Regeneron Pharmaceuticals Inc. v Kymab Ltd and Another

Hearing dates: 18–20, 23–27, 30 November and 7 & 8 December 2015

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.

Introduction

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.

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.

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.

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.

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

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 to his written closing speech which set out key aspects of the technology and which did not, as a general matter, appear to be controversial. After conclusion of the oral hearing, and at my request, Michael Tappin QC and James Whyte, who appeared for Kymab, informed me of two points of substance in relation to the Annex which were in issue, and I have altered it to take account of them. The result is a relatively short summary, some parts of which I include as technical background, and which has the virtue of being agreed between the parties. This approach might be considered in other patent cases involving very complex technology. It requires co-operation between the parties' representatives, who deserve considerable credit for achieving this in the present case. I have added some diagrams from the Technical Primer to illustrate certain aspects of the text.

The following was common general knowledge at the priority date. Later in this judgment I will deal with matters where there is a dispute as to common general knowledge.

Monoclonal antibodies

By the priority date the potential uses of antibodies for use in treating human disease had been well recognised, and a number of different antibodies had been developed and approved for use, including:

(a) Muromonab-CD3 (anti CD3) approved in 1986, which was one of the earliest examples of a mouse monoclonal antibody;

(b) Abciximab (glycoprotein IIb/IIIa) approved in 1994, a chimeric antibody;

(c) Daclizumab (anti CD25) approved in 1997, a humanised antibody;

(d) Rituximab (anti CD20) approved in 1997, which was one of the best known...