Eli Lilly and Company v Genentech, Inc.
| Jurisdiction | England & Wales |
| Judge | Mr Justice Arnold |
| Judgment Date | 01 March 2019 |
| Neutral Citation | [2019] EWHC 387 (Pat) |
| Docket Number | Case No: HP-2017-000041 |
| Court | Chancery Division (Patents Court) |
| Date | 01 March 2019 |
[2019] EWHC 387 (Pat)
IN THE HIGH COURT OF JUSTICE
BUSINESS AND PROPERTY COURTS
INTELLECTUAL PROPERTY LIST (CHANCERY DIVISION)
PATENTS COURT
Rolls Building
Fetter Lane, London, EC4A 1NL
Mr Justice Arnold
Case No: HP-2017-000041
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
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.
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 |
| TH1/TH2 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 |
| ELISA | 119–124 |
| 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 of IL-8 and L-6 | 313 |
| 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 as well as IL-17A/A | 482–485 |
| Structures of IL-17A, IL-17 F/F IL-17A/F and binding to receptors | 486–497 |
| 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 range of effects of IL-17A | 553 |
| 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 amended | 617 |
| Summary of principal conclusions | 618 |
Introduction
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.
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.
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...
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