Regeneron-v-Kymab - eplaw

[pic] Neutral Citation Number: [2016] EWHC87 (PAT) Case No: HP-2013-000001/HP-2014-000001
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT Royal Courts of Justice
Rolls Building
Fetter Lane
London
EC4A 1NL Date: 01/02/2016 Before : THE HON MR JUSTICE HENRY CARR
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Between : | |Regeneron Pharmaceuticals Inc | |
| | | |
| |Claimant | |
| |- and - | |
| |Kymab Limited | |
| |Novo Nordisk A/S | |
| |Defendants | |
| | | | - - - - - - - - - - - - - - - - - - - - -
- - - - - - - - - - - - - - - - - - - - - Justin Turner QC, Joe Delaney and William Duncan (instructed by Allen &
Overy LLP) for the Claimant
Michael Tappin QC & James Whyte (instructed by Powell Gilbert LLP) for the
First Defendant
Piers Acland QC (instructed by DLA Piper UK LLP) for the Second Defendant
Hearing dates: 18-20, 23- 27, 30 November and 7 & 8 December 2015
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Approved Judgment
I direct that pursuant to CPR PD 39A para 6.1 no official shorthand note
shall be taken of this Judgment and that copies of this version as handed
down may be treated as authentic.
............................. MR JUSTICE HENRY CARR
Introduction 4 Technical Background 5
Monoclonal antibodies 5
VDJ recombination / somatic hypermutation 6
Immunoglobulin Locus Size 8
Transgenics 10
Targeting Vectors 10
Screening for Integration 12
Making Targeting Vectors 13
BACs and BAC Libraries 13 The Expert Witnesses 14
Sir Martin Evans 14
Professor Stewart 14
Professor Ploegh 15
Professor Howard 16 The Witnesses of Fact 17
Dr Andrew Murphy 17
Dr Yancopoulos, Professor DeFranco and Professor Ishida 17
Dr Friedrich 17 The Skilled Team 17 Common General Knowledge 18
An undiscovered 5' enhancer (construction and infringement) 18
Size of insertions and deletions by homologous recombination (sufficiency)
20
Homology arms (sufficiency) 20
Site-specific recombination (sufficiency) 21
RMCE 21
Recombineering 22
BACs and BAC libraries (sufficiency) 23
Modifying the endogenous mouse Ig loci (inventive step) 24
Inactivating the endogenous murine locus (construction) 30 The Patents 30
LTVECs and the MOA assay 30
Example 1 34
Example 2 35
Example 3 36
Materials and Methods of Example 3 38
The first proposed approach 38
The second proposed approach 40
The light chains 41 The Claims in Issue 41
In situ replacement 43
Assessment 49
Scope of Claim 1 of 287 49 Claims 5 and 6 of the 287 Patent 50 Claim 1 of the 163 Patent 51 Infringement 52
Inversion and displacement upstream of mouse sequences 54
Infringement of the claims in issue 55 Sufficiency 56
Legal principles 56
Ordinary methods of trial and error/undue burden 57
Excessive claim breadth 58
Insufficiency: the facts 61
Claim 1 of 287 - breadth of claim 61
Regeneron's work 63
The second proposed approach of Example 3 64
The importance of Example 3 64
The Macdonald paper 65
Multiple insertions without deletion 67
Repetition of the homologous recombination process 68
Assessment of insufficiency 71
Further insufficiency objections 71
Effect of long homology arms 71
The reduced amount of DNA 72
MOA Improvements 74
Identifying the 5' end 74
Submissions following circulation of the draft judgment 75 Cross-anticipation 78 The Prior Art 79
Kucherlapati 79
Brüggemann 1997 81 Added Matter 83
Legal Principles 83
The 287 Patent 83
The 163 Patent 86 Conclusion 87 Mr Justice Henry Carr:
Introduction
1. This is a claim brought by the Claimant ("Regeneron") for infringement
of European Patent (UK) No. 1 360 287 ("the 287 Patent") and European
Patent (UK) No. 2 264 163 ("the 163 Patent"). The 163 Patent is a
Divisional of the 287 Patent. The specifications are the same in all
material respects, although the claims are different. The claimed
priority date of the patents is 16 February 2001. The patents
generally relate to transgenic mice that can be used as platforms for
therapeutic antibody discovery. More specifically, they concern the
replacement of mouse variable (VDJ/VJ) gene with human variable genes
to produce immunoglobulin loci that will undergo the natural process
of rearrangement during B cell development to produce hybrid
antibodies. A locus comprising a combination of human variable gene
segments and endogenous mouse constant gene segments is known as a
"reverse chimeric locus". Subsequently, fully human antibodies can be
made by replacing the mouse constant regions with the desired human
counterparts.
2. The first Defendant ("Kymab") is offering to the pharmaceutical
industry various strains of transgenic mice that are alleged, either
per se or through the process by which they are produced, to infringe
the patents. Kymab denies infringement and counterclaims for
revocation. The second Defendant ("Novo") was alleged to be jointly
liable with Kymab for infringement in the United Kingdom. However the
claim against Novo in these proceedings was abandoned shortly before
the start of the trial. Novo nonetheless maintained its challenge to
the validity of both patents. Novo adopted Kymab's Grounds of
Invalidity and its opening and closing submissions.
3. There have been concurrent opposition proceedings before the EPO in
respect of the 287 Patent, in which Kymab and Novo were opponents. The
163 Patent was granted on 14 October 2015 and will be subject to
opposition at the EPO. The parties agreed to its late introduction
into these proceedings as the issues in respect of both patents are
similar. By a decision dated 28 November 2014 the Opposition Division
revoked the 287 Patent. Shortly before the UK trial the Technical
Board of Appeal allowed an amended claim set in respect of the 287
Patent and the trial has proceeded on the basis of those amended
claims. Consequential amendments to the specification have not yet
been made by Regeneron. However, I was told that they are unlikely to
be significant. Although the result of the hearing before the TBA is
known, the written reasons for its decision have not yet been handed
down.
4. Only claims 5 and 6 of the 287 Patent and claim 1 of the 163 Patent
are alleged to be infringed. Claim 1 of the 287 Patent is relevant to
the construction of claims 5 and 6 and to the issues of validity that
I need to consider. The parties did not suggest that I needed to
consider any other claims in order to resolve the issues raised in
these proceedings.
5. Kymab challenges validity on the basis of insufficiency. Kymab also
claims "cross-anticipation" based on alleged loss of priority (i.e.
that the patents are anticipated by matter that retains priority in
the application for the other patent). It alleges lack of novelty and
lack of inventive step in the light of PCT/US91/00245 published as WO
91/10741 on 25 July 1991 ("Kucherlapati"); and obviousness in the
light of publication entitled "The Preparation of Human Antibodies
from Mice Harbouring Immunoglobulin Loci" published in 1997 in the
textbook "Transgenic animals; generation and use" ("Brüggemann 1997").
It also pursued an attack of lack of inventive step in the light of US
Patent 5,770,429 ("Lonberg"). However, Lonberg was abandoned by Kymab
in its written closing speech following conclusion of the evidence.
Finally, it pursues an attack of added matter against claim 1 of the
287 Patent, which, if successful, would lead also to invalidity of
claims 5 and 6 of that patent; and against the 163 Patent.
Technical Background
6. The subject matter of the patents and the prior art is of great
technical complexity, and there are lengthy textbooks concerning
genetic engineering and immunology, which are the relevant areas of
expertise. The parties prepared an agreed Technical Primer. Although
I found it very helpful as an introduction to the technology, it is
too long to reproduce in this judgment. Justin Turner QC, who appeared
with Joe Delaney and William Duncan for Regeneron, attached an Annex