Eli Lilly and Company v Janssen Alzheimer Immunotherapy
| Jurisdiction | England & Wales |
| Judge | Mr Justice Arnold |
| Judgment Date | 25 June 2013 |
| Neutral Citation | [2013] EWHC 1737 (Pat) |
| Date | 25 June 2013 |
| Court | Chancery Division (Patents Court) |
| Docket Number | Case No: HC11C03400 |
[2013] EWHC 1737 (Pat)
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Royal Courts of Justice, Rolls Building
Fetter Lane, London, EC4A 1NL
The Hon Mr Justice Arnold
Case No: HC11C03400
Andrew Waugh QC and Thomas Mitcheson (instructed by Simmons & Simmons) for the Claimant
Simon Thorley QC and Charlotte May (instructed by Linklaters LLP) for the Defendant
Hearing dates: 24 26, 29 30 April, 1, 3 May 2013
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 | 2–9 |
| Lilly's witnesses | 2–4 |
| JAI's witnesses | 5–9 |
| Technical background | 10–105 |
| The structure of the brain | 12–18 |
| The cells of the brain | 19–21 |
| Amyloidosis | 22–23 |
| AD | 24–30 |
| Aβ | 31–38 |
| Transgenic mouse models | 39–41 |
| Approaches to the treatment of AD | 42 |
| Blood-brain barrier | 43–46 |
| Innate and adaptive immunity | 47–51 |
| Phagocytosis | 52–54 |
| Antigen-Presenting Cells | 55–57 |
| T cells | 58–62 |
| B cells | 63–70 |
| The structure of antibodies | 71–75 |
| Antibody classes or isotypes | 76–80 |
| Fc receptor-mediated phagocytosis | 81–84 |
| The complement pathways | 85–86 |
| Antibody-dependent cellular cytotoxicity (ADCC) | 87–88 |
| Plasma half-life of antibodies | 89 |
| Monoclonal antibodies | 90–95 |
| Active and passive immunisation | 96–105 |
| The Patent | 106–149 |
| Background | 107–109 |
| Summary of the claimed invention | 110 |
| Definitions | 111 |
| Detailed description | 112–121 |
| I General | 113 |
| II Therapeutic Agents | 114–117 |
| III Patients Amendable to Treatment | 118 |
| IV Treatment Regimes | 119–120 |
| V Diagnosis | 121 |
| Examples | 122–149 |
| I Prophylactic Efficacy of Aβ Against AD | 123–126 |
| II Dose Response Study | 127 |
| III Screen for Therapeutic Efficacy Against Established AD | 128–136 |
| IV Screen of Aβ Fragments | 137–139 |
| V Preparation of Polyclonal Antibodies for Passive Protection | 140 |
| VI Passive Immunization with Antibodies to Aβ | 141–143 |
| VII Comparison of Different Adjuvants | 144 |
| VIII Immunse Responses to Different Adjuvants in Mice | 145 |
| IX Therapeutic Efficacy of Different Adjuvants | 146 |
| X Toxicity Analysis | 147 |
| XI Prevention and Treatment of Subjects | 148–149 |
| The claims | 150 |
| The skilled team | 151–153 |
| Common general knowledge | 154–161 |
| Terminology with regard to Aβ | 156 |
| Methods for assisting the passage of antibodies across the BBB | 157–159 |
| Effect of CFA on the BBB | 160 |
| Aβ as a target for AD research | 161 |
| Matters that were not common general knowledge | 162–168 |
| The Schenk Paper | 163–166 |
| DeMattos 2001 and the peripheral sink hypothesis | 167–168 |
| Construction | 169–206 |
| Immune response | 171–181 |
| An antibody to Aβ | 182–189 |
| For use in preventing or treating a disease characterised by amyloid deposit in a patient | 190–204 |
| Aggregated Aβ | 205 |
| Dissociated Aβ | 206 |
| Added matter | 207–217 |
| Disclosure of an antibody which does not induce an immune response | 209–215 |
| Disclosure of an antibody that is of the human IgG1 isotype | 216–217 |
| Novelty | 218- |
| Konig | 220–226 |
| Disclosure of human IgG1? | 227–229 |
| Disclosure of efficacy? | 230 |
| Obviousness | 231–247 |
| The law | 231–233 |
| Obviousness of claim 1 over Konig | 234–245 |
| Obviousness of claim 1 over Becker | 246 |
| Agrevo obviousness | 247 |
| Insufficiency | 248–313 |
| The law | 248–257 |
| Classical insufficiency | 250 |
| Excessive claim breadth | 251 |
| Post-dated evidence | 252–257 |
| The facts | 258–313 |
| Is it plausible? | 259–271 |
| Can the invention be performed without undue burden? | 272–297 |
| Is the claim of excessive breadth? | 298–313 |
| Infringement | 314–353 |
| Is solanezumab specific for monomeric Aβ? | 319–343 |
| Does solanezumab which crosses the BB induce any downstream effects? | 344 |
| Does solanezumab affect the equilibrium in the brain? | 345–348 |
| Does solanezumab induce FcRn-mediated clearance? | 349–353 |
| Summary of main conclusions | 354 |
Introduction
The Defendant ("JAI") is the proprietor of European Patent (UK) No. 1 994 937 ("the Patent") entitled "Prevention and treatment of amyloidogenic disease". The Patent discloses and claims pharmaceutical compositions comprising an antibody to β-amyloid peptide, also referred to as amyloid-β or Aβ. The Patent is one of four patents granted pursuant to divisional applications from a parent application which matured into EP 1 033 996. The Claimant ("Lilly") seeks an order for revocation of the Patent and a declaration that dealings in pharmaceutical compositions comprising an antibody called solanezumab, which Lilly currently has in Phase 3 development for the treatment of Alzheimer's Disease ("AD"), will not infringe the Patent. Lilly attacks the validity of the Patent on the grounds of added matter, lack of novelty, obviousness, and insufficiency. There is no challenge to the claimed priority date of 2 December 1997. JAI has applied to amend the Patent by deleting claims 13, 14 and 15 and by omitting two words from claim 11. That application is unopposed.
The witnesses
Lilly's witnesses
Lilly called a single expert witness, Professor Thomas Wisniewski. Prof Wisniewski has been Professor of Neurology, Pathology and Psychiatry at New York University ("NYU") School of Medicine since 2005. He obtained an MBBS from King's College London ("KCL") in 1983. He moved to New York in 1984 to pursue his interest in neurodegenerative research. Having completed residences in Anatomical Pathology, Neurology and Neuropathology at NYU Medical Center and Columbia University, in 1990 he took up an academic position as Clinical Instructor in Neurology at NYU. From 1990 to 1994 he worked with the immunologist Professor Blas Frangione. He became an Assistant Professor of Neurology and Pathology in 1992 and a tenured Assistant Professor of Neurology, Pathology and Psychiatry in 1999. He has been Director of the Conformational Disorders Laboratory at NYU since 1997 and Director of the Neuropathology Core of the NYU AD Center since 2002. He has held a number of other academic and hospital appointments. These positions allow him to divide his time equally between treating patients and research. His research focuses on neurodegenerative disorders, in particular the pathogenesis and treatment of AD and prion-related diseases. He has been on the editorial boards of several academic journals. He has published 217 full length peer-reviewed publications. He has won a number of awards. He is a named inventor on a number of patents. He was an investigator in the Phase 3 trials of both JAI's product bapineuzumab and Lilly's product solanezumab.
Prof Wisniewski had expertise in neuroscience, immunology and clinical treatment. Counsel for JAI rightly accepted that Prof Wisniewski was both highly expert and gave his evidence clearly and fairly, but submitted that on some points Prof Wisniewski had had difficulty in putting himself in the position of the addressee of the Patent rather than viewing matters from his own perspective. I think there is some force in this, and I have taken this into account when assessing his evidence.
In addition, Lilly adduced unchallenged factual evidence from Dr Ronald DeMattos. He obtained a PhD in Molecular and Cellular Biochemistry from the State University of New York at Stony Brook in 1998. From October 1998 to June 1999 he held a post-doctoral position at Stony Brook. From June 1999 to 2002 he held a post-doctoral position in David Holtzman's laboratory at Washington University School of Medicine. In September 1999 he received funding for a project to analyse physiologically relevant apolipoprotein/Aβ interactions in mouse models of AD. This work led first to the filing of US Patent Application 60/184601 in February 2000 (and later to further patent applications) and secondly to the publication of DeMattos et al, "Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases Aβ burden in a mouse model of Alzheimer's disease", PNAS, 98(19), 8850–885 (2001) ("DeMattos 2001") on 17 July 2001. This was the starting point for the development of solanezumab. In late 2002 Dr DeMattos joined Lilly, where he is now a Research Fellow in Neuroscience Discovery Research. In his witness statements Dr DeMattos described aspects of the development of solanezumab.
JAI's witnesses
JAI called two expert witnesses, a neuroscientist, Professor Paul Francis, and an immunologist, Dr Michael Owen. Prof Francis is Professor of Neurochemistry at KCL. He obtained a BSc in Physiology and Biochemistry from the University of Reading in 1979 and a PhD in Neuroscience from the same institution in 1984. From 1982 to 1990 he was a Post-Doctoral Research Fellow and from 1990 to 1995 an Honorary Lecturer at the Institute of Neurology, Queen Square. In 1995 he became Senior Lecturer in Biochemistry and Molecular Biology at the United Medical and Dental Schools of Guy's and St Thomas' Hospitals, which merged with KCL in 2000. He was appointed Reader in 2004 and Professor in 2008. In 2008 he also became Director of Brains for Dementia Research. He is the author of over 122 publications in refereed journals. His research includes work on the mechanisms of AD and other types of dementia, such as frontotemporal dementia, Lewy body dementias and vascular dementia. He has been involved in some clinical trials relating to AD, in particular a trial of memantine in people with Down's syndrome.
As counsel for Lilly pointed out, Prof...
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