do so reading both documents through the eyes of the skilled team with their common general knowledge. Expert evidence directed specifically to this issue is not required. Nevertheless, counsel for Genentech
submitted that it was significant that
Lilly
had not adduced any expert evidence in support of its case on added matter. In my judgment, this is a point of minor significance.
330. On the other hand, I should say that I do not accept counsel for Lilly’s
riposte, namely that the absence of expert evidence was a point against
Genentech
since
Genentech
bore the burden of proof. While it is true to say that
Genentech,
as the party seeking to amend the Patent, bears the legal burden of showing that the proposed amendments satisfy the applicable statutory requirements, the question of added matter is not one which falls to be resolved by reference to the burden of proof since it involves an objective comparison by the court of the two documents. In any event, as will appear, counsel for
Genentech
did
elicit
evidence from Dr Tite as to the disclosure of the Patent which he relied upon in support of
Genentech’s
answers to
Lilly’s
objections.
331. Lilly’s
first objection is that added matter arises from the fact that new claims 1 and 14 describe the antibody as specifically binding to an “IL-17A/F heterodimeric complex” rather than to an IL-17A/F polypeptide.
332. Genentech
relies upon Example 1 as providing support for this aspect of the claims. As discussed above, the skilled team would appreciate that Example 1 is part of the central core of the disclosure of the Application and the Patent. It discloses IL-17A/F as being a heterodimer of IL-17A and IL-17F, joined by two interchain disulphides. It is described using various terms, including “heterodimeric complex” in the sentence in [0398] of the Patent which says: “specific antibodies which bind selectively to the novel heterodimeric complex of IL-17A/F have been identified”. As stated in paragraph 307 above, the skilled reader would conclude that the word “selectively” was being used synonymously with “specifically” here.
334. Accordingly, I conclude that the reference to an “IL-17A/F heterodimeric complex” in new claims 1 and 14 does not amount to added matter. I therefore respectfully disagree with the Opposition Division, which held at [3.6] that there was added matter in this respect.
335. Lilly’s
second objection is that the Application does not disclose that the antibody “inhibits the activity of the IL-17A/F heterodimeric complex to induce the production of IL-8 and IL-6” as required by new claims 1 and 14, because that activity is not disclosed in combination with an antibody.
Lilly
refer to the fact that there is a very broad definition of “activity” in the passage of the Application which corresponds to [0131] of the Patent and argues that production of IL-6 and IL-8, let alone inhibition of such production by an antibody, is not singled out. The Comptroller takes essentially the same point.
336. Genentech
relies upon the fact that Example 1 states in the passage corresponding to [0398] that “specific antibodies which bind selectively to the novel heterodimeric complex of IL-17A/F have been identified which may serve to modulate the activity of this novel cytokine [emphasis added]”. It then immediately proceeds to refer to the pro-inflammatory activity of IL-17A/F of inducing production of IL-6 and IL-8, with reference to Figure 5. As Dr Tite agreed, the skilled person would understand that the reference to the antibodies modulating the activity of the cytokine was a reference to inhibiting the activity of inducing IL-6 and IL-8 production.
339. Lilly
have a subsidiary point, based on the fact that the passage corresponding to [0131] states that “one preferred biological activity includes inducing activation of NF-[κB] and stimulation of the production of proinflammatory chemokines IL-8 and IL-6”. The suggestion is that referring to inducing the production of IL-8 and IL-6 in the claims, but not referring to activation of NF-κB, adds matter. I disagree with this for the reasons already explained. Furthermore, Prof Krueger agreed that the skilled person would know that production of IL-6 and IL-8 requires activation of NF-κB, so the reference in the claims to IL-6 and IL-8 production carries with it activation of NF-κB.
340. Lilly’s
third objection is that the Application does not disclose an antibody which combines the features of (i) specifically binding to an isolated IL-17A/F heterodimeric complex (ii) inhibiting the activity of the IL-17A/F heterodimeric complex to induce production of IL-6 and IL-8 and (iii) being either human or humanised found in new claim 1 (the first two, but not the third, are to be found in new claim 14).
341. Genentech
contends that, if the question is approached through the eyes of the skilled team, there is no new technical teaching. I agree with this.
345. Lilly’s
fourth objection is that there is added matter in claims 2 and 15 because they refer to a Kd of “at least about 10 -8 , 10 -9 , 10 -10 , 10 -11 or 10 -12 M”.
Lilly
point out that, in the passage of the Application corresponding to section [D] of [0118] in the Patent, further Kds are referred to, namely 10 -4 , 10 -5 , 10 -6 and 10 -7 M.
347. Lilly
argue that the Kds span a range from about 10 -4 to about 10 -12 and that the claim is to an undisclosed subset of that range. This is incorrect. What the Application discloses is not a range of affinities. Rather, each Kd is disclosed individually in a series of narrowing embodiments; they are independent disclosures. Accordingly, it does not add matter to identify only some of the disclosed Kds in the claim.
348. Lilly’s
fifth and final objection is that the reference to RA and psoriasis in claims 12, 20 and 22 amounts to an impermissible selection from the much longer lists contained in the passages of the Application corresponding to [0023], [0136] and [0351] of the Patent (and reflected in claim 57 of the Application).
351. Lilly
rely upon the decision of the Enlarged Board of Appeal in G1/93 Advanced Semiconductor Products/Limiting feature [1995] EPOR 97 that matter may be added by the addition of a limiting feature where that creates an inventive selection not disclosed in the application as filed or derivable therefrom. That statement of principle is not in doubt, but in my view it does not apply to the present case because the narrowing of these claims to RA and psoriasis is not an inventive selection. I should make it clear, however, that the impact of this on the question of plausibility is a separate question. I shall consider that below.
Conclusion in relation to Genentech’s
amendment applications
The prior art
353. When opening the case, Lilly
relied upon six prior art citations. These fell into three groups, two of which are considered in this section. I will refer to the sixth citation later.
The IL-17A/F prior art: US344
“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.”
355. US344 states at column 4, lines 15-26:
“Golstein et al. … reported a species they initially identified as ‘human CTLA-8’. However, examination of the sequence of the Golstein et al. species and the human CTLA-8 (B18) sequence of the present invention readily reveals that they are two different proteins, although they are homologous with each other and with the rat CTLA-8 and herpes CTLA-8 identified herein. The Golstein et al. species has now been renamed interleukin-17 (IL-17). Because of the homology between applicants’ human CTLA-8 (B[1]8) and IL-17, these proteins are expected to share some activities.
It has also been preliminarily determined that human CTLA-8 (B18) forms homodimers when expressed. As a result, human CTLA-8 proteins may possess activity in either monomeric or dimeric forms. Human CTLA-8 proteins can also be produced as heterodimers with rat and herpes CTLA-8 proteins and with human IL-17. These heterodimers are also expected to have activities of the proteins of which they are comprised.”
357. At column 8 lines 19-31 US344 states (emphasis added):
“Autoimmune disorders which may be treated using a protein of the present invention include, for example, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis , autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitis, myasthenia gravis, graft-versus-host disease and autoimmune inflammatory eye disease. Such a protein of the present invention may also to be useful in the treatment of allergic reactions and conditions, such as asthma or other respiratory problems. Other conditions, in which immune suppression is desired (including, for example, asthma and related respiratory conditions), may also be treatable using a protein of the present invention.”
The IL-17A/A prior art: WO717, US711, JP046 and Lubberts 2001
359. In opening, Lilly
relied upon no less than four items of prior art as disclosing IL-17A/A as a target for RA therapy, one of which was Lubberts et al , “IL-1-Independent Role of IL-17 in Synovial Inflammation and Joint Destruction During Collagen-Induced Arthritis”, J Immunol , 167, 1004-1013 (2001, “Lubberts 2001”), a paper co-authored by Dr Lubberts. Both in
Lilly’s
skeleton argument and in counsel for
Lilly’s
oral opening submissions, the disclosure of each of these four items of prior art was summarised in some detail. In
Genentech’s
skeleton argument it was accepted that the key findings of Lubberts 2001 were part of the skilled rheumatologist’s common general knowledge. Although
Lilly’s
written closing submissions referred back to their skeleton argument, no arguments were advanced specifically by reference to any of these items of prior art. I asked counsel for
Lilly
if
Lilly
were still relying on Lubberts 2001, and he replied that they were not, having regard to the common ground as to the common general knowledge concerning IL-17A/A. With the benefit of hindsight, my question was misdirected. In reality, given the evidence as to the common general knowledge,
Lilly
do not need specifically to rely upon any of these items of prior art. I will nevertheless summarise the disclosure of the three citations that, formally at least, are still pursued.
363. Under the heading “Summary of the invention”, WO717 states at page 2 lines 7-12:
“The present invention relates to a method of treating a mammal afflicted with a condition that relates to an inflammatory response, in particular, rheumatoid arthritis, by administering an IL-17 antagonist that inhibits IL-17 mediated signalling to a cell via membrane-bound IL-17 receptor. Suitable IL-17 antagonists include soluble IL-17 receptor, antagonistic antibodies that specifically bind IL-17 and antagonistic antibodies to the IL-17 receptor and combinations thereof.”
364. Under the heading “Detailed description of the invention”. WO717 states at page 2 lines 28-32:
“The subject methods involve administering to the patient an IL-17 antagonist or IL-17 inhibitor that is capable of reducing the effective amount of endogenous biologically active IL-17, by preventing the binding of IL‑17 to its receptor. Such antagonists include … antibodies directed against IL-17 (antibodies that bind IL-17 and inhibit binding thereof to IL-17 receptor) ….”.
365. At page 4 lines 27-34 WO717 states:
“… antibodies that specifically recognize a component of the IL-17 receptor and that prevent signalling through the receptor by IL-17 can be used to inhibit IL-17 activity. IL-17 antagonists that are antibodies include but are not limited to polyclonal antibodies, monoclonal antibodies (mAbs), humanized or chimeric antibodies… Thus, such antibodies can … be utilized as part of inflammatory disorder treatment methods.”
366. At page 5 lines 31-33 WO 717 states that “Preferably, for use in humans, the antibodies are human or humanised; techniques for creating such human or humanised antibodies were well known and commercially available ”.
“… isolated genes encoding proteins of the invention, variants of the encoded protein, e.g., mutations (muteins) of the natural sequence, species and allelic variants, fusion proteins, chemical mimetics, antibodies and other structural and functional analogs. …
an antibody which specifically binds to a primate CTLA-8 protein or peptide thereof; the antibody is raised against a protein sequence of SEQ ID NO: 2 [mouse IL-17A], 4 [viral IL-17A], 6 [human IL-17A fragment], 8 [human IL-17A] or 10 [mouse IL-17A fragment]; the antibody is a monoclonal antibody; the antibody blocks the CTLA-8 induced secretion of an inflammatory mediator, e.g., IL-6, IL-8 and/or PGE2; or the antibody is labelled.”
372. Methods of modulating the physiology of a cell by regulating CTLA-8-induced secretion of an inflammatory mediator are described including by using an antibody which specifically binds mammalian IL-17A (column 2 lines 47-54). The cell can be a synovial, epithelial, endothelial, fibroblast or carcinoma cell (column 2 lines 55-57).
“Purified CTLA-8, when cultured with synoviocytes, is able to induce the secretion of IL-6 from these cells. This induction is reversed upon the addition of a neutralizing antibody raised against human CTLA-8-8. Endothelial, epithelial, fibroblast and carcinoma cells also exhibit responses to treatment with CTLA-8. This data suggests that CTLA-8 may be implicated in inflammatory fibrosis, e.g., psoriasis, sclerodermia, lung fibrosis, or cirrhosis. CTLA-8 may also cause proliferation of carcinomas or other cancer 25 cells inasmuch as IL-6 often acts as a growth factor for such cells.”
377. Under the sub-heading “VII Antibodies”, US711 describes the production and screening of antibodies to CTLA-8. It is said that (column 26 lines 28- 32):
“Monoclonal antibodies are prepared from cells secreting the desired antibody. These antibodies can be screened for binding to normal or defective CTLA-8 proteins, or screened for agonistic or antagonistic activity, e.g., mediated through a binding partner. These monoclonal antibodies will usually bind with at least a K D of about 1mM, more usually at least 300µM, typically at least about 10µM, more typically at least about 30µM, preferably about 10µM, and more preferably at least about 3µM or better.”
378. This section goes on (column 27 lines 32-34):
“The antibodies … of this invention can have significant diagnostic or therapeutic value. They can be potent antagonists that bind to a binding partner and inhibit antigen binding or inhibit the ability of an antigen to elicit
a biological response.” (column 26, lines 33-37)
“The polypeptides and antibodies of the present invention may be used with or without modification, including chimeric or humanized antibodies”
379. Under the sub-heading “VIII Uses”, US711 states (column 28 lines 5-17 and lines 25-26):
“The CTLA-8 protein (naturally occurring or recombinant), fragments thereof, and antibodies thereto, along with compounds identified as having binding affinity to CTLA-8 protein, should be useful in the treatment of conditions associated with abnormal physiology or development, including abnormal proliferation, e.g. cancerous conditions or degenerative conditions. Abnormal proliferation, regeneration, degeneration, and atrophy may be modulated by appropriate therapeutic treatment using the compositions provided herein. For example, a disease or disorder associated with abnormal expression or abnormal signal[l]ing by a CTLA-8 antigen should be a likely target for an agonist or antagonist of the protein.”
“Recombinant antibodies which bind to CTLA‑8 can be purified and then administered to a patient.”
380. US711 contains a number of examples. The isolation of human CTLA-8 and its biochemical characterisation using SDS-PAGE are described in Example III (columns 34-35). A human genomic library was obtained and screened with murine CTLA-8. Three human cDNA clones covering the full sequence of human CTLA-8 were identified. The open reading frame identified encoded a 155 amino acid polypeptide with a predicted molecular weight of 17kDa.
382. Two antibodies, Ab25 and Ab16, referred to as being antibodies specific for CTLA-8, were selected for use in a sandwich ELISA
(Ab25 was used as the coat antibody) used to determine levels of human CTLA-8 in various cells and patient samples. No further details about those antibodies are provided (in particular, no amino acid sequences are disclosed). The inventors claim that the lowest concentration of human CTLA-8 detected was 0.015ng per ml, but no underlying data is included.
383. In Example V, synoviocytes were taken from controls and RA patients and incubated with increasing concentrations of human CTLA-8-8 (columns 37-38). The reference to “CTLA-8-8” is not properly explained, although there is a reference to it in column 36, line 34 which appears to indicate that it is used as a way of describing the purified human CTLA-8 protein. Concentrations of IL-6 secretions are measured using ELISA.
No data are shown, but the inventors report that IL-6 was secreted in a dose-dependent manner.
386. Under the heading “Prior art” JP046 explains:
“[0003] Various cytokines, such as IL-1, IL-6, and TNF-a play an important role in the pathological development of RA. A particularly representative inflammatory cytokine is IL-6, and RA treatment by blocking IL-6 signal transmission has been attempted. …
[0004] In recent years, interleukin-17 (hereinafter, ‘IL-17’) was discovered and its function was investigated (Clinical Immunology, 29, 678-682 (1997)). IL-17 is known not only to cause the production of inflammatory cytokines such as IL-6, IL-8, and GCSF, but also to induce the differentiation of mature neutrophils. Recently, IL-17 was surmised to possibly be involved in inflammatory diseases. However, IL-17 is a new cytokine derived from T-cells, so its role in the pathological development of RA is still unknown. …
[0008] The cells that control bone metabolism are osteoblasts and osteoclasts, and these cells intimately interact with one another in a phenomenon called coupling. Osteoblast/osteoblast-like stromal cells are known to adhere to osteoclast precursor cells and mature osteoclasts, respectively inhibiting osteoclast differentiation/maturation and the bone resorption activity of mature osteoclasts. The theory has been proposed that osteoblast/osteoblast-like stromal cells produce osteoclastogenesis differentiation factors (ODFs) on the cell membrane by receiving signals via 3 different signal transmission systems for the various bone resorption factors: specifically, intranuclear D3 receptors in the case of activated vitamin D3, protein kinase in the case of interleukin-1 (IL-1), parathyroid hormone (PTH), prostaglandin fa (PGfa), etc., and gp130 in the case of the inflammatory cytokine IL-6 …”
387. Under the heading “Problems to be solved by the invention”, JP046 states at [0010]:
“Although IL-17 is a new cytokine derived from T-cells, its role in osteoclast formation is almost completely unknown. The present inventors discovered that IL-17 has an important relationship with the pathology of RA….”
388. Under the heading “Means for solving the problem”, JP046 states at [0011]:
“The present invention relates to a chronic rheumatoid arthritis treatment drug whose active ingredient is a substance that suppresses or neutralizes IL-17 activity in the body and/or a substance that inhibits the transmission of IL-17 signals that induce osteoclastogenesis. More specifically, examples of the substance that neutralizes interleukin-17 activity may be interleukin-17 neutralizing antibodies …”
389. Under the heading “Mode for carrying out the invention”, JP046 states:
“[0012] As shown in the embodiments below, the research of the present inventors showed that IL-17 levels in synovial fluid are significantly higher in RA patients than in patients with osteoarthritis (p<;0.001). Also, it was discovered that IL-17-positive cells exist among CD4+ and CD45RO+ T-cells in synovial fluid and tissue. In this way, IL-17 is suggested to be deeply involved in the pathological development of RA. … As described above, the present inventors discovered for the first time that IL-17 was markedly increased in RA patients, that increased IL-17 promoted the formation of osteoclasts and bone destruction, and that this sort of bone destruction was selectively inhibited by osteoclastogenesis inhibitory factors (OCIFs).
[0013] As described above, IL-17 levels were shown to be significantly higher in RA patients compared with osteoarthritis patients (p<;0.001), and since IL-17 produced a bone resorption effect by markedly inducing osteoclastogenesis, it was discovered to be a cytokine that was deeply involved in RA lesions such as joint and bone resorption. In addition, these results revealed that suppressing or neutralizing IL-17 activity in the body and/or inhibiting osteoclastogenesis inducing signal transmission could be a treatment for RA. Therefore, a substance with properties that suppress or neutralize IL-17 activity and/or a substance that inhibits IL-17 osteoclastogenesis inducing signal transmission could be used as an active ingredient in a drug to treat RA … use of an IL-17 neutralizing antibody or OCIF is particularly preferable.”
“[0015] … Also, for a humanized antibody, a monoclonal antibody that neutralizes human IL-17 activity and that also has high affinity for human IL-17(lowest dissociation constant possible, for example, 10 -10 M or below) is selected from among the mouse anti-monoclonal antibodies obtained by the above-described methods.
[0016] … By using a protein A column to purify the culture solution of the antibody-producing hybridoma, a complete human antihuman IL-17 monoclonal antibody can be obtained. The humanized anti-human IL-17 monoclonal antibody that is the objective of the present invention can be obtained by selecting a human monoclonal antibody that neutralizes human IL-17 activity and exhibits high affinity for human IL-17.”
391. Embodiment 1 ([0023]) describes use of polyclonal anti-IL-17A antibodies to neutralise IL-17A activity thereby supressing osteoclastogenesis in a co-culture of osteoblasts and bone marrow cells. The inventors comment that the “results clearly show that polyclonal neutralizing antibodies to IL-17A supress joint and bone resorption caused by increased IL-17A levels in the synovial fluid in RA and that these antibodies have utility as a drug for treating RA.”
396. Under the heading “Effect of the invention”, JP046 states at [0033]
“The present invention provides a RA treatment drug whose active ingredient is a substance that suppresses or neutralizes IL-17 activity in the body and/or a substance that inhibits osteoclastogenesis inducing signal transmission due to IL-17 …”
Obviousness over US344
397. Lilly
contend that claims 1, 2, 13, 14 and 15 are obvious over US344, and so too are claims 12, 20 and 22 in so far as those claims are directed to RA. There is no dispute as to the relevant principles of law, which are very familiar, and so there is no need for me to set them out.
The disclosure of US344
398. Counsel for Genentech
did not dispute in his closing submissions that, as the evidence of Prof Krueger and Prof Kamradt confirmed, column 4 lines 30-32 of US344 is an enabling disclosure of the recombinant production of a heterodimer between “human CTLA-8” (i.e. IL-17F) and “human IL-17” (i.e . IL-17A), that is to say, IL-17A/F. Although it is not explicitly stated that the heterodimer is to be produced recombinantly, this is implied by the reference to forming heterodimers between human CTLA-8 and rat and herpes CTLA-8 proteins. Although actual production of the heterodimer is not described in US344, there is no dispute that the skilled team would know how to do this using their common general knowledge. Although counsel for
Lilly
at times appeared to suggest that US344 disclosed naturally occurring IL-17A/F, it plainly does not.
Obviousness 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.
Obviousness of claims 12, 20 and 22 in so far as directed to RA
403. Lilly
contend that it was obvious in the light of US344 to try humanised anti-IL-17A/F antibodies for the treatment of RA. As noted above, it was common ground between Dr Lubberts and Prof Kamradt that the skilled rheumatologist would have a good expectation that inhibiting IL-17A/A would be effective to treat RA.
Genentech
agrees that, given the disclosure of the Patent, the RA skilled team would have considered it plausible that humanised anti-IL-17A/F antibodies would be efficacious in the treatment of RA.
Genentech
contends, however, that, absent the disclosure of the Patent, the RA skilled team would not have had any expectation that humanised anti-IL-17A/F antibodies would be efficacious. This is because it was the Patent which showed for the first time that IL-17A/F existed in humans, being produced in activated T cells and having the effect of inducing the production of IL-6 and IL-8. It was this disclosure,
Genentech
contends, which made IL-17A/F a therapeutic target for RA.
404. Lilly
rely in support of this aspect of their case on the evidence of Dr Lubberts. As counsel for
Genentech
pointed out, however, Dr Lubberts was not instructed by
Lilly’s
legal team to address it in his first expert report, even though he had been given US344 to read before reading the Patent. (This was because
Lilly’s
legal team had asked Prof Krueger to address it in his first report, and were trying to avoid duplication. As counsel for
Lilly
acknowledged, this was a mistake on the part of
Lilly’s
legal team.) It was only in his second report that Dr Lubberts was asked to consider it, by which time he was familiar with the Patent. Counsel for
Genentech
submitted that, in those circumstances, it was likely that Dr Lubberts’ evidence on this point was tainted by hindsight. I agree that this method of proceeding created a real risk of hindsight. It remains necessary, however, to consider the cogency of Dr Lubberts’ reasoning.
“The skilled person would expect IL-17A/F to have similar effects to IL-17A and would conduct studies in relation to the function of IL-17A/F including to compare the effects and potency of IL-17A/F against IL-17A and IL-17F in inducing the production of proinflammatory cytokines by synovial fibroblasts. If, as expected, those studies were positive, IL-17A/F would be a therapeutic target as with IL-17A for RA.”
Novelty over the IL-17A/A prior art
411. Lilly
contend that, if the claims are construed in the manner contended for by
Genentech,
as I have accepted, then claims 1, 2, 13, 14 and 15 are lacking in novelty over all the IL-17A/A prior art, and claims 12, 20 and 22 in so far as those claims are directed to RA are lacking in novelty over WO717 and JP046.
Lilly
put their case in three different ways. 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.
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 over the IL-17A/A prior art
413. Lilly
contend that, even if they are novel, claims 1, 2, 13, 14 and 15, and claims 12, 20 and 22 in so far as those claims are directed to RA, are obvious over the IL-17A/A prior art. As noted above, it does not particularly matter for
Lilly’s
purposes which of the items of prior art one starts from, or indeed whether one starts from the common general knowledge that there was a good expectation that targeting IL-17A/A would be effective for treating RA.
Lilly’s
case is that, even if it was not inevitable that working the prior art would produce antibodies that bound to IL-17A/F as well as IL-17A/A, nevertheless obvious methods of working the prior art would do so.
414. This part of the case has led to experiments being conducted by Lilly
which have been heavily criticised by
Genentech.
This has led to extensive expert evidence from Dr Tite, Dr Reichmann and Prof Lesk on the one hand and Prof Martin and Prof Carr on the other hand. A number of issues of considerable complexity have been raised. It is
Lilly’s
contention, however, that, despite the number and complexity of the issues that have been raised, in substance
Genentech’s
criticisms of the experiments consist of points which do not make any practical difference. Moreover,
Lilly
contend that, for reasons that will appear, many of the criticisms of the experiments, even if well-founded, do not prevent
Lilly
from succeeding in their obviousness case.
415. I would add that it seems to me that at least some of these issues arose because the case was presented by Lilly
primarily as a novelty attack and only secondarily as an obviousness attack.
An outline of the issues
416. Lilly’s
experiments involved characterising three murine antibodies referred to as mAb 5, mAb 16 and mAb 25, producing certain humanised versions of those murine antibodies, and characterising those humanised versions. The experiments can be divided into the following groups:
i) Experiments carried out by the laboratory of Professor Anton van de Merwe at the University of Oxford on mAbs 5, 16 and 25 to assess their characteristics:
a) indirect ELISA
experiments to assess binding activity against IL-17A/A, IL-17F/F and IL-17A/F (producing EC 50 values);
b) SPR experiments to assess binding affinity to IL-17A/A and IL-17A/F (producing Kd values as well as on- and off-rates);
c) bioassays to assess the inhibition of IL-17A/A-induced production of IL-6 and IL-8 (producing an IC 50 value with respect to each of IL-6 and IL-8); and
d) bioassays to assess the inhibition of IL-17A/F-induced production of IL-6 and IL-8 production (producing an IC 50 value with respect to each of IL-6 and IL-8).
ii) Humanisation of mAbs 5, 16 and 25 to produce 12 humanised versions of each antibody. As noted above, this work was carried out by Absolute.
iii) Experiments conducted on a subset of 11 of the 36 humanised mAbs, namely similar indirect ELISA,
SPR and IL-6 and IL-8 bioassays to those set out in (i) above.
417. Genentech
does not dispute that the skilled team could without undue burden make humanised antibodies which bind to and inhibit IL-17A/A using prior art techniques. Nor does
Genentech
dispute that
Lilly’s
experiments demonstrate that mAbs 5, 16 and 25, and their humanised counterparts, bind to and inhibit both IL-17A/A and IL-17A/F (but do not bind to IL-17F/F).
Genentech
contends, however, that the experiments do not establish that it is inevitable that anti-IL-17A/A antibodies produced in accordance with the prior art would also bind to IL-17A/F.
418. In summary, Genentech
contends that the experiments suffer from the following defects:
i) mAbs 5, 16 and 25 are not representative of murine antibodies that would be produced following the teaching of the prior art.
ii) The humanisation techniques used involved the use of post-July 2003 or other unjustified techniques, including:
a) the use of IMGT definitions of the CDRs;
b) the use of germline sequences for the antibody frameworks;
c) the use of a post-July 2003 modelling program called Phyre 2 ;
d) the use of post-priority structures for homology modelling; and
e) the choices for the combinations of residues to back-mutate.
The use of mAbs 5, 16 and 25 as a starting point
419. Dr Tite was asked by Lilly’s
solicitors, Allen & Overy, to produce protocols for the production of antagonistic human or humanised antibodies to IL-17A/A following the teaching of WO717 and US711. He did so on 26 October 2017. He indicated that the skilled person would proceed by using purified biologically active recombinant human IL-17A/A either for the immunisation of animals and the generation of hybridomas producing IL-17A/A-specific monoclonal antibodies or to select scFv antibodies which bound to IL-17A/A from a phage display library. In the former case the skilled person would then test the panel of resultant antibodies for binding to and neutralising activity against IL-17A/A and select antibodies for humanisation using certain criteria. In the latter case the skilled person would convert the scFv antibodies into full human antibodies.
Genentech
makes no criticism of Dr Tite’s protocols. It points out, however, that
Lilly
did not follow the immunisation part of the first two protocols. Nor did
Lilly
follow the phage display protocols.
420. Dr Tite explained that Allen & Overy subsequently informed him that, due to time and ethical constraints, it was not practical to perform the immunisation sections of his first two protocols for the purposes of this litigation. Those stages would have taken at least four months to carry out assuming that all the capabilities were aligned and there were no experimental delays, which was typically not the case. Furthermore, the appropriate ethical permissions would have been required for the use of the animals. In his experience, getting a Home Office licence could be tricky and time-consuming. What Dr Tite did not say (presumably because he did not know), but counsel for Lilly
informed me without contradiction from counsel for
Genentech,
is that experiments on animals are not permitted for the purposes of patent litigation under section 5C of the Animals (Scientific Procedures) Act 1986.
421. Counsel for Genentech
submitted that
Lilly
could have followed Dr Tite’s phage display protocols instead, which would have avoided the ethical constraint. It would still have taken time, however. It is not clear to me from the evidence whether or not there was sufficient time available in which to do this. Moreover, I think there is something in the point made by counsel for
Lilly
that, since ixekizumab is a humanised (rather than human) antibody, it made sense for
Lilly
to focus on methods of producing humanised (rather than human) antibodies. But in any event,
Genentech’s
principal point is a different one.
Taking mAbs 5, 16 and 25 forward
i) the murine antibody’s level of binding to other known IL-17 family members and a primate orthologue of human IL-17A/A;
ii) the antibody’s potency in inhibiting the stimulation of cells by IL-17A/A to produce IL-8 and IL-6; and
iii) the antibody’s affinity of binding to IL-17A/A as measured by SPR.
434. As Prof Martin agreed, the skilled team in 2003 would expect in the vast majority of cases to be able to humanise antibodies using routine techniques so as to achieve comparable affinity for the target and equivalent biological activity to those of the murine antibodies. The skilled person would expect the humanised version of an antibody to bind the same epitope, and certainly that would be their aim. Prof Carr agreed that, if an antibody binds IL-17A/A so as to inhibit its activity, then if it bound to IL-17A/F it should also inhibit it.
435. Lilly
contend that it follows from this evidence that if (as I have concluded) mAbs 5, 16 and 25 are representative of the murine antibodies that would have been produced in accordance with the IL-17A/A prior art, then claims 1 and 2 are obvious on
Genentech’s
construction, because mAbs 5, 16 and 25 bind to and inhibit IL-17A/F as well as well IL-17A/A, it would be obvious to humanise them using routine techniques and success would be expected, meaning that the humanised antibodies would also be expected to bind to and inhibit both IL-17A/A and IL-17A/F. To that extent, it does not matter whether the humanisation work carried by Absolute as part of
Lilly’s
experiments was representative of what the skilled person would have done in 2003. I accept this contention. Nevertheless, I must go on to consider the humanisation work.
The humanisation work
436. So far as relevant to the present dispute, the process of humanisation involves two main steps:
i) First, the grafting of the CDRs from the murine antibody onto a suitable human antibody framework. This is designed to make the antibody appear more human and less immunogenic to the patient (via the human framework regions), without losing its specificity to the desired epitope (which comes from the murine CDRs). The CDRs need to be identified in order to be grafted. Further, a suitable framework has to be identified from the available sequences for human antibodies.
ii) Secondly, since the grafting process tends to reduce the affinity of the antibodies for their target, often below acceptable levels, residues in the framework regions are “back mutated” to those residues from the original murine antibody to try to reinstate some or all of the affinity of the humanised antibodies. Accordingly, the skilled person needs to identify the framework residues for back mutation.
Use of IMGT definitions of CDRs
437. In July 2003 at least three CDR definitions were known, referred to as Kabat, Chothia and IMGT. The IMGT definitions were introduced as part of the international ImMunoGeneTics (IMGT) database of antibody sequences established in 1989. They are shorter in some instances and longer in others than either the Kabat or the Chothia definitions. Absolute used the IMGT definitions of CDRs in its humanisation work for Lilly’s
experiments.
Genentech
contends that this approach would not have been used by the skilled person.
438. Counsel for Genentech
submitted that Dr Riechmann had accepted this. This is an issue where the evidence needs to be analysed with care. In paragraph 13 of his second report Dr Riechmann said that the IMGT CDR definitions were known prior to 2003, but accepted that they were “not common” because, like Prof Martin who had addressed this question in his first report, he knew of no examples of them being used for humanisation prior to 2003. In cross-examination it was suggested to Dr Riechmann, without showing him the actual passage, that he had agreed in his second report that the skilled person would not have used the IMGT CDRs definitions, and Dr Riechmann agreed. It was then put to him that, in that regard, what Absolute had done was not representative of what the skilled person in 2003 would have done, and Dr Riechmann again agreed. In my assessment, all that Dr Riechmann can be taken to have accepted was that it was far from inevitable that the skilled person would have used the IMGT CDRs for humanisation. No reason was put to him as to why the skilled person could not or would not have used the IMGT CDRs if the skilled person wished to do so. All that was being relied upon was Dr Riechmann’s acceptance that there was no known example of it actually having been done by July 2003.
Use of germline sequences
Choice of residues to back mutate
445. It is common ground that the choice of back mutations would be made by the skilled person based upon the methods taught in the prior art, in particular patents and applications from CellTech (US Patent No 5,829,205 published on 12 June 1999 (“Adair”)), Genentech
(US Patent No 6,407,213 published on 18 June 2002 (“Carter”)) and Protein Design Labs (International Patent Application No WO 90/07861 published on 26 July 1990 (“Queen))”. In each case, there are also relevant papers: Adair et al , “Humanization of the murine anti-human CD3 monoclonal antibody OKT3”, Hum Antibody Hybridomas , 5, 41-47 (1994); Carter et al , “Humanization of an anti-p185HER2 antibody for human cancer therapy”, Proc Natl Acad Sci USA , 89, 4285-4289 (1992); and Queen et al , “A humanized antibody that binds to the interleukin-2 receptor”, Proc Natl Acad Sci USA , 86, 10029-10033 (1989).
446. A small point which is convenient to address here is that counsel for Genentech
suggested that Dr Riechmann had only relied on the Adair and Carter patents when preparing his reports, and not the corresponding papers. This is incorrect: Dr Riechmann listed the papers in paragraph 7 of his first report as being ones he had read for the purposes of preparing that report; he referred to the skilled person relying upon the “publications and patents” at paragraphs 30 and 32 of that report; in paragraph 41 he stated that he had “reviewed … the selection of academic literature and patents that would have been well known to the skilled person in 2003 (listed in paragraph 7 … above)” in order to assess Absolute’s choice of back mutations; and in paragraph 42 he said that “the back mutations … are supported overall by the literature”. Moreover, in paragraph 29 of his second report he referred to both the Adair and Carter papers. It is fair to say that in his annexes justifying each back mutation he only made specific reference to the Adair and Carter patents, but he was clearly relying upon the Adair and Carter papers as well.
i) Adair involves a “hierarchy of positions” for identifying important locations within the framework, identifying lists of residues which should be donor.
ii) Carter uses a consensus sequence for the human acceptor. Carter also explains the use of models to identify residues of interest which have the effect of (i) non-covalent binding of the antigen, (ii) interacting with a CDR or (ii) participating in the V H /V L interface, and thus should be back mutated. The patent further provides a list of residues one or more of which can be selected for substitution.
iii) Queen uses a distance criterion approach to identifying residues for back mutation as explained in more detail below.
448. As Dr Riechmann explained in paragraph 40 of his first report, and Prof Martin accepted:
“As there is a degree of flexibility and personal judgement, on which residues to back mutate, different labs starting from the same murine antibodies would in all likelihood produce different humanised variants. However, all of these would be designed applying well established and routine principles. And while the exact framework sequence of the final humanised antibodies produced in the different labs may vary, each successfully humanised antibody will have an antigen affinity comparable to its parental murine antibody.”
450. Lilly
did not adduce any evidence from Dr Wilkinson explaining why Absolute had chosen to back mutate the residues they did. It is common ground, however, that Absolute used a modelling program called Phyre 2 which was not available in July 2003 and used structures which were not available in July 2003.
451. Instead, Lilly
adduced evidence from Dr Riechmann seeking to justify Absolute’s choices by reference to each of the Adair, Carter and Queen approaches and information which would have been available in July 2003. As I will explain, in the case of the Queen approach, Dr Riechmann relied upon the models produced by Prof Lesk.
452. The analysis in Dr Riechmann’s first report assumed that the skilled person would have used the IMGT CDR definitions. The analysis in his second report instead assumed that the skilled person would have used the combined Kabat and Chothia CDR definitions. Counsel for Genentech
relied upon Dr Riechmann’s acceptance that, because the skilled person would not have used the IMGT CDRs, his first analysis could be forgotten about. For the reasons explained above, however, I do not accept this.
453. Adair . As mentioned above, in the annexes to his reports, Dr Riechmann cited passages in the Adair patent, which sets out a protocol for humanisation. Prof Martin advanced two criticisms of Dr Riechmann’s analysis which are maintained by Genentech.
457. Furthermore, as counsel for Lilly
pointed out, these two criticisms do not apply to two of the humanised mAb5 antibodies and two of the humanised mAb25 antibodies (in the case of the first point) and to the mAb16 antibodies (in the case of the second point). That leaves two humanised mAb5 and two humanised mAb25 antibodies to which neither point applies.
459. Secondly, Prof Martin pointed out that Dr Riechmann’s analysis did not justify the mutations made by Absolute to residues H1, H61 and L1, although Prof Martin acknowledged that H61 could have been justified. This point appears to be a sound one. As counsel for Lilly
pointed out, however, it only affects the humanised mAb5 antibodies (in relation to H1) and two of the humanised mAb25 antibodies (H61) tested in the repeat experiments. Thus it does not apply to two of the humanised mAb25 antibodies or any of the humanised mAb16 ones.
465. Furthermore, as Prof Martin also pointed out in his second report (served on 11 December 2018), Prof Lesk’s models generated numerous distances that were less than the van der Waals radii of the two atoms in question. That meant that the atoms were effectively superimposed in the models, which was not realistic and meant that the models could not reliably be used in a distance criterion approach. Prof Lesk said that some of the apparent clashes would properly be regarded as short hydrogen bonds, rather than true clashes, but did not suggest that this applied to all of the clashes identified by Prof Martin.
466. Although Prof Lesk admitted in paragraph 9 of his fourth report (served on 20 January 2019) that he was aware of this problem when he created his models, and he was also aware that Dr Riechmann was relying on the distances they generated, it appears that he did not mention the problem to anyone on Lilly’s
side at that time.
469. He also said that it would have been possible for the skilled person in 2003 to have removed sidechain clashes by using software. But, as counsel for Genentech
submitted, that just goes to highlight the difference between the models he had created and those which the skilled person in 2003 would have created.
471. Counsel for Genentech
submitted that Prof Lesk’s models could not be relied on for the purposes of applying a distance criterion as it would have been applied in July 2003. I accept that submission.
The affinities of the humanised antibodies
473. As well as criticising the methods used in Lilly’s
experiments,
Genentech
relies upon the end results, in terms of the affinities of the humanised antibodies, as indicating that there was something unusual about them.
474. The humanised versions have affinities for IL-17A/A as measured by SPR which are 3-10 fold (for mAb 5), 3-7 fold (for mAb 25) and 4-12 fold (for mAb 16) greater than the affinities of their murine parents. Prof Martin said that in his experience it was highly unusual to see such a consistent and high level of improvement in affinity. He accepted that an increase of three-fold would not be surprising, but said that the increases found in this case would not be expected. He acknowledged that it might happen very occasionally, however. Dr Riechmann’s experience was any increase was highly unusual, although he noted that the Carter paper claimed a three-fold increase.
476. Counsel for Lilly
asked Prof Carr about the possible effect of using a polyclonal murine capture antibody of the kind sold by GE Healthcare Life Sciences as a standard reagent versus a monoclonal human capture antibody. Prof Carr did not know exactly how the polyclonal capture antibody would bind, but said that the reagent would not be fit for purpose if it affected the binding of the captured antibody. In his opinion this did not explain the differences in the SPR data. As he acknowledged, however, in order definitively to answer the question, further experiments would be required.
477. As Dr Tite pointed out, there is another set of experimental data which sheds light on this question, namely chimera ELISA
data generated by Absolute which was annexed to
Lilly’s
Notice of Experiments as part of the work-up material they were required to disclose. The chimera has all of its variable region from the mouse and all of its constant region from a human source, so can be compared to humanised antibodies because the same anti-human detection antibody is used (unlike when comparing to the original murine antibody, which must use an anti-murine detection antibody). The data indicates that the humanised antibodies bound slightly less well than the chimera.
478. Counsel for Genentech
submitted that
Lilly
were not entitled to rely upon the results of the chimera
ELISA
experiments because they were not the subject of any request for admissions in the Notice of Experiments. In my judgment
Lilly
should be permitted to rely upon these results for the following reasons. First, the party seeking to make a quantitative comparison between the SPR results is
Genentech,
not
Lilly,
but
Genentech
did no experiment in reply on this point. Secondly, although
Genentech
served a response to the Notice of Experiments, it did not notify
Lilly
that it intended to take a point based on a quantitative comparison between the SPR results until it served its expert evidence in reply. Had
Genentech
raised the point sooner,
Lilly
could have included the chimera as a benchmark in the witnessed SPR repeats. Thirdly, the chimera
ELISA
experiments were disclosed with the Notice of Experiments and thus will not have taken
Genentech
by surprise when Dr Tite referred to them.
479. Counsel for Genentech
also pointed out that the chimera
ELISA
data had not been put to Prof Carr or Prof Martin. Neither of them were immunologists, however, unlike Dr Tite. In any event, this does not detract from the point that the chimera could have been used as a benchmark. Furthermore, the results of the chimera
ELISA
experiments are consistent with the
ELISA
and bioassay data included in
Lilly’s
Notice of Experiments, which Prof Martin was asked about. As he accepted, the latter are more consistent with what one would expect. Prof Martin made the point that SPR is the gold standard, and that the SPR results suggested that something different was happening. His conclusion was that it was “just puzzling”.
481. Thus I conclude that the majority of the humanised antibodies produced in Lilly’s
experiments are representative of what the skilled team would have produced implementing the IL-17A/A prior art using obvious methods. In the case of the remainder it is uncertain whether they are representative or not.
Inevitability of binding to and inhibition of IL-17A/F as well as IL-17A/A
482. As I have explained, it is Lilly’s
case that it is inevitable that antibodies to IL-17A/A produced in accordance with the prior art will also bind to and inhibit IL-17A/F. As well as attacking
Lilly’s
experiments,
Genentech
relies upon the evidence of Prof Carr as showing that this is not inevitable, but on the contrary it is probable that some IL-17A/A antibodies will not bind to IL-17A/F at all and some may not inhibit IL-17A/F even if they bind. If I am right in my conclusions so far, it is not strictly necessarily for me to address this issue. For reasons that will appear, however, I consider that the evidence on it reinforces the conclusions that the claims in dispute are not lacking in novelty, but are obvious.
483. It may be helpful if I make two observations at the outset. The first is that the parties’ cases on this issue were to some extent like the proverbial ships sailing in the night. As explained above, Prof Carr approached the matter as a structural biologist and not as an immunologist. By contrast, Dr Tite approached it as an immunologist and not as a structural biologist. Consistently with that approach to the evidence, Genentech
contends that it is the structural analysis that matters, while
Lilly
contends that it is the immunological considerations which matter.
484. The second is that Lilly
rely heavily upon the fact that a considerable number of antibodies have been reported which bind to and inhibit IL-17A/F as well as IL-17A/A, but none that only bind IL-17A/A. In particular, there is no suggestion that
Genentech
has found one, despite working in this field for many years.
Genentech
contends that this does not prove that such antibodies cannot exist.
485. These observations lead me to a threshold submission advanced by counsel for Lilly
with respect to this part of the case. He pointed out that, as I shall explain in more detail below, Prof Carr had not been instructed to consider what the skilled person would in fact have achieved by working the prior art. Rather, he had been instructed to consider the matter from a theoretical perspective based on current knowledge. Counsel for
Lilly
submitted that this was the wrong question, of purely academic interest and of no assistance to the Court. I disagree. Prof Carr’s evidence was directed to the issue of inevitability. For that purpose, it was appropriate for
Genentech
to instruct him in the manner it did.
486. Structures of IL-17A/A, IL-17F/F and IL-17F/F and binding to receptors . Prof Carr was instructed by Genentech
to explain what was known today about the structures of IL-17A/A, IL-17F/F and IL-17A/F and their interactions with their receptors based on public available information. He set this out in paragraphs 37-96 of his first report. Prof Lesk agreed with this part of Prof Carr’s report, and thus there is no dispute as to its accuracy. Prof Carr’s evidence may be summarised as follows.
i) Hymowitz et al , “IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding”, EMBO J , 19, 5332-5341 (2001) disclosed the structure of Il-17F/F;
ii) Ely
et al , “Structural basis of receptor sharing by interleukin 17 cytokines”, Nature Immunol , 10, 1245-1252 (2009) published a structure of IL-17F/F bound to IL-17RA;
iii) Gerhardt et al , “Structure of IL-17A in complex with a potent, fully human neutralizing antibody”, J Mol Biol , 321, 851-862 (2009) published a structure of IL-17A/A homodimer bound by an inhibitory Fab fragment;
iv) Liu et al , “Crystal structures of interleukin 17A and its complex with IL-17 receptor A”, Nature Comm , 4, 1-9 (2013) published a structure of free IL-17A/A and a structure of IL-17A/A bound to IL-17RA; and
v) Goepfert et al , “The human IL-17A/F heterodimer: a two-faced cytokine with unique receptor recognition properties”, Nature Sci Rep , 7, 1013 (2017) published the IL-17A/F structure and a structure of IL-17A/F bound to IL-17RA.
493. Of the various representations of the sites in the papers, perhaps the clearest is that of the sites in the IL-17F/F – IL-17RA complex (below, taken from Ely).
Broadly the same locations of sites are found in the A/A and A/F – IL-17RA complexes, but there are differences between the sites in the three cytokines because of the different residues in the subunits and, in some cases, because of conformational differences.
i) mAbs 5, 16 and 16 and their humanised variants discussed above;
ii) ixekizumab;
iii) secukinumab, an antibody marketed by Novartis under the trade mark Cosentyx for the treatment of psoriasis and other conditions;
iv) A2027F/c631 and A2031F/c632 disclosed in International Patent Application No WO 2009/082624 in the name of Zymogenetics Inc;
v) OREG 203, 207 and 210 disclosed in International Patent Application No WO 2014/001356 in the name of Orega Biotech (although OREG 203 and 207 have the same CDRs and so are not independent examples);
vi) mAb6785/Fab6468 disclosed in US Patent No 8,519,107 in the name of Janssen Biotech Inc;
vii) XAB1 disclosed in International Patent Application No WO 2014/122613 in the name of Novartis AG;
viii) CA 028_496 disclosed in US Patent No 8,679,494 in the name of UCB Pharma SA; and
ix) 14 antibodies disclosed in US Patent No 8,779,101 in the name of AbbVie Inc.
512. In addition, there is confidential evidence concerning the following:
i) two murine antibodies produced by eBioscience, one of which binds to IL-17A/F and one which may or may not bind; and
ii) five murine antibodies produced by Genentech,
all of which bind to IL-17A/F but whose inhibitory effect has not been determined.
514. Genentech
points out that
Lilly
do not contend that ixekizumab is representative of antibodies that would be produced by the skilled person following the prior art in 2003. That is true, but irrelevant for present purposes just as it is irrelevant that Prof Carr relied upon post-July 2003 information for his analysis. It remains the case that ixekizumab is an IL-17A/A antibody which binds to IL-17A/F (which is why it is alleged to infringe).
515. Genentech
contends that some of these antibodies may have been selected for their ability to bind IL-17A/F as well as IL-17A/A. Except in the case of the AbbVie antibodies, there is no positive evidence that this was the case, however. In any event, the fact remains that they bind to both.
516. Genentech
points out that mAb6785/Fab6468 was raised against a mutant IL-17A/A and not native IL-17A/A.
Genentech
says that an antibody raised to native IL-17A/A might not have bound to IL-17A/F, but there is no evidence of any such antibody.
517. Conclusion on inevitability . As stated above, the overall conclusion I draw on this part of the case is that Lilly
have not established that it is inevitable that anti-IL-17A/A antibodies also bind to IL-17A/F. In my judgment the evidence shows, however, that it is highly probable that such antibodies will also bind to and inhibit IL-17A/F.
Conclusion on obviousness
519. Genentech
contends that, even if claim 1 is obvious, claim 2 is not obvious, in particular in respect of the higher affinities specified.
Genentech
argues that the skilled team would aim for an antibody with an affinity to IL-17A/A in the range of 10-100 pM. Even if they succeeded in making an antibody which bound to IL-17A/A with an affinity of 10 pM which also bound to IL-17A/F, it would bind to IL-17A/F with lower affinity, and hence with an affinity lower (i.e. worse) than 10 -10 M. In my judgment this is again a point which is good against lack of novelty, but not against obviousness. It is clear from the evidence of Dr Tite and Prof Martin that would be obvious to aim for the highest possible affinity for IL-17A/A. Although the evidence shows that the affinity to IL-17A/F would tend to be lower, it would remain obvious to obtain antibodies with the affinities specified. There is no evidence that this could not be achieved or would require special, non-obvious techniques. (If there was, claim 2 would be insufficient because the Patent does not disclose any such techniques.)
520. In the draft of this judgment which I circulated to the parties before it was handed down, I stated that I did not understand there to be any dispute that, if claims 1 and 2 were obvious over the IL-17A/A prior art, then so too were claims 13, 14 and 15, and claims 12, 20 and 22 in so far as they are directed to RA (or at least, in the case of claims 12, 20 and 22, obvious over WO717 and JP046). Counsel for Genentech
informed me that this was incorrect, and that
Genentech
relied upon the conditional amendments to claims 13, 14 and 20 to incorporate the language “[for use] as an antagonist of the IL-17A/F heterodimeric complex” or “[for] antagonizing the IL-17A/F heterodimeric complex” as an answer to
Lilly’s
case that those claims were obvious. As counsel for
Lilly
pointed out in response, however,
Genentech’s
submissions at trial on this point were only directed to
Lilly’s
lack of novelty case. Be that as it may, I do not consider that the new integer added by the conditional amendments does provide an answer to the obviousness case because the antibodies which I have found it would be obvious to make would satisfy this requirement.
Insufficiency: plausibility of the psoriasis claims
522. As is common ground, in order for claims 12, 20 and 22 to be valid in so far as they are directed to psoriasis, 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 psoriasis. If not, the claims will be insufficient. (Lilly
contend that they would be obvious as well, but I consider that in the present case the objection is more conveniently analysed as one of insufficiency.)
The law
523. The law has recently been considered by the Supreme Court in Warner-Lambert Co LLC v Generics (UK) Ltd [2018] UKSC 56. The Court divided 3:2 on this issue. The judgment of the majority was given by Lord Sumption. That case was concerned with a second medical use claim in Swiss form of a known pharmaceutical. The present case is concerned with a first medical use, given that the claimed antibodies were not known, although there are claims framed as second medical use claims both in Swiss form (purpose-limited process claims, namely claim 12 and 20) and in EPC2000 form (a purpose-limited product claim, namely claim 22). There is no dispute that the guidance given by Lord Sumption is applicable, although Genentech
contends that it is necessary when applying it to bear in mind the different context. I accept that.
“The Court of Appeal's reference to ‘armchair inventors’ suggests that what they meant by speculative claiming was claiming by persons who had done nothing new or inventive at all but had simply sought to patent abstract possibilities. That may well be a particular risk in the case of patents for new uses of known compounds, especially when they are commercially successful in their existing use. In reality, however, speculative claiming of this kind is simply one of a number of ways in which a patentee may attempt to claim a monopoly more extensive than anything which is justified by his contribution to the art. Other ways in which this can happen include claiming a monopoly wider than the disclosure in the patent can support. An over-broad claim will not necessarily be speculative. The inventor may really have invented something corresponding to the full breadth of the claim. Research may subsequently demonstrate this. But the claim will still exceed his contribution to the art if that contribution is not sufficiently disclosed in the patent”
“The principle is that the specification must disclose some reason for supposing that the implied assertion of efficacy in the claim is true. Plausibility is not a distinct condition of validity with a life of its own, but a standard against which that must be demonstrated. Its adoption is a mitigation of the principle in favour of patentability. It reflects the practical difficulty of demonstrating therapeutic efficacy to any higher standard at the stage when the patent application must in practice be made. The test is relatively undemanding.
But it cannot be deprived of all meaning or reduced … to little more than a test of good faith.”528. Lord Sumption went on at [37] (emphases and line breaks added):
First , the proposition that a product is efficacious for the treatment of a given condition must be plausible.
Second , it is not made plausible by a bare assertion to that effect, and the disclosure of a mere possibility that it will work is no better than a bare assertion. ….
But, third , the claimed therapeutic effect may well be rendered plausible by a specification showing that something was worth trying for a reason, ie 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. The disclosure of those grounds marks the difference between a speculation and a contribution to the art. This is in substance what the Technical Board of Appeal has held in the context of article 56, when addressing the sufficiency of disclosure made in support of claims extending beyond the teaching of the patent. In my opinion, there is no reason to apply a lower standard of plausibility when the sufficiency of disclosure arises in the context of EPC articles 83 and 84 and their analogues in section 14 of the Patents Act. In both contexts, the test has the same purpose.
Fourth , although the disclosure need not definitively prove the assertion that the product works for the designated purpose, there must be something that would cause the skilled person to think that there was a reasonable prospect that the assertion would prove to be true.
Fifth , that reasonable prospect must be based on what the TBA in SALK (para 9) called ‘a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se.’
Sixth , in SALK , this point was made in the context of experimental data. But the effect on the disease process need not necessarily be demonstrated by experimental data. It can be demonstrated by a priori reasoning. For example, and it is no more than an 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; or to some unifying principle that relates the product or the proposed use to something else which would suggest as much to the skilled person.
Seventh , sufficiency is a characteristic of the disclosure, and these matters must appear from the patent. The disclosure may be supplemented or explained by the common general knowledge of the skilled person. But it is not enough that the patentee can prove that the product can reasonably be expected to work in the designated use, if the skilled person would not derive this from the teaching of the patent.”
529. At [40] Lord Sumption added:
“The question is not whether [the medicament] works but whether the contribution to the art consisting in the discovery that it can be expected to work has been sufficiently disclosed in the patent. The inherent difficulty of demonstrating this before clinical trials is taken into account in the modest standard (ie plausibility) which is applied to test it. … This does not mean that subsequent data is never admissible in a dispute about sufficiency, but the purpose for which it is admitted is strictly limited.
Where the asserted therapeutic effect is plausible in the light of the disclosure in the patent, subsequent data may sometimes be admissible either to confirm that or else to refute a challenger's contention that it does not actually work… But it cannot be a substitute for sufficient disclosure in the specification.”530. As counsel for Genentech
pointed out, there is no reference in any of the judgments of the Supreme Court to the previous decision of the Supreme Court on plausibility in Human Genome Sciences Inc v
Eli
Lilly
and Co [2011] UKSC 51, [2012] RPC 6 given just seven years previously, even though it was applied by the lower courts and even though it was cited in argument. The legal context of HGS was different in that the issue was that of industrial applicability. As Lord Sumption said, however, the fundamental principle is the same. Counsel for
Genentech
submitted that the test laid down in Warner-Lambert was the same as that in HGS , and that HGS was of assistance in applying that because, like the present case, it was concerned with a new member of a known family.
531. In my judgment, I am bound by the law as stated in Warner-Lambert . As Lord Sumption acknowledged, the application of the requirement of plausibility depends on context. I accept that, in applying the principles laid down by Warner-Lambert to the facts of present case, it is necessary to take into account the fact that the Patent concerns a new (at least in the sense of being newly found to exist in humans) member of a known family. I do not accept that this requires any modification of those principles, if that is what counsel for Genentech
was suggesting.
Assessment
532. It is important to be clear as to two points at the outset. First, Genentech
does not rely upon any common general knowledge of the skilled dermatologist regarding IL-17. By contrast, it does rely upon their common general knowledge concerning IL-6 and IL-8. For their part,
Lilly
rely upon the common general knowledge of the skilled person concerning the other cytokines implicated in psoriasis, and in particular their knowledge regarding TNFα and IFN g . Secondly, it is common ground that, in considering the plausibility of the claims, the dermatologist would obtain and read the key papers cited in the Patent at [0015]-[0019], in particular the three papers cited at the end of [0019] as concerning the role of IL-17 in psoriasis, but also certain other papers. Accordingly, it is necessary to begin by considering what the skilled person would learn from those papers if he or she was not already aware of them.
“In conclusion, the induction of secretion by stromal cells of IL-6, IL-8, and PGE 2 but not of IL-1 or TNF, and the lack of detectable activity on monocytes suggest a limited proinflammatory role of IL-17 in T cell-driven inflammatory pathological processes such as psoriasis …”
534. Chabaud . Chaubaud et al , “Enhancing effect of IL-17 on IL-1-induced IL-6 and leukaemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines”, J Immunol , 161, 409-414 (1998) reported synergy between IL-1β and IL-17 in the production of IL-6 by RA synoviocytes.
535. Prof Krueger pointed out that Chabaud is mis-cited in the Patent at [0015]. The Patent cites Chabaud in support of the statement that IL-17 “synergizes with other cytokines including TNFα and IL-1β to further induce chemokine expression”. Chabaud does not itself contain any data about synergism between IL-17 and TNFα, although it does report the finding in Fossiez concerning GM-CSF. GM-CSF is a haemopoetic cytokine which was not considered to play an important role in psoriasis pathogenesis. Moreover, Chabaud is concerned with IL-6, which is not a chemokine either. These are minor points, however.
538. In the introduction the authors note that:
i) CD4 + T cells can be detected in early and fully developed psoriatic lesions;
ii) keratinocytes in these lesions exhibit unusual expression of MHC class II and ICAM-1, which are induced on keratinocytes by IFN g ; and
iii) IL-17 has been demonstrated to stimulate production of IL-6, IL-8 GM-CSF and PGE2 in epithelial, endothelial and fibroblastic cells and to induce ICAM-1 expression on fibroblasts.
539. The authors demonstrate that:
i) the dosing of normal human keratinocytes with IL-17 increased the expression of the pro-inflammatory cytokines IL-6 and IL-8, but not IL-1α or IL-15, and was synergistic in the presence of IFN g , leading to a 10-fold increase in IL-6 and IL-8 after co-stimulation;
ii) IL-17 weakly induced expression of ICAM-1 and human leukocyte antigen DR (HLA-DR), and had a slight additive effect with IFN g on the expression of ICAM-1;
iii) of 12 CD4 + and five CD8 + T cell clones derived from psoriatic skin, nine CD4 + and three CD8 + clones produced IL-17 mRNA when stimulated; and
iv) IL-17A mRNA was detected in skin biopsies from lesional skin using normal skin as a control.
541. The authors report the activity of the IFN g used in their study by reference to the manufacturer’s units, not the international standard IU. Prof Krueger had personal knowledge about the conversion which enabled him to conclude that 10-fold higher concentrations of IL-17 than IFN g were used to produce the same response. As I think he accepted, the skilled reader without that knowledge would not be able to compare the concentrations used. Counsel for Genentech
submitted that the skilled person would therefore take the results at face value. In my judgment the skilled person would appreciate that there was some uncertainty as to the true significance of the results so far as the comparison between IL-17 and IFN g was concerned, and hence as to the relative potencies of IL-17 and IFN g . Moreover, the skilled person would appreciate that it was not known if the same concentrations of IL-17 were present in vivo .
543. Albanesi . Albanesi et al , “Interleukin-17 is produced by both Th1 and Th2 lymphocytes and modulates interferon-γ- and interleukin-4-induced activation of human keratinocytes”, J Invest Dermatol , 115, 81-87 (2000) performed IL-17 ELISAs
on CD4 + T-cells obtained from patients with allergic contact dermatitis (ACD) to nickel.
544. In the introduction the authors note that:
i) IL-17 is a pleiotropic cytokine active on a wide variety of cell types, in particular it stimulates macrophages, fibroblasts and endothelial and epithelial cells to release cytokines and prostaglandins and to express ICAM-1;
ii) the effects of IL-17 are potentiated by TNF a , IFN g and IL-1 b ;
iii) IL-17A has been detected in skin affected by ACD and psoriasis and is expressed by a portion of nickel-specific CD4 + cells;
iv) IL-17 exerts important regulatory effects on human keratinocytes by enhancing IFN g -induced ICAM-1 expression and regulating IL-8 and RANTES (another chemokine); and
v) T cell-driven keratinocyte activation plays a relevant role in the pathogenesis of chronic inflammatory skin disorders including ACD and psoriasis involving the infiltration of T lymphocytes and the production of cytokines.
i) about 50% of nickel-specific Th0, Th1 and Th2 clones released IL-17 on activation;
ii) IL-17 on its own and in combination with IL-4, and IL-4 and IFN g , decreased the ratio of IL-1R to IL-1 a , which is proinflammatory;
iii) IL-17 caused production of cytokines from keratinocytes including GM-CSF, IL-6, Gro- a and was synergistic with IFN g and IL-4; and
iv) IL-17 strongly increased IFN g -induced expression of ICAM-1 on keratinocytes.
551. Aggarwal 2002 . I have summarised this review in paragraph 243 above. Genentech
relies upon it for the statement about IL-17 inducing IL-8 and Groα. In relation to the association between IL-17 and psoriasis, however, Aggarwal 2002 simply cites Teunissen, Albanesi and Homey. Thus it would add nothing to the skilled person’s understanding of IL-17’s role in psoriasis after reading those papers. It is convenient to note here that
Lilly
pleaded Aggarwal 2002 as prior art, to show that everything in the Patent about the role of IL-17 in psoriasis was in the prior art and thus to support a case that the Patent made no technical contribution with regard to psoriasis. Counsel for
Lilly
did not rely upon Aggarwal 2002 as founding a case of obviousness in closing submissions, however.
555. Prof Krueger made some minor criticisms of the experiments in Example 2 in his reports. Counsel for Genentech
submitted that these criticisms had been undermined in cross-examination. It is not necessary for me to consider whether this is correct because counsel for
Lilly
did not rely upon these points in closing submissions. Nor were they of significance to Prof Krueger’s analysis of plausibility.
“…. I consider that the disclosure of the Patent amounts to no more than the disclosure of a mere possibility that an antibody which binds to and inhibits IL-17A/F (whether only or in addition to IL-17A/A and/or IL-17F/F) will work to treat psoriasis. The Patent discloses no reasonable scientific grounds for expecting that such an antibody might well work to treat psoriasis. There is nothing in the Patent that would cause the skilled person to think that there was a reasonable prospect that the assertion that such an antibody would treat psoriasis would prove to be true. The skilled person could not point to a direct effect of such an antibody on a metabolic mechanism specifically involved in psoriasis, this mechanism being either known from the prior art or demonstrated in the Patent itself. The Patent does not point to a property of such an antibody which would lead the skilled person to expect that it might well produce the claimed therapeutic effect of treating psoriasis nor any unifying principle that relates to such an antibody which would suggest such an effect to the skilled person. I do not consider that the skilled person can derive from the Patent that such an antibody can reasonably be expected to work to treat psoriasis.”
Prof Krueger maintained these views in cross-examination, describing the claims in the Patent at one point as “tenuous”.
563. Counsel for Genentech
submitted that the teaching in the Patent at [0015]-[0019] was retrospectively vindicated by Prof Krueger’s December 2017 presentation. I do not accept this. It is true that Prof Krueger referred to the findings of Fossiez and Teunissen; but he identified the turning point as being the publication by Cua of two critical papers in 2003 and 2005 (the first of these is the paper discussed in paragraph 234 above) which led to the discovery of Th17 T cells as a distinct subset under IL-23 regulation mediated by IL-17A. It is this “IL-23/Th17 axis” or “pathway” (as Prof Krueger described it) that is targeted by ixekizumab.
564. Similarly, counsel for Genentech
submitted that the teaching in the Patent was also retrospectively vindicated by Mylle, but Mylle’s analysis (at page 628) is entirely consistent with that of Prof Krueger in his presentation:
“Now, the IL-23/Th17 axis has been suggested as the main attributer for psoriatic disease. For instance, intradermal injection of IL-23 in mice induced erythema and induration, histopathologically resembling psoriasis [51]. IL-17A promotes the production of IL-6, IL-8, intercellular adhesion molecule (ICAM)-1 and granulocyte–macrophage colony-stimulating factor (GM-CSF) in keratinocytes, which strongly resembles the psoriatic phenotype found in humans. Finally, inhibition of IL-17A in humans consecutively resulted in reductions in hyperplasia and infiltration of the dermis and epidermis [52].”
References 51 and 52 were published in 2006 and 2012 (the latter is a paper co-authored by Prof Krueger).
565. Counsel for Genentech
also sought to contrast Prof Krueger’s evidence concerning IL-17A/F with his evidence concerning two other therapeutic targets for psoriasis, namely CTLA4Ig and IFNγ.
“The current authors believe that IFN-γ is a pivotal cytokine in the development and maintenance of psoriatic lesions. Fig. 3 outlines a sequential pathway of type 1 T-cell activation, release of T-cell–derived cytokines, and production of several inflammatory mediators that the authors term the type 1 pathogenic pathway. IFN-γ is produced by effector memory CD8 + T cells, epidermal Tc1, CD4+ T cells, and NK and NK-T cells. Psoriatic CD8 + Tc1 cell lines and clones have been shown to produce heterogeneous levels of IFN-γ [15]. There is also evidence of the effects of IFN-γ at the tissue level in psoriatic lesions: keratinocytes show increased levels of HLA-DR, intercellular adhesion molecule-1 (ICAM-1) [27], and CD40 [28]; increased CXCR3 expression on lymphocytes [8]; and greater levels of keratinocyte-derived MIG and IP-10 [8]. Furthermore, this cytokine may also increase expression of costimulatory molecules on DCs [29]. IFN-γ potently activates macrophages and may also induce TNF-α release from monocytes and macrophages, which acts synergistically with IFN-γ in an inflammatory response [30]. Endothelial cells are also responsive to IFN-γ, up-regulating several adhesion molecules, such as ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1), which facilitates the complex process of leukocyte trafficking into tissues. The sum of cytokines and chemokines made in response to IFN-γ and TNF-α (see Fig. 3) can explain many features of the pathogenic process: angiogenesis and vascular ectasia, T-cell and neutrophil emigration into lesions, and some components of the psoriatic epidermal response.”
References 8, 15, 27, 28 and 30 were published prior to 2003, while reference 29 appears to have been published in June 2003.
568. Counsel for Genentech
pointed out that there was no proof that IFNγ was going to be a clinically effective target in psoriasis, but that did not prevent it from being a plausible target. That I accept, but I do not consider that this detracts from Prof Krueger’s evidence regarding the lack of plausibility of targeting IL-17, and in particular IL-17A/F. There was simply more evidence that IFNγ had a pathogenic role in psoriasis at that stage.
575. Prof Kamradt’s evidence . Although Prof Kamradt was not in a position to speak to the plausibility of the claims from the perspective of a dermatologist, counsel for Lilly
relied on his evidence by way of contrast to that of Prof Prens. Prof Kamradt said that “the two pillars of checking if something is a valid therapeutic target are … finding it overexpressed in the diseased tissue versus controls and finding a role in an animal model”. Neither of Prof Kamradt’s “pillars” is present in the Patent with respect to psoriasis.
578. Given that I have concluded that plausibility has not been established on the basis of the Patent and the common general knowledge, later evidence is not admissible to demonstrate plausibility. Genentech
did not in terms rely upon later evidence as supporting its case on plausibility, but did rely upon it in relation to infringement. Accordingly, I shall discuss the evidence relied on in that context. It is convenient to note here, however, that, so far as the evidence goes, no-one has made an antibody which binds to IL-17A/F, but not IL-17A/A, and tested its effect on psoriasis. As the Patent notes, it is theoretically possible that, by binding to IL-17A/F, such an antibody could remove a competitive antagonist to IL-17A/A, thus exacerbating IL-17A/A’s pro-inflammatory effects. Nor is there any evidence that blockade of IL-6 or IL-8 is therapeutically beneficial in psoriasis. Indeed, current evidence suggests otherwise. More generally, as Prof Krueger explained, there is later evidence that inhibition of IL-17A/F has failed as a treatment for three of the indications listed in the Patent, namely (i) chronic obstructive pulmonary disease, (ii) asthma and (iii) inflammatory bowel disease.
Insufficiency: other grounds
Ambiguity
579. Lilly
contend that the claims are insufficient because the requirement “which specifically binds to” is ambiguous if it is not construed in the manner contended for by
Lilly.
The short answer to this is that is not ambiguous on
Genentech’s
construction, which I have accepted, either.
Undue burden
580. Lilly
also contend that the claims are insufficient because it would be an undue burden on the skilled team to identify human or humanised antibodies that bind and inhibit IL-17A/F, not IL-17A/A (or IL-17F/F).
Genentech
contends that this insufficiency does not arise on its construction of the claims, since they are satisfied by antibodies that bind to IL-17A/F and IL-17A/A and there is no dispute that the skilled person can make such antibodies without undue burden. I do not accept this. It is well established that the specification must be sufficient to allow the invention to performed without undue burden across the full scope of the claims: see e.g. Regeneron Pharmaceuticals Inc v
Genentech
Inc [2013] EWCA 93, [2013] RPC 8 at [95] (Kitchin LJ, as he was). Here the claims plainly encompass anti-IL-17A/F only antibodies. If the skilled team cannot make such antibodies, or cannot do so without undue burden, then the claims are insufficient.
The development of ixekizumab
582. Lilly
rely as part of their case on the evidence of Dr Kikly concerning the development of ixekizumab. Having regard to my other conclusions, this evidence is of little relevance. I should nevertheless make the appropriate findings of fact in case they become relevant to any appeal.
584. In December 2002 the Lilly
team sent a third-party contractor a quantity of human IL-17A and requested it to generate antibodies specific to IL-17A. The contractor used a proprietary phage display technique to generate a pool of murine Fabs (antigen-binding fragments) specific to IL-17A.
Lilly
put these through initial tests, and selected an appropriately genetically diverse group of 10 individual Fabs to evaluate further in about July 2003. After the contractor had produced and purified further quantities of these, further tests were carried out, which showed (among other things) that none of the 10 Fabs cross-reacted with any of the other IL-17 family members then known.
586. The result of this work was the identification and presentation of a lead candidate (Mab 2321 also known as LA426-2321) to Lilly’s
Program Sanction committee in May 2004. Mab 2321 was chosen on the basis of various criteria, including binding with high affinity to both human and cynomolgus IL-17A and specificity to IL-17A in that it did not cross-react with other IL-17 family members.
587. After having obtained Program Sanction, the Lilly
team proceeded to humanise Mab2321. This work was subsequently described in Liu et al , “Generation and characterization of ixekizumab. A humanized monoclonal antibody that neutralizes interleukin-17A”, J Infl Res , 9, 39-50 (2016). In summary, six humanised versions were created. Four of these Mabs were subjected to various tests. In May 2005 the humanised antibody LY2439821 (later named ixekizumab) was selected as a candidate for human clinical trials for RA and multiple sclerosis.
588. Between May 2005 and July 2006 the Lilly
team carried non-clinical pharmacology studies on LY2439821. A Phase I safety, tolerability and efficacy study in patients with RA receiving background disease-modifying drugs (DMARDs, a diverse group of drugs such as methotrexate which slow the progression of RA) was carried out between November 2006 and February 2008. The results were positive. A Phase II dose-ranging study in patients with concomitant DMARD therapy was commenced in August 2009.
590. Ultimately, Lilly
applied for an EU marketing authorisation for psoriasis and psoriatic arthritis on 23 April 2015. The marketing authorisation was granted almost exactly a year later.
592. Once they knew of IL-17A/F, Lilly
took it upon themselves to undertake various studies to establish its relevance or otherwise to ixekizumab. Initial studies showed that ixekizumab did not interfere with the binding of IL-17A/F in an
ELISA
obtained from a commercial source. At that stage
Lilly
could not carry out experiments with IL-17A/F itself as they did not have a readily available source of the heterodimer. Once it became commercially available,
Lilly
carried out further tests between February 2010 and April 2011. The key information
Lilly
ascertained as a result of these tests is included in paragraph 595 sub-paragraphs (i) and (iv) below.
593. Ixekizumab is the subject of a family of patents obtained by Lilly.
Infringement
Ixekizumab
594. Ixekizumab is a recombinant humanised IgG4 monoclonal antibody. Its sequence and various other properties are set out in Lilly’s
Amended Confidential Product Description. For present purposes the only points that matter are as follows:
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.
Which specifically binds to
595. There is no dispute that, as I have construed this requirement of the claims, it is satisfied by ixekizumab. (Nor is there is any dispute that ixekizumab inhibits the activity of IL-17A/F to induce the production of IL-6 and IL-8, a matter which Genentech
established by experiment.) Accordingly, dealings in ixekizumab would infringe claims 1, 2, 14 and 15 if valid.
596. Genentech
contends that, even if the claims are construed as limited to antibodies which bind only to IL-17A/F, dealings in ixekizumab infringe by virtue of the doctrine of equivalents established by the decision of the Supreme Court in Actavis v
Lilly
(cited above).
598. In my judgment the answers to the three questions identified by Lord Neuberger in Actavis v Lilly
at [64] are as follows:
i) Does the variant achieve substantially the same result in substantially the same way as the invention? The variant on this hypothesis would be an antibody which inhibited IL-17A/A as well as IL-17A/F, rather than just IL-17A/F. On current evidence, both of these are pro-inflammatory molecules involved in the pathogenesis of psoriasis, and which act upon the same receptor and through the same inflammatory pathways. It is theoretically possible that inhibiting just IL-17A/F may increase inflammation, but there is no evidence that this is actually the case (see further paragraph 605 below). It is more probable that an antibody which binds and inhibits IL-17A/A as well as IL-17A/F has an extra effect, but that in my view does not detract from the proposition that the variant does achieve substantially the same result in substantially the same way.
ii) Would it be obvious to the skilled person reading the Patent at the priority date, but knowing that the variant achieves substantially the same result as the invention, that it does so in substantially the same way as the invention? There are likely to be few cases in which this question will be answered in the negative. In the present case the answer must be yes.
iii) Would the reader conclude that the patentee nevertheless intended that strict compliance with the literal meaning of the claims was an essential requirement of the invention? The skilled addressee would see that there is nothing in the Patent to indicate that it is essential to the invention that the antibodies should bind to IL-17A/F only when used for therapeutic purposes. Even were the scope of the Patent’s claims to be limited due to considerations concerning other applications as Lilly
contends, the skilled addressee would not see those as applicable or relevant when considering therapy. On the contrary, binding IL-17A/A in addition to IL-17A/F would be seen as likely to be beneficial.
Use … for: contribution of inhibition of IL-17A/F to the therapeutic effect
600. Although it is common ground that ixekizumab has been shown to be efficacious in the treatment of psoriasis, ixekizumab binds to both IL-17A/A and IL-17A/F. As Prof Prens acknowledged, these is no direct evidence of IL-17A/F having been found in psoriasis lesions or of it being upregulated compared to normal skin. Genentech
nevertheless contends that there is evidence that IL-17A/F has a pathogenic role in psoriasis, such that inhibition of IL-17A/F would be expected to make a contribution to the therapeutic effect of ixekizumab.
Genentech
relies upon four items of evidence.
601. First, Genentech
relies on the European Medicines Agency’s assessment report relating to Taltz dated 25 February 2016 which states (at paragraph 2.1) that the “biologically active form of IL-17A consists of either IL-17A homodimers or IL-17A-IL-17/F heterodimers”. Dr Kikly accepted that the document was based on information by
Lilly
and therefore this statement represented
Lilly’s
understanding at that date. She was not asked about the meaning of this statement, however. In her witness statement, she had referred to tests
Lilly
carried out to see “whether IL-17A/F was biologically active (i.e. could activate human cell receptors)”, which were in vitro tests. The results corroborate Figure 5 of the Patent, but no more.
602. Secondly, Genentech
relies upon a passage in Papp et al , “Brodalumab, an anit-interluekin-17-receptor antibody for psoriasis”, New Eng J Med , 366, 1181-1189 (2012), of which Prof Krueger was a co-author (at page 1187):
“Increased understanding of the immunopathogenesis of psoriasis has led to the development of multiple biologic drugs targeting specific molecules that are essential for the development of psoriatic plaques. Overproduction of interleukins 17A, 17F, and 17A/F induces the expression of proinflammatory cytokines with pathologic consequences, including the proliferation of keratinocytes and inflammation of epithelial cells in psoriasis. Therapies targeting this pathway, including interleukin-17 and interleukin-17R, are currently under investigation for the treatment of inflammatory conditions, such as psoriasis and rheumatoid arthritis. 19,28-30 Brodalumab, which targets interleukin-17RA, blocks signalling of interleukins 17A and 17F and the interleukin-17A/F heterodimer, all of which play a role in the inflammation of psoriasis.”
604. Thirdly, there is evidence in the post-July 2003 literature and in Lilly’s
own Investigators’ Brochure that both IL-17A and IL-17/F are upregulated in psoriasis lesions. Prof Prens’ opinion was it was therefore it was inherently likely that T cells in psoriasis lesions also expressed IL-17A/F. Prof Krueger’s opinion was that this did not necessarily follow, since there was evidence that some T cell clones expressed IL-17A and others IL-17F.
605. Fourthly, and most importantly, Genentech
relies upon Liang et al , “An IL-17A/F heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment”, J Immunol , 179, 7791-1199 (2007). This shows that differentiated T cells expressed IL-17A/F in significantly higher amounts than either IL-17A or IL-17F. Although this was an in vitro test, it was common ground between the experts that differentiated T cells are an approximation to how T cells present in vivo in peripheral organs (such as skin) respond after secondary stimulation. Prof Prens considered that this supported the hypothesis that T cells in psoriatic lesions expressed IL-17A/F. Prof Krueger maintained that one did not know what the position was in vivo until one had done the test, a point that Prof Prens accepted.
606. For the purposes of infringement, the question to be answered is whether inhibition of IL-17A/F makes a more than insignificant contribution to the therapeutic effect of ixekizumab. Genentech
bears the burden of proof on this question, and it has not carried out any experiment to establish that there is such a contribution (but nor has
Lilly
established by experiment that there is not). Counsel for
Genentech
accepted that there was no evidence which clearly established the position one way or the other. He nevertheless submitted that, on the available evidence, it was more likely than not that it did. Having regard in particular to the Liang paper, I accept that submission.
Infringement of claims 1 and 2
607. Claim 1 and 2 are straightforward product claims. Genentech
alleges infringement of these by
Lilly
pursuant to section 60(1)(a) of the Patents Act 1977.
Lilly
admits that
Eli
Lilly
& Co Ltd has kept, disposed of and offered for disposal Taltz, the active ingredient of which is ixekizumab, and that
Eli
Lilly
& Co is jointly liable for those acts. Accordingly, it follows from my previous conclusions, that if claims 1 and 2 are valid, they have been infringed by
Lilly.
Infringement of claims 13, 14, 15 and 22
608. Claims 13, 14, 15 and 22 are all EPC2000 purpose-limited product claims. Genentech
alleges infringement of these by
Lilly
pursuant to section 60(1)(a) alternatively section 60(2). It is sufficient to deal with
Genentech’s
case under section 60(2).
609. Genentech
contends that Taltz is means relating to an essential element of the invention of these claims and that
Eli
Lilly
& Co and
Eli
Lilly
& Co Ltd know, or it is obvious, that the means are suitable and intended for putting the invention into effect in the UK.
610. The law on the mental ingredient of infringement under section 60(2) was set out in Grimme Landmaschinenfabrik GmbH & Co KG v Scott [2010] EWCA Civ 1110, [2011] FSR 7 at [105] and KCI Licensing Inc v Smith & Nephew plc [2010] EWCA Civ 1260, [2011] FSR 8 at [53] . In summary, it is enough if (at the time of supply or offer to supply) the supplier knows (or it is obvious to a reasonable person in the circumstances) that some ultimate users will intend to put the invention into effect in the UK using the “means essential”.
612. Further, I find that Eli
Lilly
& Co and
Eli
Lilly
& Co Ltd know (or at least it is obvious) that some ultimate users will intend to put the invention into effect. As mentioned above, Taltz is authorised for the treatment of psoriasis. Further,
Eli
Lilly
& Co and
Eli
Lilly
& Co Ltd know (or it is obvious) that ixekizumab acts as an IL-17A/F antagonist. The only question is whether they know (or it is obvious) that inhibition of IL-17A/F makes a more than insignificant contribution to the therapeutic effect of ixekizumab. In my judgment
Lilly
acquired this knowledge, or it became obvious to a reasonable person, as a result of the evidence given at trial, although I am not satisfied that this was the case before that. I will fix the relevant date as the last day of the trial (1 February 2019).
613. Accordingly, it follows from my previous conclusions that, if valid, Eli
Lilly
& Co and
Eli
Lilly
& Co Ltd have infringed these claims by acts committed since 1 February 2019.
Infringement of claims 12 and 20
614. Claims 12 and 20 are Swiss form claims directed to the treatment of, so far as relevant to infringement, psoriasis. Genentech
alleges infringement of these by
Lilly
pursuant to section 60(1)(c). In Warner-Lambert (cited above) the Supreme Court divided 2:2:1 on question of whether infringement of Swiss form claims pursuant to section 60(1)(c) involved a mental element, and if so what it was. Moreover, all of the judgments on this question were obiter.
615. In the present case, however, I do not think it matters which test is to be applied for the purposes of claims 12 and 20. This is because (i) the parties alleged to infringe and the manufacturers of Taltz are Lilly
companies, (ii)
Lilly
intend that Taltz is to be used for the treatment of psoriasis and (iii) the outward presentation of Taltz makes it clear that it is for use for the treatment of psoriasis. Counsel for
Lilly
submitted that there was no evidence of (ii) and (iii), but I disagree: both facts are plain from the marketing authorisation for Taltz.
616. Accordingly, it follows from my previous conclusions that, if valid, Eli
Lilly
& Co and
Eli
Lilly
& Co Ltd have infringed these claims.
Infringement of claims 13, 14 and 20 if conditionally amended
617. Genentech’s
conditional amendments to claims 13, 14 and 20 incorporate the language “[for use] as an antagonist of the IL-17A/F heterodimeric complex” or “[for] antagonizing the IL-17A/F heterodimeric complex”. This potentially gives rise to a difficult question on infringement. Although
Genentech
made written submissions on it,
Lilly
barely addressed it. Given my other conclusions, the issue does not arise. I should, however, make a finding of fact in case the issue becomes live in another court. That concerns the date on which
Lilly
acquired knowledge of the antagonistic effect of Taltz on IL-17A/F, if at all.
Genentech
contends that
Lilly
had such knowledge at least from the date of its application for a marketing authorisation. I accept that contention.
Summary of principal conclusions
618. 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.