Approved Judgment - EPLAW Patent Blog


Dec 5, 2012 (4 years and 6 months ago)


Neutral Citation Number:
[2012] EWCA Civ 1234

Case No








The Hon Mr Justice Arnold


Royal Courts of Justice

Strand, London, WC2A 2LL





























MedImmune Limited





Novartis Pharmaceuticals UK Limited


Medical Research Council

And Between:

Novartis Pharmaceuticals UK Limited


(1) MedImmune Limited

(2) Medical Research Council


Part 20













































Roger Wyand QC, Richard Meade QC

and Tom Mitcheson

(instructed by

Marks & Clerk Solicitors LLP
on behalf of MedImmune Limited

Simon Thorley QC, Justin Turner QC and Joe Delaney

(instructed by

Allen & Overy LLP
appeared on behalf of Novartis Pharmaceuticals UK Limited

Hearing dates :
11 July 2012






















Approved Judgment

Judgment Approved by the court for handing down.

MedImmune v Novartis

Lord Justice Kitchin



These appeals concern two judgments of Arnold J given in related
proceedings. In
action HC09C047
70 MedImmune Limited (


), formerly known as
Cambridge Antibody Technology Limited (


), alleged Novartis Pharmaceuticals
UK Limited (


) h
ad infringed Europea
n Patents (UK) Nos. 0 774 511
and 2
055 777 (“


or “the patent”) by selling a product called ranibizumab
which is used for the treatment of wet age
related macular degeneration of the eye.
Novartis di
sputed infringement a
nd counter
claimed for revocation of the patent


The judge held that both patents

were invalid on the grounds of obviousness and
because the claims were not entitled to priority from the relevant priority document, it
being conceded that if they were not e
ntitled to priority then the patents were invalid.
He also held the claims did not cover the process by which ranibizumab was made.
MedImmune was granted permission to appeal against the judge’s findings in respect
of both patents but has only pursued th
e appeal in respect of the 777 patent. It
contends the judge erred in making each of these findings. By way of respondent’s
notice, Novartis contends the judge ought additionally to have found the 777 patent
nvalid for insufficiency,

and that it was not

infringed for the further reason that
ranibizumab is not “obtained directly” by means of the claimed process.


In the second action HC11C01304, Novartis sought a declaration that a
Supplementary Protection Certificate (

the SPC

) granted in respect of the
777 patent
was invalid. It necessarily followed from the judge’s findings in the first action that
the SPC was invalid but the judge held that even on the hypothesis that his earlier
findings were wrong, the SPC was nonetheless invalid

because it
was gran
ted in
respect of a product which was not identified in the wording of the
claim as a
product deriving from the process in question
. MedImmune

appeals against that
further finding.


Upon these appeals

we have had the benefit of a scientific advisor, Professor Brian
Henderson of University Colleg
e London. Professor Henderson is
Professor of
Biochemistry at the UCL
Eastman Dental Institute
. Prior to the

hearing he
gave us

ins” about the back
ground technology. During the hearing he sat with us
and provided us with further assistance in understanding the technical issues. He has
also read through this judgment in draft for technical accuracy. At no time has
Professor Henderson expressed any opi
nion to us
about any of the
matters in di
He has been immensely helpful and we are very grateful to him.


At the outset of these appeals we decided to hear full argument on the obviousness
and priority issues. Having heard those arguments, we rea
ched the clear conclusion
that the judge’s decision on obviousness must be upheld and so informed the parties.
We also indicated that it appeared to us that conclusion was dispositive of both
appeals and that it would not be in the interests of justice to

hear further argument on
all the other issues. The parties agreed. We also indicated we would provide our
reasons in writing in the usual way. That I now do.

Judgment Approved by the court for handing down

MedImmune v Novartis

The patented technique

an outline


The 777 patent claims

from a number of applicatio
ns, but the only one of
relevance to these proceedings was filed on

12 Novembe
r 1990
. The patent
concerned with a
technique called antibody phage display
. The invention described in
the patent was developed by CAT

(as MedImmune was then known)
in close
operation with scientists at the Medical Research Council (“the MRC”) and the patent
is therefore jointly owned by MedImmune and the MRC. The MRC was joined to the
actions so as to be bound by their result, but has played no part in the proceedings.


tibody phage display provides a particularly advantageous way of selecting
desirable antibody fragments based upon their ability to bind to particular antigens.
The method makes use of
filamentous bacteriophages. Bacteriophages,
often referred

to simply as phages, are viruses which infect bacteria. They consist of
a protein coat or capsid encapsulating nucl
eic acid. Filamentous phages are non
meaning they are extruded from an infected bacterial cell which continues to live and
more phage
s. Filamentous

phages may be distinguished from lytic phages,
such as lambda phage
, which are
released when the host cell bursts.


A filamentous phage consists of a single
stranded DNA genome packe
d in a long tube
composed of
a protein coat
. One end comprises two proteins, one of which is called
pIII. This particular protein plays a vital role in the process of infection. It has three
domains; two N terminal domains extend from the phage surface,
the third, the C
terminal domain

is b
uried in the phage particle. The phage infects a bacterial cell
through long slender protein
aceous appendages called pili on the cell surface. The

is first bound by the N2 d
omain of pIII and then the
N1 domain
of pIII
binds to a
bacterial surface p
rotein. The phage DNA is then inserted into the b
cytoplasm where it is
used to make more DNA and for protein expression. When
enough DNA and p
rotein have been generated,
production of new phage particles
begins. Assembly of the new phages occ
urs in the cytoplasmic membrane of the
bacterium and various non
coat proteins create a ch
annel for the passage of each


out of the cell
. The DNA is extruded into the phage body
, the capsid
completed and the phage released from the bacterial


The 777 patent describes the generation of filamentous phage particles that have an
antibody fragment displayed on their surface by fusion to one of the viral coat
proteins, particularly the pIII protein, while the DNA sequence encoding that an
fragment is included within the genome inside the phage particle. The displayed
antibody fragment is correctly folded and functional when fused to
the viral coat

, so that it can bind to
its antigen or, more precisely, its target epitope. The
display of the antibody fragment on the phage surface means that the ability of the
displayed antibody fragment to bind
to an antigen can be tested
in vitro
. Typically
antigen is immobilised on a so
lid substrate and then presented with a library of
potential binders
, the phage antibody library. Those antibody fragments

that bind to
the antigen will attach to the immobilised antigen while those that do not bind can be
washed away. Once the non
rs have

been washed away, the selected phage
antibody can be released from the antigen by a process known as elution. The
essential elements of the process are

depicted diagrammatically below:

Judgment Approved by the court for handing down

MedImmune v Novartis


One of the key featu
res of phage display is that each

body fragment is physically
associated with the nucleic acid encoding its sequence
which is contained within the
phage upon which the antibody fragment is displayed
. Having selected the relevant

, the sequence of the antibody fragment polype
ptide can
readily be
elucidated by sequencing the DNA of
the phage which displayed it.

Further, t

allows scientists
to screen very large libraries of different antibody

The technical background


The invention required the bringing t
ogether of developments in two technologies,
antibody engineering and phage display.


Antibodies are protein molecules which are generated by an animal’s immune system
to assist in neutralising or destroying foreign matter, for example bacteria and viruses.

The surface of bacteria and viruses contains proteins. When such foreign proteins
enter the bloodstream, the immune system of the host recognises them as being
foreign and sets about trying to destroy or neutralise them by producing antibodies.
foreign molecule
s are known as

and the
in the


recognised by the antibodies

are called epitopes
. Each antibody locks on to
a single

epitope but, since each epitope is different, different antibodies have to be
made to loc
k on to each of them.


The structure of antibodies, the way they are generated and their functions are
described in the technical primer agreed betwe
en the parties and at

[62] of the
judgment. For the purpose of this appeal, I would emphasise the f


Antibodies are generated by specialist cells called B l
ymphocytes. Each cell can
a single design of antibody. Nevertheless, humans have the ability to
generate a vast array of different antibodies, in part by the rearrangement of
small genes encoding
variable part

of the antibody prote
in during B cell development

also by a process called affinity maturation in which the genes of
producing antibodies which have detected a particular antigen are hyper
mutated to
produce a further range of antibodies, with those clones producing higher affinity
antibodies being favoured.


here are five
classes of antibo
dies, the most prevalent being the

class known as
G (“IgG”). An IgG
comprises four chains

of amino acids
held together by chemical bonds
, specifically disulphide bonds
. There are two
identical long chains, referred to as
heavy (H) chains, and two identical short
chains, referred to as
light (L) chains

and they are all held together t
o create a
symmetrical Y
shaped molecule. Each of the chains contains a variable domain
Judgment Approved by the court for handing down

MedImmune v Novartis

located at the ends of
the arms of the Y
. These are referred to as the V

(heavy chain
variable) and V

(light chain variable) domains. The remaining domains are sai
d to
be constant. The domains are referred to as variable and constant to reflect the extent
to which the amino acid sequence
s in them vary

antibody molecule to
. In each of the heavy and light chain variabl
e domains there are three
variable regions, referred to
as complementarity
determining r
egions (



which define the antigen binding sites of the molecule. They sit on a scaffold of the
remaining parts of
the variable domains
called the framework regions.


This account
, whil
st technically accur
ate, does not adequately describe

the three
onal conformation

which the
molecule adopts in its natural state.
The ability of an antibody to bind to an antigen is critically dependent upon this three
dimensional conforma
tion and, specifically, the antigen
binding site of the antibody
(called the paratope) is determined by the three
dimensional conformation of the
CDRs and the adjacent framework residues.


As Dr
Huse, one of the experts who gave evidence on behalf o
f Novartis
explained, in seeking sources of antibodies for research, scientists have for decades
been able to enrich preparations of antibodies by inoculating a laboratory animal with
an antigen of interest and purifying
IgG from its serum. Such antib
odies are said
to be “polyclonal” because they comprise mixtures of different antibodies, each of
which binds to
a different epitope

on the same antigen.


In 1975
Köhler and
Milstein, working at the L
aboratory of Molecular
in Cambridge

developed a technique for making monoclonal antibodies, that
is to say antibodies which are homogeneous in structure and
have the same binding
properties. It involves the immunisati
on of a host, usually a rodent, harvesting its B
cells and fusing


with myeloma cells to produce
large numbers of
known as
Dilution of these cells allows individual hybridomas to be
isolated and cultured, a process termed cloning.
individual hybridomas (each of
which produces a single an
tibody) are then screened for the

clone producing
antibody with the desired properties. This is a laborious process and a positive result
is not guaranteed but, if successful, hybridoma cells
derived from the selected clone
can be used to make monoclon
al antibodies in substantial quantities.


ortant though it undoubtedly was and remains
the hybridoma technique has

number of significant limitations. First, it is limited to the antibody repertoir
e of the
. Second, monoclonal antibodies derived
from rodent hybridoma cells are
strongly immunogenic

in human
s and induce

an immune

response known as the

mouse antibody or HAMA

response which can neutralise their biological
and clinical effects.


Attempts were therefore made to adapt the h
ybridoma technique to
antibodies from human B

cells. Unfortunately this did not prove possible for a

of reasons. First, human cell
derived hybridomas are not as productive as
their rodent equivalents and are unstable. Second, it is diffic
ult to select human
antibodies against particular antigens because of the ethical issues involved in
immunising human volunteers with antigens.


During the 1980s a good deal of research was therefore carried out into methods for
obtaining mouse monoclonal a
ntibodies and then making them compatible with the
Judgment Approved by the court for handing down

MedImmune v Novartis

human immune system while maintaining antigen specificity and affinity.

was to fuse the antigen
binding variable region of a mouse antibody to a
human constant region to create a “chi
maeric a
ntibody”. This
preserved the antigen
inding ability of the mouse
antibody while reducing, but not eliminating

immune re
sponse. A further development

called CDR grafting, or simply
humanisation, involved taking the CDRs of a mouse antibody and
inserting them into
a homologous huma
n antibody framework, or
changing the human antibody CDRs to
the desired mouse sequences. Unfortunately, it was found that putting mouse CDRs
into a human framework resulted in a significant loss of affinity.


The early

1980s saw another significant development, namely the polymerase chain
reaction (PCR). This is a powerful and versatile me
thod for copying DNA and allows

scientists to amplify and isolate particular genes of interest. In the context of
hybridoma technol
PCR allowed scientists to amplify
the antibod
y genes in the
hybridoma cells
and then humanised or chimaeric antibodies could be made by
manipulation of those genes.

It also allowed scientists easily to make parts of IgG
molecules using recombinant met
hods. For example, it was possible to make each of
the two arms of the molecule, called Fab (Fragment antigen
binding) fragments

the variable domains, called Fv (Fragment variable) fragments.


These techniques also required an expression system
, howeve
. It was known that
antibodies and antibody fragments could be expressed recombinantly in eukaryotic
cells such as Chinese Hamster Ovary (CHO) cells or mouse myeloma cells. But these
were rather cumbersome to manipulate. Bacterial expression s
ystems we
recognised as

an attractive alternative because of their ability to replicate quickly and
produce proteins in large quantities. Scientists had also accumulated a considerable
body of knowledge and experience of ba
cterial genetics. But

expression of an
in bacteria had proved very difficult, the principal problem being that the antibodies
did not fold properly and combined together to
form insoluble complexes of proteins
called “inclusion bodies” which were generally toxic to the host bacteria.



breakthrough came in
1988 with the publication in the same edition of

of the work of two groups working in parallel.
Mark Better and others

at International
Genetic Engineering Inc
achieved the expression in



of a chimaeric
human Fab protein

, 240, 1041
1043 (1988))(“Better”)

n and Arne Skerra from the Max
Institut für Bio
chemie described the
expression in

of a functi
onal recombinant Fv fragment
, 240, 1038


As Dr Huse explained, both groups realised that a key step in the folding of anti
was the formation of
disulphide bonds between the heavy and light chains. This
required an oxidising environment
, which is normally provided by the endo
reticulum of the B cell. Fortunately, the periplasmic space of Gram
negative bacteria
(the region of bacteria between the inner and outer membrane)

also provides an
oxidising environment
. The solution arrived at by both groups was to direct the
tibody fragment for secretion into the periplasmic space using a leader peptide from
a particular enzyme called
. The antibody fragments expressed were
soluble and
fully functional and the
ir affinity
was essentiall
y identical to that of
the native

Judgment Approved by the court for handing down

MedImmune v Novartis


Shortly afterwards, in October 1988, Robert Bird and co
workers at Genex
Corporation described the expression in


of recombinant polypeptides
comprising a V

sequence tethered to a V

sequence to form a single
chain Fv
fragment or

imes referred to as single
chain antibody or SCA)
242, 423
426 (1988))



The following year saw a series of further important publications demonstrating the
use of PCR techniques to make variable chain cDNA libraries. In August 1989
Richard Lerner’s
group at the Scripps Institute
sylvania State University and Dr Huse at Stratagene
published a paper (
Natl. Acad. Sci. USA,

86, 5728
5732 (1989))


describing the cloning of a
highly diverse V

ibrary from mouse spleen cells.


In October 1989 Sally Ward and Greg Winter and co
workers at the MRC Laboratory
of Molecular Biology in Cambridge published a paper (
, 341, 544
546 (1989))


describing the use of PCR to generate a diverse libra
ry of V

genes from
spleen genomic DNA and then the expression
and secretion from


of those



Finally there is the important paper by Dr Huse,
Lerner and c
December 1989 (
, 246, 1275
1281 (1989))

This desc
ribes the use of
phage to express in


a combinatorial library of Fab fragments of the
mouse antibody repertoire. It explains that, subject to certain reservations, a
phage library of the size of the mammalian antibody reperto
ire may readily be
constructed and that very large numbers of clones may be screened each day.


In 1990 the skilled team would have known of various methods for screening a library
of the kind described in Huse, as the judge explained

“It will be a
ppreciated from what has been said above that
researchers often want to screen large libraries of antibodies or
antigens for an antibody or antigen of interest. In 1990 an
established technique for doing this was a method called
“replica plate
lift”. In th
is method, the vector containing DNA
for each member of the library is inserted into bacteria, which
are spread onto a plate containing an appropriate
medium. The bacteria grow into colonies, each colony
expressing that particular member of the libr
ary in large
quantities. Once the colonies have grown, a nitrocellulose filter
is overlaid and
he proteins of interest in each colony stick to
the nitrocellulose and then can be probed with antibody or
antigen probes (depending on whether it was an antige
n or
Bound molecules can be detected by
Clones showing a positive signal can simply
be cut out and re
plated to grow more colonies and amplify the
clone (and also separate out the desired clone from any others
that may h
ave also been accidentally re

A variant of
this technique involves plating out the bacteria at sufficiently
high dilution for a uniform lawn of bacteria to grow, which is

with holes (“plaques”) where the bacteria
Judgment Approved by the court for handing down

MedImmune v Novartis

have been killed

by bacteriophage (as to which, see below).
This variant was known as “plaque lift”.


Around 50,000
plaques can be screened on each plate producing a practical upper
limit (in terms of the library size that can be screened) of around 10

different clones.


In the m
eantime, Professor George Smith at the University of Missouri was pursuing
a rather different line of research using filamentous phage vectors. He appreciated
that the gene III protein

of filamentous phage ha

at least two functional component
parts, an N
terminal domain
that is exposed on the surface and i
s necessary for
infection; and a C
terminal domain that i
s buried in the phage;
and he had the idea
that foreign polypeptides might be displayed on the surfa
ce of the phage without
impairing their infectivity by fusion at appropriate positions withi
n the N
or between that domain and the C
terminal domain.


In the course of a sabbatical from the summer of 1983 to the summer of 1984,
Professor S
mith cloned fr
agments of the gene for the Eco
RI endonuclease gene into
phage and found he was able to display
a 57 amino acid fragment of this protein
the surface of the phage

and he demon
strated it bound to an anti
RI antibody.
Professor Smith app
reciated the power of this techniq
ue and believed that a thousand
fold enrichment could be expected after a single round o
f purification and

antibodies might be used to isolate desired clones from a library of random inserts in a
phage ve
ctor. This seminal work was published in

in 1985
(“Filamentous fusion phage: novel expression vectors that display cloned antigens on
the virion surface


288, 1315
1317 (1985)) (“Smith”).


Over the course of the next few years, Professor
Smith and his graduate student, Steve
Parmley, developed an improved phage
display vector based upon
, a ve
rsion of
filamentous phage modified by the insertion of a gene conferring resistance to the
antibiotic tetracycline
, which

bacteria t
o be selected for successful
incorporation of th
e vector. A further

significant improvement was to move the
cloning site from between the N
al and C
terminal domains to a position two to
amino acids from the N
terminal end, leaving the majorit
y of the gene III
sequence uninterrupted. This work was published in

in September 1988
selectable filamentous fd phage vectors: affinity purification of target

3, 305
318; 1988”) (“Parmley &


This paper was the basis
of one of the obviousness attacks on the patent at the trial
and was the focus of a good deal of attention on th
e appeal. The authors describe

production of five fusion phage and a series of experiments to assess the particle yield
of the clones, thei
r infectivity and the ability of the peptides encoded by the inserted
sequences to be bound by known antibodies. It was found that none of the fusion
proteins had a significant effect on the yield of phage particles produced
propagation in

. But a number of the inserts did affect the infectivity of the
phage particles. Nevertheless

the authors describe affinity purification

which they
call “biopanning”

of phage carrying a target insert from a library containing a 10

fold excess of phage without the insert

very small amounts of antibody.


The discussion section of the paper is of some importance and contains the following
description of the limitation
s of the technique

Judgment Approved by the court for handing down

MedImmune v Novartis


fUSE vectors display foreign ant
determinants with little loss of phage function

The new fusion phage vectors, fUSE1 and fUSE2, accept
inserts in gene
with little or no loss of phage function;
inserts are stable. The foreign
[amino acids] encoded in the
inserts are expressed

on the surface of the phage; two clones
carrying fragments of a target gene were shown to express
determinants recognized by antibody to the gene product.
These results demonstrate the ability of fUSE vectors to accept
inserts up to 335 bp (perhaps more)
and e
xpress the foreign aa

encoded in the inserts on the surface of the virion.

Some inserts by their very nature will affect pIII function.
Inserts that contain anchor domains or other hydrophobic

may stop transfer of pIII

into the host membrane
(Davis and Model, 1995) and presumably would not be

Inserts that exceed 335 bp may lead to excessive
breakdown of the fusion protein or otherwise impair pIII
function, so for the time being we recommended [sic] using
fragments of 100
300 bp


vertheless, the authors explained the benefits of phage display as compared to other
more conv
entional methods of screening e
topes in these terms:

In fUSE vectors, in contrast, the amino acids

encoded by the
foreign inserts are displayed on the

virion i
tself. This allows
recombinant phage to be

purified in infectious form by affinity
to antibody;

thus antibody is used directly to
for the



The authors were particularly interested in the investigation of epitopes, including
their map
ping with a view to designing, for example, vaccines

as appears from this
further passage:

(e) Prospects for an ‘epitope library’


epitope library

would contain, say, 10

clones expressing
a sho
, synthetic random coding

sequence. Such a library
ht be expected to

contain clones reactive with almost any

antibody, since protein epitopes are typically about



and virtually all 64 million 6 aa


would be
represented multiple times in different contexts.

Biopanning the
epitope library with an antibody


interest and sequencing the
inserts in a

number of positive clones might provide

about the epitope(s) recognized by the antibody,

information that could be used, for example, to

design vaccines,
identify gene
s, or map epitopes

without the need to clone the
relevant natural gene


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Finally, the authors recognised that the true power of the technique could not be
exploited fully until they had the ability to generate much larger libraries, noting that
ibraries with more than 10

were difficult to achieve with any

vector that must
be introduced into host cells by transfection because of the limited capacity of
competent cells.


From 1989 to 1990, Dr Jamie Scott, a post doctoral research

in Professor Smith’s
laboratory, therefore set about constructing a large phage peptide l
ibrary. She and
Professor Smith
this library
an “ep
itope library” and demonstrated that
antibodies could be used to affinity
select rare clones displaying anti
peptides. This work was
published in 1990 in

earching for Peptide
Ligands with an Epitope Library”,

249, 386

(“Scott &

Smith”). The
describe the construction and characterisation of a mixture of fusion phage
heoretically displaying approximately 4 x 10

different hexapeptide epitopes and then
the use of biotinylated monoclonal antibodies to select clones by successive rounds of
affinity purification.


In the meantime, in 1988, Professor Smith had read

e paper by Robert Bird
and his co
workers at Genex Corporation. He was also aware
of the work carried out
by Dr
Winter’s group in Cambridge

and Professor

Lerner’s group at the Scripps
Institute to express recombinant antibody genes in bacteria. He recogn
ised that one of
the aims of these workers was to generate and screen libraries of recombinant
antibodies for the ability to bind to a particular antigen but appreciated that many of
the recombinant antibody constructs were relatively large, comprising abo
ut 500
amino acids a
nd two

polypeptide chains. The single
chain antibodies described by
Robert Bird were, by co
ntrast, relatively short, comprising only about 250 amino
acids and
one polypeptide chain. It was apparent to Professor Smith that these scFvs
might be displayed on his phage display vectors and then screened using the same
selection approaches that had worked for phage peptide libraries.


Professor Smith th
erefore amended a grant application

that he had submitted to the
United States
ional Institute o
f Health to include the generation

of a library of
fusion phage displaying, not foreign antigens, but rather antibodies with a great
diversity of antigen
binding specificities. These cloned antibodies would be scFvs
and would be generated

in vitro

using degenerate synthetic oligonucleotides. He also
made contact with Robert Bird to discuss the possibility of expressing scFvs as part of
a phage coat protein and acquiring some
of his
antibody clones.


On 26 April 1990, Professor Smith gave a

presentation at a conference entitled
“Vectors for
Cloning Immune Response” which was held at the Banbury Center at
Cold Spring Harbor Laboratory
, New York
. It was
organised by Professor Lerner
and Dr Winter
, although Dr Winter did

not actually attend the conference.

This is the
which the judge found
the patent obvious. The judge made a
series of important findings as to the substance of
that presentation at

[374] of
his judgment.
The following are p
articularly relevant


First, participants received a letter summarising the background

to the conference in
these terms

“Recently the separate groups of Winter and Lerner have
cloned and expressed the antibody repertoire in
E. coli

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MedImmune v Novartis

plasmid or lamb
da phage technology (Sastry et al.

Acad. Sci. USA

1989; Ward et al

1989; Orlandi et al
Natl. Acad. Sci.
1989; Huse et al, In Press,
). Extensions
of their results open the possibility of circumventing the
hybridoma methodology to
prepare antibodies and ultimately
may lead to a generic antibody library which would obviate the
need to immunize animals. As one begins to approach these
goals, questions concerning the size and screening of the
antibody repertoire emerge. This meeting wi
ll address these
issues and hopefully speed up progress toward creating
in vitro


At the conference, Professor Smith described in general terms th
e work the subject of
Scott &
Smith and introduced at an early stage the idea of putting an scFv o
n a fusion
phage as a means of creating a paratope, that is to say antibody, library.


Professor Smith then discussed the epitope
library referred to in Scott &

Smith and
talked about his technique of biopanning by affinity purification on a plate as

ibed in Parmley &

Smith. He explained that his group had shown that the
presence of a peptide on pIII did not destroy the infectivity of the phage. He also
explained that this enabled fusion phage, which were eluted from the plate, to be
propagated and s
equenced to identify the nucleotide sequence corresponding to the
peptide expressed on the fusion phage.


Professor Smith then said that the same approach “might be useful in screening an
antibody library with antibody displayed on pIII and antigen on the p
late”, reversing
the roles of the antibody and antigen. He illustrated this proposal with the following


I would observe that this slide shows three different phage particles, each displaying a
different antibody fragme
nt, only one of which binds

to the

biotinylated antigen.

Judgment Approved by the court for handing down

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Professor Smith explained that his group were going to test this approach by
to express
an anti
fluorescein SCA

(that is to say an scFv)
on p
III. He also
suggested that, if such an experiment showed that fusion pha
ge expressing this SCA
could bind to fluorescein antigen in a panning experiment, the approach might work
to identify SCAs from a library of SCAs.


The judge then turned to various concerns raised by Professor Smith and possible
solutions should problems ar
ise, and made these findings:


At this point Professor Smith raised t
question “
Will it fold right?
recognising the
possibility that in such an environment the confo
ation of
the SCA might be compromised.
He explained that
some of the pIII protein

embedded in the inner membrane

with the bulk in the periplasm,
s then transferred into the growing virio
n. He went on, however,
to say

, if folding were a concern,
use could be made of
a known
approach for producin
g recombinant proteins in bacterial cells, where a
process of denaturation
using 6M urea at pH 2.2
and renaturation is

in order to achieve the required folding
. S
uch an approach was
feasible in the context of fusion phage because phage


survive th




Professor Smith then said that, a
lthough degradation m

be an
impediment to the successful display of large peptides, as had
suggested in Pa
ley & Smith,
the contrary view was that

it m

be of
fit. The



systems of bacteria exist to remove malfolded

therefore suggested that such degradation might result in the
removal of malfolded SCAs

which might work in the experimenter

favour and make the detection of correctly
olded SCAs (if they were not
degraded) cleaner.


Professor Smith

suggested that

if the SCA on the surface of the fusion
phage interfered with the phage

s ability subsequently to infect bacteria, it
could simply be removed with trypsin.


or Smith also
introduced the idea that an SCA

which had been isolated from a
fusion phage could repeatedly be muta
ted and selected for
better binding.


Finally, Professor

described two approaches to making a library. One was to
construct antibody
libraries from the natural repertoire. The other was to make a
synthetic library using degenerate oligonucleotides to produce random CDRs with
various specificit
ies, an approach similar to the one
he had used to create his
hexapeptide library.


Despite the

various concerns that Professor Smith had, he explained in the course of
his cross
examination that he was trying to sell a

phage display as an idea to

that he was trying to be
upbeat about
the technology and that he was interested in
people to try it for themselves.

Judgment Approved by the court for handing down

MedImmune v Novartis


Professor Smith eventually obtained an scFv clone from Genex in May 199
0 and over
the course of that

summer a graduate student, Ned Watson,
a pha
ge antibody
experiment under his supervision
. The scFv was designed to bind to fluorescein and
it was compared to a mutant which did not bind
fluorescein. The experiment
showed that the fusion phage with the anti
fluorescein scFv was able to bind
specifically to fluorescein rather than rhodamin
e, whereas the mutant did not bind to
fluorescein. However, discrimination between specific and non
specific binding was
less than 100
fold but it did

demonstrate the principle of antibody phage display.


Professor Smith did not pursue the work further bec
ause by then the inventors of the
patent, John McCafferty

and co
workers (including Dr Winter) at
the MRC
Laboratory and CAT had published the results of their own work in a letter to Nature
et al
., “P
hage antibodies

filamentous phage display
ing antibody
variable domains”,
348, 6 December 1990, 552
554). As Professor Smith
said in a passa
ge in his witness statement upon

which he was not cross

I was satisfied that antibody phage display

was being
pursued by the CAT group a
nd by others, including the group

Scripps. I also
id not regard myself as having any claim to
scientific priority in the field of

phage antibodies, because I
considered phage display of antibodies to be a fairly obvious

extension of the newly
chain antibodies and
our published work on phage

display in general (especially

y and Smith

) to the ongoing work by Greg Winter

group, Le

s group at S
ripps, and

others, whose efforts to

clone the imm
ne response

were very prominent in the

community of molecular biologists by the end of 1988.

I have been asked whether I would have continued work on
phage display of antibodies

were it not for the fact that CAT
and Scripps were also working on it. I am sure that I

have done so, as I believed that the strategy was sound and the
approach had

enormous potential.

The p


I must now outline aspects of the teaching of the patent because they bear on one of
the arguments adv
anced by MedImmune as part of its attack

on the finding of
, namely that the judge mischaracterised the nature of the skilled team to
whom the patent is addressed.

They are also relevant to the priority issue.


The specification be

[0001] by explaining that the invent
ion relates
to methods for producing members of specific binding pairs and to binding molecules
produced by such methods.


Paragraphs [0002]

[0003] describe the impo
rtant advance of

nal antibodies
and how these are traditionally
made by establishin
g an immortal mammalian cell line
derived from a single immunoglobulin producing cell secreting one form of antibody
molecule with a particular specificity.

Judgment Approved by the court for handing down

MedImmune v Novartis


Paragraphs [0004]

[0006] describe the structure and functional eleme
nts of
antibodies and how it

been shown that the fu
nction of binding antigens c

performed by fragments of a whole an
tibody including an

v fragment consisting of
the V

and V

domains of a single arm of an antibody.

It continues that

although the
two domains of an

Fv fragmen
t are cod
ed for by separate genes, it has

proved possible
to make a synthetic linker enabling them to be m
ade as a single protein chain


Paragraphs [0007]

[0010] explain that although monoclonal antibodies produced by
human immortal cell lines hold great

promise for the treatment of a wide range of
diseases, such antibodies have a number of limitations. The first is that immortal
antibody producing human cell lines are very difficult to establish and give low yields
of antibody. By contrast, equivalent
rodent cell lines yield high amounts of antibody
but, if administered to hum
ans can generate
the HAMA response, leading to harmful
hypersensitivity reactions.


The second problem

mentioned is a practical one. The number of different
specificities expressed

at any one time by lymphocytes of the murine immune system
is thought to be about 10
, and in the case of the human immune system the figure is
even higher at about 10
. However, the hybridoma technology only allows the
sampling of about 10

to 10



Paragraphs [0011]

[0013] describe how these problems have, at least in part, been
addressed by the application of recombinant DNA methods to the isolation and
production of antibodies and fragments of antibodies with antigen binding abi
lity in
bacteria such as

. The description continues that the use of bacterial cells
allowed the production of large numbers of binding molecules. It
also afforded an
opportunity to produce tailor
made antibodies and fragments. But many o
f the
problems presented by systems based u
pon immortalised cells persist. In particular, it

still impractical to screen the very large numbers of clones necessary to begin to
sample the range covered
by natural antibody variation.


Against this backgr
ound, paragra
ph [0014] says
there i
s a need f
or a screening system
that will

allow the sampling of very large numbers of antibodies or fragments
and the
rapid transfer of
the DNA
encoding them
to the next stage.


Paragraph [0015] explains that the most att
ractive candidates for large scale screening
are prokaryotic organisms because they grow quickly, are simple to manipulate and
create large numbers of clones. However,
the co
expression in a single host
cell of variable H

L chains
has been di
sclosed, that expression

produced insoluble
protein which required extensive processing to generate antibody fragments with
activity. The paragraph continues that it has

been sho
wn that antibody
fragments can

be secreted through bacterial membrane
s by using an appropriate signal
peptide but this method requires

the screening of individual

es for binding activity
the same way as murine monoclonal antibodies.


Paragraphs [001

[0022] refer to
various papers and patent applications, some
ished after
the date of filing of the relevant
priority document,

describing the use
of bacterio
phages. Of these, I should mention an application by Protein Engineering
orporation WO 90/02809
which proposes the insertion of the coding sequence for

pancreatic trypsin inhibitor


into a coat protein of the filamentous
phage M13. However, the description continues, the proposal was not shown
Judgment Approved by the court for handing down

MedImmune v Novartis

to be operative. In particular, there was no demonstration of the expression of BPTI
sequences a
s fusions with the
protein and display on the surface of M13.



problem of how to use bacteriophages is developed

in paragraph [0023]. It says

that the protein must be inserted into the phage in such a way that the integrity of the
phage coat is no
t undermined, and the protein itself must be

and retain its
ability to bind its antigen. Then, in paragraph [0024], the description continues that,
surprisingly, the applicants have been able to construct a bacteriophage that expresses
and disp
lays at its surface a large biologically functional bi
nding molecule which
remains in
tact and infectious. Where the binding molecule is an antibody or an
antibody derivative or fragment, the applicants call the package a “phage antibody




raph [0025] explains that pAbs have a range of applications in selecting
antibody genes encoding antigen binding activities. For example, they may be used to
screen large combinatorial libraries and that rounds of selection using pAbs may help
in rescuing

higher affinity antibodies from such libraries. It continues that pAb
s may
also allow the construction

of entirely synthetic antibodies. Alternatively, they may
allow the construction of antibodies which have some synthetic sequences and some
derived sequences. Moreover, libraries of pAbs could
generated and
particular pAbs
selected by binding to an antigen, hypermutated
in vitro

in the
binding loops or V domain framework regions, and subjected to further
rounds of selection and mutagenesis.


Paragraph [0081] define
s the term “derivative”

“This is a substance which derived from a polypeptide which is
encoded by the DNA wit
hin a selected bacteriophage particle.
The derivative polypeptide may differ from the encoded
polypeptide by the addition, deleti
on, substitution

or insertion
of amino acids, or by the linkage of other molecules to the
encoded polypeptide. These changes
may be made at the
nucleotide or protein level. For example, the encoded
polypeptide may be a Fab fragment which is then linked to an
Fc tail from another source. Alternatively markers such as
enzymes, flouresceins etc may be linked to eg Fab, scFv


Paragraph [0082] sets out the elements of the method of claim 1 of the patent.

Paragraph [0091] explains that in
this method the gene sequence en
coding the binding
molecule of desired specificity is separated from a general population of filamentou
phage particles having a range of specificities because it binds to a specific target.
Paragraph [0092] continues that the bound particle may be recovered by washing with
eluant and that variation of the washing conditions permits the recovery of
ticles with different binding affinities

for the epitope
. The nucleic acid may then
be recovered from the particle and used or modified to produce a derivative.


Paragraphs [0107]

[0115] explain that the applicants have recognised that gene III of
ntous phage is an attractive possibility for the insertion of biologically active
foreign sequences but that, prior to the present application, no substantially complete
domain or folded unit had been displayed on phage. They continue that they chose to
Judgment Approved by the court for handing down

MedImmune v Novartis

nsert the gene coding sequence for biologically active antibody fragments into the
gene III region after amino acid 1 of the mature protein and that, in order to retain the
structure and function of gene III, the majority of the original amino acids were
ynthesised after the inserted immunoglobulin sequence. Surprisingly, they say, by
manipulating gene III, t
hey have constructed a bacterio
phage that displays on its
surface large biologically functional antibody, enzyme and recept
or molecules while
ng in
tact and infectious. Further, phages bearing an
tibodies of desired

can be selected from a background of phages not showing that specificity.


There follows a series of examples which demonstrate that the claimed method can
achieve a thousa
nd fold enrichment in one round of purification and a million fold
enrichment in two such rounds. That brings me to claim 1, the only claim in issue,
which reads (broken down into integers):


A method for producing a molecule with binding specificity
a particular target, which method comprises:


producing a population of filamentous bacteriophage particles

displaying at their surface a population of binding molecules

having a range of
binding properties


wherein the binding molecules compris
antibody antigen
binding domains

for complementary specific binding pair


wherein the binding molecules are displayed at the surface of
the filamentous bacteriophage particles by
fusion with a gene
III protein

of the filamentous bacteriophag
e particles,


and wherein each filamentous bacteriophage particle contains
nucleic acid encoding the binding molecule expressed from the
nucleic acid and displayed by the particle at its surface;


selecting for a filamentous bacteriophage particle
displaying a
binding molecule with a desired binding property by contacting
the population of filamentous bacteriophage particles with a
particular target


so that individual binding molecules displayed on filamentous
bacteriophage particles with the de
sired binding property bind
to said target;


separating bound filamentous bacteriophage particles from the


recovering separated filamentous bacteriophage particles
displaying a binding molecule with the desired binding


ng nucleic acid encoding the binding molecule from
separated filamentous bacteriophage particles;

Judgment Approved by the court for handing down

MedImmune v Novartis


inserting nucleic acid encoding the binding molecule, or a
fragment or derivative thereof with binding specificity for the
target, in a recombinant syste
m; and


producing in the recombinant system separate from
filamentous bacteriophage particles a molecule with binding
specificity for the target,


wherein the molecule is said binding molecule or a fragment or
derivative thereof with binding specif
icity for the target

The skilled t


It is well established that a patent specification is addressed to those
likely to
have a practical interest in the subject matter of the invention

such persons will
practical knowledge and
experience of the kind of work in which the in
vention is
intended to be used. They will also be equipped with the common general knowledge
in the art, a matter to which I return below.


As the judge explained
in this case
there was
a dispute as to the ide
ntity of the team
to whom the patent is addressed. MedImmune contended it is addressed to a team
consisting of an immunologist and a molecular biologist, perhaps assisted by a
chemist. Novartis argued the patent is addressed to a team of scientists with
backgrounds in areas such as immunology, in particular antibody structural biology,
molecular biology and protein chemistry, but with a common interest in antibody
engineering. As the judge identified, the essential difference
between the two
rmulations lies

in the degree of specialisation of the team in the field of antibody


The judge

preferred Novartis’ submission on the basis that the evidence showed that
real research teams in the field were teams of the kind contended for by N
ovartis. He
added that, in his view, the specification of the patent is consistent with this
characterisation of the skilled team.


MedImmune contended
that the judge fell into error in so finding because the
invention has a broad application and is not co
nfined to antib
ody engineering. It

that expertise in immunology and molecular biology is sufficient to
implement its teaching.


I have no doubt that the judge identified the skilled team correctly. As Jacob LJ
explained in
Schlumberger Holdings
Ltd v Electromagnetic Geoservices AS
EWCA Civ 819, [2010] RPC 33 at [42]
, the court will have regard to the reality of the
position at the time and the combined skills of real research teams in the art. A little
later, at [53]

he continued that wh
ere the invention involves the use of more than one
skill, if it is obvious to a person skilled in the art of any one of those skills, then the
invention is obvious. Finally, at [65]

he explained that in the case of obviousness in
view of the state of th
e art, a key question is generally “what problem was

patentee trying to solve?”

That leads one in turn to consider the art in which the
problem in fact lay. It is the notional team in that art which is the relevant team
making up the person skilled i
n the art.

Judgment Approved by the court for handing down

MedImmune v Novartis


The judge found that by 1990 antibody engineering was an established field. The
three leading teams were those led by Dr Winter at the MRC Laboratory of Molecular
y and CAT, by Professor Lerner at the Scripps Institute
and by

kthun at the Max
Institut für Biochemie. Other

were also

including the

by Professor Stefan Dübel at the


and teams at
Genentech, Genex Corporation
, SmithKline Beecham and

Institute. All of these teams
were likely to
have a practical interest in the subject matter of the invention, in methods for
preparing binding molecules including, specifically, antibodies and fragments of
them, and selecting those with specific
ity for particular antigens. They had a need for
a system which would allow them
to screen
very large numbers of d
ifferent binding
. The invention was therefore plainly of interest to antibody engin
eers and
the fact that it may have a broader ap
plication is neither here nor there.



The common general knowledge of the notional skilled addressee is all that
knowledge which is generally known and generally regarded as a good basis for
further action by the bulk of those engag
ed in a particular art:
t Technologies Inc
v Valmet Paper Machinery Inc

[1997] RPC 489 at 494
495. It also includes all that
material in the field in which the skilled addressee is working which he knows exists,
which he would refer to as a matter o
f course if he cannot remember it and which he
understands is generally regarded as sufficiently reliable to use as a foundation for
further work:
Raychem Corporation’s Patent

[1998] RPC 31 at 40; [1999] RPC 497
at 503



There was very little dispute
between the parties as to the scope of the common
general knowledge of the skilled addressee, that is to say the skilled team to which I
have referred. It included all the matters set out in the technical background other
than those relating to phage disp
lay. Specifically it was accepted that, in relation to
antibody engineering, it included the B
kthun, Bird, Lerner
, Ward and Huse
papers. The skilled team would therefore have been well aware of the important
advances in the late 1980s in
g the use of
PCR to clone gene sequences
encoding antibody fragments, the generation of libraries of vectors coding for these
fragments, the use of these vectors to infect


and the expression of functional
antibody fragments. But selecting a molecu
le of interest from a large library of
ody fragments using the available techniques
presented, in the words of Dr
Teillaud, one of the experts who gave evidence on behalf of MedImmune, a
formidable challenge.


The dispute between the parties,
such as it was, related to whether phage display
formed part of the common general knowledge. The judge found the b
asic concept of
phage display at

a high level was common general knowledge by November 1990. It
was, he held, an established technique, alt
hough not one which was in routine use.


MedImmune contended

the judge fell into error in making this finding because there
had been only six published studies using the technique. As a m
atter of principle, it
, a technique so little used in pra
ctice cannot amount to common general

Judgment Approved by the court for handing down

MedImmune v Novartis


I am unable to accept this submission. As Aldous LJ explained in
at 497, the
fact that a concept has not been used at all does not mean that it cannot form part of
the common general knowledge, thoug
h it makes it unlikely. In the present case

November 1990, Professor Smith’s group had published the three papers to which I
have referred
, namely Smith, Parmley & Smith and Scott & Smith,

and at least three
other groups had published work on phage di
splay. Moreover, the judge found on the
evidence that other groups were also using the technique, including in relation to
antibodies, but had not yet published their work. In all these circumstances the judge
had ample material upon which to find as a f
act that
the concept of
phage disp
have been known to the person skilled in the art.




Novartis attacked the patent as being obvi
ous over Parmley & Smith and

Smith’s presentation at the
. Althou
gh Novartis did not, in the
end, press its case on Parmley & Smith, it did not abandon it, and so the judge dealt
with both disclosures in his judgment. He found the patent to be obvio
us over the
Banbury presentation
but not over Parmley & Smith.


contends that the
judge fell into error in finding the patent obvious for a number of reasons including,
most importantly

that the judge’s reasoning in relation to Parmley & Smith was
equally apposite to the Banbury presentation

and should have led to the same
conclusion. But before summarising the judge’s reasoning and

for criti
sing it, I must first address the relevant legal principles.

The relevant legal principles


The starting point is that
an invention
must involve

an inventive step, and it is to be
taken to involve an inventive step if it is not obvious to a person skilled in the art
having regard to matter which properly forms part of the state of the art at the priority

sections 1(1) and 3 of th
e Patents Act 1977, corresponding to Articles 52(1) and
56 of the European Patent Convention)


It is often convenient, but by no means essential, to consider an allegation of
obviousness using the structured approach explained by this court in


[2007] EWC
A Civ 588, [2007] FSR 37



Identify the notional

person skilled in the art


Identify the relevant common general knowledge of that


Identify the inventive concept of the claim in question or if that

cannot readily be done, construe it;


Identify what, if any, differences exist between the matter cited
as forming part of the

state of the art

and the inventive
concept of the claim or the claim as construed;

Judgment Approved by the court for handing down

MedImmune v Novartis


Viewed without any knowledge of th
e alleged invention as
claimed, do those differences constitute steps which would
have been obvious to the person skilled in the art or do they
require any degree of invention?


Step (2) may pose some problems.
In some cases, as in this one, t
he part
what the inventive concept
is. This has the advantage of limiting the obviousness
analysis to the essence of the invention. But often the parties do not agree and in such
cases it will usually be a futile exercise for the court to se
ek to resolve their

disagreement, for ultimately all that matters is what the patentee has claimed.
As Lord
Hoffmann said in
Conor v Angiotech

[2008] UKHL 49,
PC 716 at [19]:

“… the patentee is entitled to have the question of obviousness
determined by reference to the claim and not to some vague
paraphrase based upon the extent of his disclosure in the


I would add, so too

is the defendant. The patentee may
have drawn his claim so
broadly that it includes products or processes that owe nothing to the inventive
contribution he has made, rendering the claim
vulnerable to an allegation
of obviousness.


Step (3) presents little conceptual difficulty.

It simply requires the court to identify the
differences between the prior art and the claim.


It is step (
4) which is key and requires
the court to consider whether the



obvious to the skilled
but unimaginative

at the priori
ty date

is equipped with the common general knowledge
he is deemed to have

read or
ed to the prior disclosure properly and in that sense with interest
he has the
prejudices, preferences and attitudes of those in the field

he has
no knowled
ge of
the invention.


One of the matters which it may be appropriate to take into account is whether it was
obvious to try a particular
route to an improved product or process. There may be no
certainty of success but the skilled person might nevertheless
assess the prospects of
success as being sufficient to warrant a trial

In some circumstances this may be
to render an invention obvious.
On the other hand
, there are
areas of
such as pharmaceuticals and biotechnology
which are heavil
y dependent
on research
, and where workers are faced with many possible avenues to explore but
have little idea if any one of them will prove fruitful. Nevertheless they do pursue
them in the hope that they will

find new and useful products
. They plainly w
ould not
carry out this work if the prospects of success were so low as not to make them
. But denial of patent protection in all such cases would act as a significant
deterrent to research


these reasons, the judgments of the courts in Engla
nd and Wales and of the
Boards of Appeal of the EPO often reveal an enquiry
by the tribunal
into whether it
was obvious to pursue a particular approach with a reasonable
or fair
expectation of

as opposed to a hope to succeed. Whether a route has a
or fair

of success will depend upon all the circumstances including an ability
rationally to predict a successful outcome, how long the project may take, the extent
Judgment Approved by the court for handing down

MedImmune v Novartis

to which the field is unexplored, the complexity or otherwise of any ne
such experiments
can be performed by routine


the skilled person will have to make a series of correct decisions along the

ord Hoffmann

the position in

this way in
at [42]:

In the Court
of Appeal, Jacob LJ dealt comprehensively with
the question of when an invention could be considered obvious
on the ground that it was obvious to try. He correctly
ed the authorities, starting with the judgment of
Diplock LJ in
Manville Corpo
ration’s Patent

RPC 479, by saying that the notion of something being obvious
to try was useful only in a case where there was a fair
expectation of success. How much of an expectation would be
needed depended on the particular facts of the case


Moreover, whether a route is obvious to try
is only one of many considerations which
it may be appropriate
for the

court to take into account
Generics (UK) Ltd v H
, [2008] EWCA Civ 311, [2008] RPC 19, at [24] and in
UKHL 49, [2008
] RPC 28 at [42]
, Lord Hoffmann approved this statement of
principle which I made at first instance in

“The question of obviousness must be considered on the facts
of each case. The court must consider the weight to be attached
to any particular
factor in the light of all the relevant
circumstances. These may include such matters as the motive to
find a solution to the problem the patent addresses, the number
and extent of the possible avenues of research, the effort
involved in pursuing them and
the expectation of success.”


Ultimately the court has to
evaluate all the relevant circumstances in order to
answer a
single and relatively simple question

of fact: was it obvious to the skilled but

make a product or carry out a
ess falling within the
As Aldous LJ said in
Norton Healthcare v Beecham Group Plc
(unreported, 19
June 1997):

“Each case depends upon the invention and the surrounding
facts. No formula can be substituted for the words of the
statute. In every c
ase the Court has to weigh up the evidence
and decide whether the invention was obvious. This is the
statutory task.”


It is the nature of this multi factorial evaluation of evidence against a simple statutory
the reluctance of an appea
l court to inference with
trial judge’s
on an issue of obviousness unless

has erred in principle.
Lord Hoffm
put it this way in
Biogen v Medeva
[1997] RPC 1

The question of whether an invention was obvious had been
called “a kind of jury question” (see Jenkins L.J. in
Svenska Elektriska A/B v. The Burntisland Shipbuilding Co.
(1952) 69 R.P.C. 63, 70
) and should be treated with
appropriate respect

by an appellate court. It is true that in
Judgment Approved by the court for handing down

MedImmune v Novartis

Benmax v. Austin Motor Co. Ltd.
955] A.C. 370

this House
decided that, while the judge's findings of primary fact,
particularly if founded upon an assessment of the credibility of
witnesses, were virtually unas
sailable, an appellate court would
be more ready to differ from the judge's evaluation of those
facts by reference to some legal standard such as negligence or
obviousness. In drawing this distinction, however, Viscount
Simonds went on to observe, at page
374, that it was “subject
only to the weight which should, as a matter of course, be given
to the opinion of the learned judge”. The need for appellate
caution in reversing the judge's evaluation of the facts is based
upon much more solid grounds than prof
essional courtesy. It is
because specific findings of fact, even by the most meticulous
judge, are inherently an incomplete statement of the impression
which was made upon him by the primary evidence. His
expressed findings are always surrounded by a penum
bra of
imprecision as to emphasis, relative weight, minor qualification
and nuance (
as Renan said
, la vérité est dans une nuance
), of
which time and language do not permit exact expression, but
which may play an important part in the judge's overall
tion. It would in my view be wrong to treat

authorising or requiring an appellate cou
rt to undertake a

evaluation of the facts in all cases in which no question of
the credibility of witnesses is involved. Where the application
of a legal standard such as negligence or obviousness involves
no question of principle but is simply a m
atter of degree, an
appellate court should be very cautious in differing from the
judge's evaluation.


More recently, in
Human Genome Sciences Inc v Eli Lilly

UKSC 51, Lord

reiterated (at [168]) the task of the trial judge is to evaluate the
against a statutory test expressed in simple terms, whose meaning is not necessarily
made much clearer by elaborate judicial exposition. Then (at [169]
[170]) he
emphasised the importance, in cases of this sort, of deference to the conclusions of
trial judge.

The person skilled in the art, the common general knowledge and the inventive concept


I have dealt with the person skilled in the art
, here a team,

and the common
knowledge of that team
. I therefore turn to the inventive concept

of the only claim in
issue, namely claim 1. The judge summarised this in non
contentious terms as
consisting of two steps: (i) producing a population of phage particles displaying at
their surface binding molecules have a range of binding specificities w
herein each
particle contains nucleic acid encoding the binding molecule; (ii) selecting particles
displaying a binding molecule with a desired specificity by contacting the population
of particles with a target epitope or antigen to which the binding mole
cule of interest

Judgment Approved by the court for handing down

MedImmune v Novartis

Obviousness over Parmley & Smith

the judge’s findings


I must summarise the judge’s findings in relation to the allegation of obviousness over
Parmley & Smith because they form the basis of one of the challenges to the judge’s
findings of obviousness over the Banbury presentation. Moreover, as the judge noted,
the Banbury presentation built upon Parmley & Smit
h and it was common ground that

if the skilled team were to consider implementing the proposal made by Professor
Smith a
t Banbury, they would read Parmley & Smith before going further if they were
not already acquainted with it.


As the judge observed, the authors’ underlying objective was to clone genes although
the paper makes clear that the potential applications of the t
echniques described go
beyond the cloning of genes and the paper suggests they could be used to create and
screen an

epitope library. Moreover, those techniques
have advantages as compared
plaque lift, namely they remove

the need to keep the antigen in

the solid phase and
the phage particles are themselves in an infectious form and can be tak
en forward for
. In the words of the paper, the antibody is used directly to select for
the desired clones.


On the other hand, Parmley & Smith is c
oncerned with expressing antigen fragments,
not antibody fragments; the inserts were linear epitopes; and infectivity decreased as
the size of the insert increased, po
ssibly due to significant break
down of recombinant


It followed

that the key differe
nce between the disclosure of Parmley & Smith and the
inventive concept is that Parmley & Smith only discloses antigen phage display,
whereas the invention involves antibody phage display.


The judge then turned to the crucial fourth

question. Here

the judge began by
summarising the expert evidence. On behalf of Novartis, Dr Huse expressed the
opinion that Parmley & Smith made it obvious to try displaying antibody fragments
on the surface of the phage and panning with an antigen instead of displayi
ng antigen
fragments and panning with an antibody, since conceptually one was a mirror image
of the other, and that Parmley & Smith would give the skilled team a reasonable
expectation of success.


On behalf of MedImmune, Professor
Brammar and Dr Te
illaud expressed the
opinion that, although the skilled team might consider reversing the roles of antigen
and antibody, Parmley & Smith would not

them a reasonable expectation
that this would be successful. Their reasons were first, that the l
inear epitopes used i
Parmley & Smith were

relatively small polypeptides without a particular tertiary
structure. By contrast, antibodies and their fragments are larger molecules and it is
critical to their function that they are correctly folded so as t
the right
conformation to lock onto the antigen epitope. Further, the antibody or antibody
fragment must adopt the correct conformation despite being attached to a phage
protein on the surface of the phage particle. Finally, Parmley & Smith would

positively discourage the skilled team from thinking that antibody fragments could be
displayed successfully. They would note, in particular, the reduced infectivity of the
largest insert, the suggestion that this may be due to break down of recombinant
and the recommendation to use fragments of 100
300 base pairs. By contrast, an scFv
would be encoded by at least twice as many base pairs, and a Fab by

even more.

Judgment Approved by the court for handing down

MedImmune v Novartis


Before assessing the rival views expressed by the experts, the judge noted an

matter which was common ground between them, namely that the teaching
in Parmley & Smith is sufficient to enable the skilled team to carry out phage display
of an antibody fragment. Professor Brammar accepted in the course of his evidence
that it require
d no technical procedure that was out of the ordinary and beyond those
described in Parmley & Smith to make phage display work in relation to antibody


The judge

nevertheless concluded that
Parmley & Smith would not lead the skilled
team to belie
ve that phage display of antibody fragments had a reasonable prospect of
success. He was particularly influenced by the express teaching in Parmley & Smith
that inserts exceeding 335 base pairs may lead to excessive break down of the fusion
protein or oth
erwise impair pIII function, as
clearly emerges from

[402] of the


What is decisive in the present case is the evidence
concerning the questions of size, infectivity,
breakdown and folding identified above. Dr Huse,
Professor Brammar

and Dr Teillaud were all agreed
that size
per se

was not an issue. So far as infectivity is
concerned, as Dr Huse pointed out, Parmley & Smith
expressly states that the lac335 fusion phage could be
effectively affinity
purified despite its reduced
vity. Nevertheless, I think it is clear that the
skilled team would be concerned at the reduced
infectivity, and the suggestion that it was due to
breakdown. Thus the main points are breakdown and
folding. Dr Huse’s evidence was the skilled team
would have

a reasonable expectation of success despite
what was said about the former and the absence of any
discussion of the latter, whereas Professor Brammar
and Dr Teillaud disagreed.


Both Professor Brammar and Dr Teillaud highlighted
the statement in Parml
ey & Smith that:

Inserts that exceed 335 bp may lead to excessive
breakdown of the fusion protein or otherwise impair
pIII function, so for the time being we recommended
using fragments of 100
300 bp

As noted above, Dr Huse considered this statement to
be ambiguous. It is not necessary to go into his
reasons, which relate to the fact he did not consider it
surprising that there was proteolysis of the particular
insert Parmley & Smith had chosen to use since it was
a fragment of much larger protein domai
n, and hence
would have exposed parts of the protein that would not
ordinarily be exposed to the relevant enzymes. The
question is how the uninventive skilled team would
react to it.

Judgment Approved by the court for handing down

MedImmune v Novartis


In my judgment this passage would be understood by
the skilled tea
m as a clear recommendation to use
inserts of less than 300 bp because of the potential for
excessive breakdown or other problems with pIII
function if larger inserts were used. This reading is
supported not merely by the evidence of Professor
Brammar and
Dr Teillaud, but also by four other
pieces of evidence.”


It followed that

the 777 patent was not obvious
Parmley & Smith.

Obviousness over the
presentation at the
Banbury c

the judge’s findings


I have detailed the substance of the presenta
tion made by Professor Smith at the
Banbury Conference earlier in this judgment. The judge rightly noted that this
presentation went further than Parmley & Smith in four important respects. First,
Professor Smith explicitly proposed phage display of anti
bodies. Secondly, he stated
he was going to try this approach by attempting to express an scFv on pIII. Thirdly,
he discussed the possible problems that might be encountered, and potential solutions
to those problems if th
ey were. Finally, he suggested

that degradation might assist the
experiment by removing mal
folded scFvs.


The judge then proceeded to identify the difference between the disclosure by
Professor Smith and claim 1 of the patent as being only that Professor Smith had not
actually got as f
ar as doing an actual experiment involving antibody phage display.


That took the judge to the fourth

question, which he expres
sed in these terms

“… I consider that there can be no serious dispute that
Professor Smith’s talk made it
obvious to try phage display of
antibodies provided that there was a sufficient expectation of
success having regard to the other factors considered above.
The only question is whether it would have given the skilled
team a reasonable expectation of succes
s within a reasonable


In addressing this question

he judge began by considering the impression the skilled
team would have received from the talk as to whether Professor Smith was himself
expecting succes
s. The judge

found (at
) the message P
rofessor Smith conveyed
was a positive one: he was reasonably confident of success, while recognising that
success was not guaranteed because there were

potential problems. Further
, as the
skilled team would have appreciated, his confidence was n
ot the res
ult of blind

but of the work and scientific analysis he had undertaken.


The judge then turned to the expert evi
given by Dr Huse for Novartis and
Professor Brammar and Dr Teillaud for MedImmun
e. After summarising that
evidence, the judge sai
d this

“ Su
bject to consideration of the secondary evidence relied on
by each side,
the conclusion which I draw from the evidence is
Judgment Approved by the court for handing down

MedImmune v Novartis

that Professor Smith’s talk at the Banbury Conference would
have given the skilled team a reasonable expectation
of success
within a reasonable time. Not merely did he explicitly propose
antibody phage display, but in addition he said that he was
going to do the experiment. Furthermore, he addressed the
concerns which arose out of Parmley & Smith and gave reasons
to why he nevertheless considered the experiment worth
carrying out, as well as explaining potential solutions if
problems were encountered. Finally, his tone was one of


This was, in effect, the expression of a preliminary view that the inv
ention was
obvious. But before reaching his final

conclusion, the judge
turned to the secondary
This fell into
three parts.


The first was Professor Smith’s own work. MedImmune relied strongly upon this as
vidence of non
obviousness. It

to the
circumstances in whi


had the idea and the statements he made in the
grant application to
ch I have referred at
] above;
second, to
Professor Smith’s
own thought
processes at the time of the Banbury
hird, to what happened when
Professor Smith

did his own experiment; and
, to
a declaration

Professor Smith

submitted to the USPTO.


The amended grant application described the project in these terms:

“Finally, let me plea for 5 years in return for
a much curtailed
budget. It’s obvious that I’ll need that long, especially
considering that my laboratory will have been unfunded for
over a year and that I’ll have to train a new technician. Perhaps
the project seems ‘speculative,’ but what can I reasonab
ly be
expected to be able to report that will make it decisively less so
after 2 years’ funding (when I’ll be forced to renew if I get only
3 years)

even granted that my vision is thoroughly sound in all
essentials and that I undertake the task with comm
competence and energy, as indeed I will?”


mune naturally focused on the five

year estimate for the project and the epithet


The amended application also discussed the proposal to create a library of infectious
antibodies and an
outline of the

various responses Professor Smith

might adopt to
possible problems. These largely correspond

to those articulated by Professor Smith
at the
conference itself and whi
ch are detailed at
] above.


Professor Smith gave evidence on
these matters which the judge summari
sed in these
terms at

“Although Professor Smith accepted in cross
examination that
the project described in the application was speculative, at least
so far as the antibody phage display was concerned, it appears

from the document that it was the reviewers who had described
Judgment Approved by the court for handing down

MedImmune v Novartis

his epitope library proposal as speculative, and that at the time
Professor Smith did not agree with this. Finally, the time scale
envisaged is clearly driven both by Professor Smith’s need for

funding, particularly given the consequences of the refusal of
the previous application, such as the need to train a new
technician, and by the “much curtailed budget”, which only
allowed for one research assistant. It also reflects the fact that
he inten
ded first to work on the epitope library, as indeed he
did, and that at the end of the five years he hoped to be
screening large libraries with multiple antigens.”


Turning to
Professor Smith’s thought processes

at the time of the Banbury
, h
e had

two main concern
, folding and non
specific stickiness.
The judge
dealt with
these at

“With regard to folding, he said during the interview that this
“loomed large in his thinking”. It remains the case, however,
that he specifically addressed this
concern in his talk, that it did
not discourage him from carrying out the experiment and that
he conveyed to the audience that it did not discourage him.
specific stickiness was another matter which he had in
mind as being a potential challenge. But he

was not sufficiently
concerned about this to mention it either in Parmley & Smith or
in his talk. ”


The next matter
relied upon
was the experiment conducted by Professor Smith and the
results achieved. As I have said, the project was started in the summer

of 1990 by a
graduate student and then continued by Professor Smith and a technician. Professor
Smith said he did not give it to a PhD student because it was “pretty speculative” and
“you w
ant to give PhD projects that a
little surer than this was”

he judge
ed how he understood this evidence


“In some ways this is the best piece of evidence in
MedImmune’s favour, but again it must be taken in context. I
understood Professor Smith to mean that he would want to
assign a project to a Ph
D student which was more clearly
certain of success. (It appears that he did not have a post
doctoral student available to do the work at the time.) Professor
Smith accepted that he could not confidently say in advance,
“Oh yes, that is going to work”; but

equally he was clear that he
thought that there was reasonable likelihood of success.”


The experiment showed that the fusion phage with the anti
fluorescein scFv was able
to bind specifically to fluorescein rather than rhodamine but Professor Smith was
sappointed with the results because he was only able to obtain enrichment of about
he judge found that despite Professor Smith’s reaction, the experiment had
worked, observing

“In saying this, I am not overlooking the fact that Profess
Smith’s experiment did not quite arrive at implementing the
core inventive concept, since it does not appear to have
Judgment Approved by the court for handing down

MedImmune v Novartis

involved selection by binding from a population with a range of
specificities (or at least it is not clear that it did). It nevertheless

demonstrated the principle of antibody phage display.”


It is thus clear the judge appreciated Professor Smith had not performed the whole of
the method of claim 1.

However, he did not pursue the project because Dr McCafferty
and his co
workers had by then

published their own paper.


MedImmune pointed to
a declaration made by Professor Smith in June 1995
in support of a US patent application in respect of whic
h he
as named as co
inventor. In

that declaration

Professor S
mith made certain comments abo
ut the

prospects of
expressing antibody fragments on phage particles in light of Parmley &
He said the possibility of degradation rendered such a project unpredictable
there could be no reasonable expectation of success.


this took the matter

further because it reflected Professor Smith’s opinion prior to the publication of Bird.


The next

part of the secondary evidence concerned the reaction to the invention. Here
MedImmune relied upon

the reaction of Dr Teillaud himself. He described the
nvention as a major development and breakthrough

but this was a matter which

judge felt carried
little weight because he was not in the field at the time.


The final

part of the secondary evidence was deployed by Novartis. It sought to rely
upon the fa
ct that a number of people or groups had the idea of phage display at
around the same time. MedImmune di
d not dispute this but submitted, and the judge
largely accepted,
they were all inventive people who had applied for their own
I need say no more about it.


The judge was now in a position to express his overall conclu
sion, which he did at

“Taking all of the different factors and evidence discussed
above into account, my conclusion is that the claimed
inventions were obviou
s in the light of Professor Smith’s talk at
the Banbury Conference. Professor Smith explicitly proposed
antibody phage display, and the skilled team would have had a
reasonable expectation that this would succeed in a reasonable
period of time.”

Did the ju
dge fall into error


At the outset I would observe that this is an unusu
al case in a number of

rst, rapid advances in antibody engineering in the

period shortly before the claimed
priority date
including, in particular, the use of PCR and bacte
rial expression systems,
had led to a need for improved screening methods.


Professor Smith
, the leader in the field of phage display

proposed the use of
antibody phage display
at the Banbury conference
, illustrat
ed it with a slide which

the essential elements of the method and explained that his group were going
to try it. The similarity between
that slide
(reproduced at

] above) and

illustration of the method contained in the
technical primer (reproduced

above) is st

Judgment Approved by the court for handing down

MedImmune v Novartis


Third, the judge had the advantage

of hearing the evidence of Professor Smith and
determined that the message he conveyed was a positive one. He was reasonably
confident of success.


, the method
can be implemented
using the techniques des
cribed in Parmley &
Smith, to which it is accepted the skilled team would refer if they were not already
familiar with it. Nothing further is required.


The step from the prior art to the invention is therefore

adopting Professor Smith’s
proposal and
ing out the me

he described, referring back to Parmley &
Smith so far as necessary
. This hardly seems promising subject matter for a patent.
I recognise that it may not have been obvious to take that step if the skilled team
would have thought ther
e was no reasonable prospect the method would work.
J put it
this way

“Patentability is justified because the prior idea which was
thought not to work must, as a piece of prior art, be taken as it
would be understood by the person skilled in the art. He will
read it with the prejudice of such a person. So that which forms
part of the state of the art really consists of two things in
combination, the idea

the prejudice that it would not work
or be impractical. A patentee who contributes something new
by showing that, contrary to the mistaken prejudice, the idea
will wor
k or is practical has shown something new. He has
shown that an apparent “lion in the path” is merely a paper
tiger. Then his contribution is novel and non
obvious and he
deserves his patent.”


The judge decided the skilled team would not have been deterr
ed and that performing
the method of the claim was an obvi
ous step to take. MedI
mmune argued

arriving at that conclusion
he fell into error in four principal respect


First, it was submitted that having
found that the invention was not obvious ove

& Smith, the judge should also
have found there was insufficient difference
between Parmley & Smith and the Banbury
onference disclosure

to come to a
different conclusion
Put another way, the judge’s finding

in relation to the Banbury
e was inconsistent with his finding in relation to Parmley & Smith. Anyone
acting, or thinking of acting, upon Professor Smith’s encouragement at the Banbury

onference would have gone back to Parmley & Smith, and would have been deterred
from starting.
rofessor Smith had done no work on antibody phage display

Parmley & Smith
. Moreover the potential solutions Professor Smith proposed if
problems were encountered
involved a scientific step backwards. The notional skilled

s expectation of success

should not change simply because the leader in the field
had developed his view and described an aspiration but pr
ovided no additional
that the

anticipated in Parmley & Smith
were illus


In assessing these submissions it is important

to have
in mind

that the disclosures of
Parmley & Smith and the Banbury conference are different in the four significant
respects t
o which I have referred at [106
] above. The
re was

no mention of antibody
phage display in Parmley & Smith at all. By contras
t, this was the specific s
ubject of
Professor Smith’s presentation

at Banbury. Moreover,
as the judge found, Professor
Judgment Approved by the court for handing down

MedImmune v Novartis

Smith conveyed a positive message. He was going to do the experiment and he was
reasonably confident of success.


, the art had moved on considerably since the publication of Parmley & Smith.
The groups of Mark Better and Andreas
Plückthun had shown it was possible to
express functional recombinant antibody fragments in

; Robert

Bird had
described t
he productio
n and
expression of ScFv fragments comprising V

and V

sequences tethered together;

’s group

described the cloning of a
highly diverse V

library; Dr Winter’s
described the use of PCR to
generate a diverse library of V


from spleen genomic DNA and then their
expression and secretion from

; and Dr Huse

and co
workers had described the

expression in


of a combinatorial library of Fab fragments. All of this work
showed it was possible to express functional an
tibody fragments in

need for
improved screening system


Professor Smith had also
carried out important

further work with his colleague Dr
on phage display, albeit not antibody phage display,
and had succeeded in
generating a library of fusion phage displaying
up to

4 x 10

different hexapeptide
epitopes and then

using biotinylated monoclonal antibodies
, had

clones by
rounds of affinity purification. This work

tly published as
Scott & Smith

Thus, whereas P
rmley & Smith discussed

the possibility of selecting
antigen candidates from a library
, Sco
tt & Smith actually demonstrated



Against this background

the judge came to consider the primary evidence, that o
f the
Dr Huse had expressed the opinion in his report that the skilled team would
have had a reasonable expectation of success in the

light of Professor Smith’s
. He maintained that position in cross examination, explaining that the
roposal was certainly going to work to some extent, the only question
being how
often it was

going to be successful. Then

the following exchange took place:


Trying to put yourself into the shoes of the ordinary

skilled person, hearing what Professor Smith had said at the

Banbury Conference, in your opinion, would they be

sufficiently encouraged by the overall message to go away and

try it or not?




Can you just
briefly explain why?


Because any new technology has limitations about the range

over which it is going to work. I think Professor Smith is

giving us here the idea that there is going to be some range

it is going to wor
k, but you have got to be cautious about

assuming exactly how big that range is.


Professor Brammar and Dr Teillaud both accepted Professor Smith was confident the
experiment was worth trying. Professor Brammar put it this way:

He would be conf
ident that it is worth trying. I would never

get the impression that he was confident that it would work,

but he was confident enough to say, ‘I am going to try it, it

Judgment Approved by the court for handing down

MedImmune v Novartis

is worth doing, but I am aware of the possible reasons


failure and I will try to deal with them’.


Dr Teillaud’s evidence was to the same effect:


…. The person listening at the Banbury

Conference, I would suggest to you, if they knew about Parmley and
Smith or saw the reservation in

Parmley and Smith about the size of
the insert would have said to themselves, whatever Dr. Smith has done
in the past 18 months, something must have encouraged him to think
that it was worthwhile to try an antibody fragment of 750 base pairs.


Yes, in
deed, it is likely so. It is why I said it was

surprising to me that he did not make any experiment in this

interval of time about antibodies.


Bearing in mind no special technique

was required to implement
Professor Smith’s

and that he

had described possible solutions should any particular problems
be encountered,
I am satisfied the judge wa
entitled to conclude that the ordinary
skilled team would have had a reasonable expectation of success if they were to try it


Second, MedI
mmune argued

that Professor Smith’s proposal constituted a research
project of uncertain length and outcome. Professor Smith had

the project as
being speculative
as being
likely to take up to five years
as being
of a

nature such
that he
would not

give it to a PhD student
. Such an assessment does not amount to a
reasonable prospect of success in a reasonable time and the judge ought to have so


I am not persuaded by any of these points. First, they do not fairly
reflect the

Professor Smith

suggested that the project might take five years in his revised grant
application filed in late 1988. There he said “let me plea for 5 years in return for a
much curtailed budget”. But this was for a project including the

creation of an epitope
library and a library of antibody fragments. The former had been achieved by the date
of the Banbury conference and the latter was not necessary to perform a method
within the scope of claim 1 of the
patent. Moreover, the epithe
t “speculative” was
originally used by the US National Institute of Health in refusing

fessor Smith’s
grant application in respect of the epitope library.

Professor Smith adopted it in his

revised application

in which he said

“Perhaps the project
seems ‘speculative,’ but what can I
reasonably be expected to be able to report that will make it
decisively less so after 2 years’ funding (when I’ll be forced to
renew if I get only 3 years)

even granted that my vision is
thoroughly sound in all essent
ials and that I undertake the task
with commendable competence and energy, as indeed I will?”


Now it is true t
o say that Professor Smith
accepted in cross examination that the
project described in the
application was
speculative so far as
the antibody
display was concerned, but this must be seen in the con
text of
first, the fact that
Professor S
mith had never done an actual e
xperiment with phage antibodies;
the ot
her evidence Professor Smith gave
, and the judge accepted, that
his talk was
Judgment Approved by the court for handing down

MedImmune v Novartis

optimistic in tenor; and third,

that Professor Smith was reasonably confident it would


As for Professor Smith’s comment that he would not give the project to a PhD student
because it was speculative, this was a matter which the judg
e had well in mind.
Indeed he described
as in some ways the best piece of evidence in M
favour. But he explained that
he understood Professor Smith to mean that he would
want to assign to a PhD student a project which was more clearly certain
of success.
That, it seems to me, was a conclusion the judge was perfectly entitled to reach

and it
does not preclude a finding that the project was an obvious one for the skilled team to


hird, the judge is said to have fallen into error in r
easoning tha
t because P
Smith thought the experiment worth trying, so too would the ordinary skilled team. In
so doing
it is said
the judge applied the wrong standard. He considered the matter
the perspective of P
rofessor Smith

ther tha

m the perspective

of the
ordinary skilled addressee.

Moreover, if the

ordinary skilled
team had obtained the
results obtained by Professor Smith, they

have found those results so
discouraging they would not have continued.


I am unable to accept these

submissions. The judge certainly did consider the matter
from the perspective of Professor Smith in seeking to ascertain first, whether
Professor Smith considered the project had a reasonable prospect of success in a
reasonable ti
me and secondly, whether
that was

the message he conveyed to his
It must be remembered that Professor Smith was not only the leader in the
field but also explained the nature of the work he had carried out since the publication
of Parmley & Smith. In these circumstances
it seems to me that i
f Professor Smith
confident of success

and conveyed his
optimism to his audience, then
that was an entirely reasonable matter for the judge to take into account in assessing
how the ordinary skilled team would have react
ed to his presentation.


As for the results Professor Smith obtained, I accept these were not as good as he
hoped they might be. He achieved a

discrimination of only 100
fold. But, as the judge
held, the experiment worked, the results are comparable to Exam
ples 4 and 6 of the
patent and Professor Smith’s unchallenged evidence was that he would have
continued with his work were it not for the fact that
it had become clear that
CAT and
the group at Scripps were also working on it.


Finally, MedImm
une argued

that the judge failed properly to consider the position of

and had insufficient regard to the evidence given by Dr

In particular, t
he immunologist would have been concerned about the
antibody fragments failing
properly to fold, about non specific binding, referred to as
“stickiness”, and about the fusion phage suffering a loss of infectivity.


In my judgment the judge was

entitled to approach the matter as he did. For the
reasons I have given

I beli
eve the

judge correctly

identified the addressee as
being, or
at least including,
a skilled team having an interest in antibody engineering. If the
invention was obvious to such a team then the fact that it might not have been obvious
to another team witho
ut such an in
terest is irrelevant
. Further,
Dr Teillaud

was not
qualified in the field
of antibody engineering in 1990 and h
is experience was gaine
sometime later by working with the MRC and CAT teams. For these reasons the
Judgment Approved by the court for handing down

MedImmune v Novartis

judge considered that, while D
r Teillaud’s evidence was of assistance in
understanding the technical issues, it did
necessarily reflect the perspective of the
skilled team, or even that of a member of the team whose background was in
immunology. The judge also noted that even maki
ng full allowance for the fact Dr
Teillaud was not giving evidence in his mother tongue, he found him to have a
tendency at times not to answer the questions put to him and to be slightly

theless, the judge did have regard to
Dr Teillau
d’s evidence
he took it
into account
. Indeed he concluded it supported a finding of obviousness.

Conclusions on obviousness


The judge made no error of principle in assessing obviousness. In the course of his
careful and

detailed judgment, he assessed

the various arguments deployed by
MedImmune on this appeal and his reasoning cannot be criticised. I am satisfied that
the judge was entitled to reach the conclusion the patent was obvious over the
Banbury conference presentation. Indeed, on the fact
s as

he found them, I believe the

came to the right conclusion.



In light of my finding in relation to obviousness it is not strictly necessary to deal with
the issue of priority. Nevertheless, since we heard full argument on the point, I will
press my conclusions in relation to it.


The judge held the patent was not entitled to priority because claim 1 extends to post
display derivatisation whereas the priority document only discloses pre
display derivatisation.


Section 5(2)(a) of th
e Patents Act 1977 provides that an invention is entitled to
priority if it is supported by matter disclosed in the priority document. By section
130(7) of the Act, section 5 is to be interpreted as having the same effect as the
corresponding provisions of

Article 87(1) of the European Patent Convention. Article
87(1) says that priority may be derived from an earlier application in respect of the
“same invention”.


The requirement that the earlier application must be in respect of the same invention
explained by the enlarged Board of Appeal of the EPO in

, [2001] OJ EPO 413; [2002] EPOR 167:

"The requirement for claiming priority of 'the same invention',
referred to in Article 87(1) EPC, means that priority of a
previous applicat
ion in respect of a claim in a European patent
application in accordance with Article 88 EPC is to be
acknowledged only if the skilled person can derive the subject
matter of the claim directly and unambiguously, using common
general knowledge, from the pr
evious application as a whole."


The approach to be adopted was elaborated

by this court
Unilin Beheer v Berry

[2004] EWCA (Civ)

1021; [2005] FSR 6 at [48]

Judgment Approved by the court for handing down

MedImmune v Novartis


…….The approach is not formulaic: priority is a
question about technical disclosure
, explicit or implicit. Is there
enough in the priority document to give the skilled man
essentially the same information as forms the subject of the
claim and enables him to work the invention in accordance with
that claim.


Abbott Laboratories Ltd v Ev

edical Devices plc
[2008] EWHC 800 (Pat), I



So the important thing is not the consistory clause or
the claims of the priority document but whether the disclosure
as a whole is enabling and effectively gives the skilled person

is in the claim whose priority is in question. I would add
that it must "give" it directly and unambiguously. It is not
sufficient that it may be an obvious development of what is


I have set out the integers of the

claim at
] above. It is
to a method which involves
carrying out phage display (integers [2]
[9]) and then isolating the nucleic acid
encoding the binding molecule
of interes
t (integer [10]), inserting the

nucleic acid

encoding that binding molecule or a derivative of it in a reco
mbinant system (integer
[11]) and
producing the

binding molecule
derivative (integers [12] and [13]).


It is to be noted that derivative is defined in paragraph [0081] of the

patent (set out at
] above) very broadly to include polypeptides which
differ from the original
encoded polypeptide by the addition, deletion, substitution or insertion of amino
acids, or by the


of a number molecules

together. As Novartis submitted
, it

therefore encompasses
any change in the amino acid sequence provid
ed it remains
specific for the target. Moreover, and importantly, it does not require the derivative to
have been selected using phage display.


The critical question, therefore, is whether
the skilled person can derive

this method
directly and unambiguousl
y, using common general knowledg
e, from the priority


MedImmune argued

that he can

and took us to a number of passages in the priority
document in support of that contention.

I will deal with them in turn.


The description begins on p
age 1, lin
es 1

The present invention relates to binding substances. The
present invention also relates to methods for the production of
binding substances eg binding molecules and to the biological
binding molecules produced by these methods. The present
ntion also relates to: a) the production of antibodies,
receptor molecules and fragments and derivatives of these
antibodies and receptor molecules; b) viruses encoding the
above identified molecules, which viruses have the ability to
present said molecule
s at their surfaces; c) packaging
comprising a virus and an above identified molecule presented
Judgment Approved by the court for handing down

MedImmune v Novartis

at the viral surface; and d) screening techniques utilising the
unique properties of these packages.


This passage tells the reader that the invention relates

to derivatives of antibodies
receptor molecules
but says nothing about how those derivatives are to be selected.


Then, at page 2, line
s 10
25, it is explained that
known molecules include deri
such as scFvs, but
have their limitations:


has been shown that the function of binding antigens can be
performed by fragments of a whole antibody. Binding
fragments are the F

fragment which comprises the V

and V

of a single arm of the antibody, and the dAb fragment (Ward,
E.S. et al., Nature 3
41, 544
546 (1989); which consists of a
single heavy chain variable domain (V

Although the F

fragment is coded for by separate genes, it has
proved possible to construct a linker that enables them to be
made as a single protein chain (known as single c
hain F

(scFv); Bird, R.E. et al., Science 423, 423
426 (1988) Huston,
J.S. et al., Proc. Natl. Acad. Sci., USA 85, 5879
5883)) by
recombinant methods.

Whilst monoclonal antibodies, their fragments and derivatives
have been enormously advantageous, there a
re nevertheless a
number of limitations associated with them.”


Clearly there is no description here of phage display, let alone a description of
derivatisation after phage display.


A more promising passage begins on page 6. After the introduction of phage
antibodies and their use in phage display for screening, the description continues
page 6, line 34 to page 7, line 3:

“The use of pAbs may also allow the construction of entirely
synthetic antibodies. For example, V
gene repertoires could be
made in
vitro by combining unrearranged V genes, with D and
J segments. Libraries of pAbs could then be selected by
binding to antigen, hypermutated in the antigen
binding loops
in vitro and subjected to further rounds of selection and


MedImmune did

not rely upon this passage
at trial
but contended before us that it
clearly discloses phage display followed by further rounds of selection and

mutagenesis. Hence, it was argued, t
he reader would understand that mutagenesis,
which is to say derivatisation
can take place after phage display.



have not found this passage easy to understand. I accept it teaches mutagenesis of
pAbs after phage display followed by further rounds of selection and mutagenesis
But the question is whether the skilled person would understand he may take the
product of phage display, make a derivative and then use it without carrying out a
Judgment Approved by the court for handing down

MedImmune v Novartis

further round of selection by phage display. Not without some hesitation, I
conclusion the skilled person would not
understand the passage that way. I
believe the skilled person would understand it to be teaching that he may make
synthetic antibodies by combining together genes encoding different antibody
fragments, create pAbs,
carry out a selection process using an antigen, hyper
the binding loops
in vitro

and then carry out further rounds of selection, mutagenesis,
selection and so on, all using phage display. I
do not believe there is here a clear and
unambiguous disclo
sure of post phage display mutation which is not followed by a
further round of phage display.


Page 9, line 31 to page 10, line 5 extend

the description of the invention to enzymes
and enzyme encoding genes:

“The applicant has also shown that enzymes can
be expressed
on the phage surface. Useful applications of this invention
include the cloning of enzyme coding genes, or the design and
selection of mutant enzymes with enhanced properties on
particular substrates. For example, conditions can be used
eby the enzyme (or modified enzyme) binds a particular
substrate., product or intermediate (or analogues of them) to
identify from a library containing a desired activity or by
subjecting phage already expressing the enzyme, to in vitro
mutagenesis, follow
ed by selection of those variants with a
desired level of binding and/or catalysts.”


This is followed by a general description of the method of the invention on page 10,
lines 16

“The present invention also provides a method for producing a
binding mol
ecule specific for a particular epitope which
comprises producing a package as described above and the
additional step of screening for said binding molecule by
binding of said molecule to said epitope. The method may
comprise one or more of the additiona
l steps of: i) separating
the package from the epitope; ii) recovering said package; and
iii) using the inserted nucleotide sequence in a recombinant
system to produce the binding molecule separate from virus.
The screening step may isolate the nucleotide

encoding the binding molecule of desired specificity, by virtue
of said binding molecule being expressed in association with
the surface of the virus.

In the above methods, the binding molecule may be an
antibody, or a fragment or derivative of
an antibody.
Alternatively, the binding molecule may be an enzyme or
receptor and fragments/derivatives of any such enzymes or


Once again, I accept that these passages describe the production of derivatives but far
from constituting the disclo
sure of phage display followed by derivatisation, they
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MedImmune v Novartis

seem to me to be disclosing precisely the opposite, namely derivatisation followed by
phage display to select the derivatives of interest.


Page 11, lines 23
30 confirms

that derivatisation may take place by mutagenesis:

“In the above methods the nucleotide sequences inserted within
the viral genome may be derived from eg mammalian spleen
cells or peripheral blood lymphocytes. The mammal may be
immunised or non
. Alternatively, the nucleotide
sequence may be derived by the in vitro mutagenesis of an
existing antibody coding sequence. The phage particle
presenting said binding molecule may remain intact and


milarly, page 16, lines 8

the invention is concerned with the
production of biological binding molecules, their fragments and their derivatives:

“The disclosure made by the present applicants is important
and provides a significant breakthrough in the technology
relating to the pr
oduction of biological binding molecules, their
fragments and derivatives by the use of recombinant methods.”


However, nei
ther of these passages discloses

selection may take place by a process
other than phage display.


Finally, there is another important p
assage from page 17, line 37 to page 18, line 31:

The population/library of phage antibodies to be screened could
be generated from immunised or other animals; or be created in
vitro by mutagenising pre
existing phageantibodies (using
techniques well
n in the art such as oligonucleotide
directed mutagenesis (Sambrook, J., et al., 1989 Molecular
Cloning a Laboratory Manual, Cold Spring Harbor Laboratory
Press). This population can be screened in one or more of the
formats described below with reference

to figure 2, to derive
those individual phage antibodies whose antigen binding
properties are different from sample c. Example

of the
possible screening formats are:



Referring to figure 2(ii) antigen ag can be bound to a solid
support s

and bound to saturation by the original binding
molecule c. If a population of mutant phage antibody (or a set
of unrelated phage antibody) p is offered to the complex, only
those that have higher affinity for antigen ag than c will bind.
In most exampl
es, only a minority of population c will be
displaced by individuals from population p. If c is a traditional
antibody molecule, all bound material can be recovered and
Judgment Approved by the court for handing down

MedImmune v Novartis

bound p recovered by infecting suitable bacteria and/or by use
of standard techniques
such as PCR.”


Plainly this passage describes mutagenising phage antibodies, but it continues that
these are screened using phage display


I have addressed the passages of the priority document upon which MedImmune
relied separately but of course the skil
led person would read them together in the
context of the whole document, and that I have also done. Nevertheless, I remain of
the view that the skilled person would understand the priority document to be
he use of phage di
play to select
a bindi
ng molecule specific for a particular
epitope, separating the package from the epitope and using the inserted nucleotide
sequence in a recombinant system to produce quantities of the binding molecule.
There is no clear and unambiguous teaching of the creat
and use
of derivatives of
such binding molecules without also putting them through a phage display selection


I therefore agree with the

judge that
is not entitled

to priority and for this
reason too the patent is invalid.



For all the reasons I have given, I would dismiss the appeal.

Lord Justice Lewison:


I agree with the comprehensive judgment of Kitchin LJ.

However, I wish to
add a
few words of my own on the question of obviousness. The EPC provides:

Art 52

Patentable Inventions

(1) European patents shall be granted for any inventions which
are susceptible of industrial application, which are new and
which involve an inventive


Art 56

Inventive Step

An invention shall be considered as involving an inventive step
if, having regard to the state of the art, it is not obvious to a
person skilled in the art.”


These articles find their domestic equivalent in sections 1 and 3 of
the Patents Act

As Jacob LJ pointed out in
Actavis UK Ltd v Novartis AG

[2010] EWCA Civ
82 [2010] FSR 18 (§ 17):

So at bottom the question is simply whether the invention is
obvious. Any paraphrase or other test is only an aid to
swering the stat
utory question.”


The same point is made in
Manville Corporation’s Patent

[1967] RPC 479,
which is the starting point in domestic law of the idea of “obvious to try”.

In that case
Diplock LJ said:

Judgment Approved by the court for handing down

MedImmune v Novartis

I have endeavoured to refrain from coining a definit
ion of
“obviousness” which counsel may be tempted to cite in
subsequent cases relating to different types of claims. Patent
law can too easily be bedevilled by linguistics and the citation
of a plethora of cases about other inventions of different kinds.
he correctness of a decision upon an issue of obviousness
does not depend upon whether or not the decider has
paraphrased the words of the Act in some particular verbal
formula. I doubt whether there is any verbal formula which is
appropriate to all classe
s of claims.


In the same case Willmer LJ said:

I would, however, desire to associate myself pa
rticularly with
what Diplock, L
J said as to the undesirability of coining
phrases for the purpose of paraphrasing the words of the Act.


These sentiments seem t
o have been largely ignored by the profession. It cannot be
said too often that the statutory question is: was
the invention

obvious at the priority
date? It is not: was it obvious to try? In my judgment too much elaboration of the
statutory question has been attached to it. The questions of the degree of expectation
of success and the length of time thought to be needed to und
ertake a trial have taken
on lives of their own. I think that this happened in our case. Insistence on the
statutory question is not a novel thought. It is also an obvious one: see
Medsystems Inc


Angiotech Pharmaceuticals Inc
[2007] EWCA Civ 5

07] RPC

(§§ 44, 45 per Jacob LJ, approved on appeal:
[2008] UKHL 49

[2008] RPC 28

42 per Lord Hoffmann; § 49 per Lord Walker; § 55 per Lord Neuberger). In
(UK) Ltd v H Lundbeck A/S

[2007] EWHC 1040 (Pat)
[2007] RPC 32


LJ (as he
then wasn’t) said:

“The question of obviousness must be considered on the facts
of each case. The court must consider the weight to be attached
to any particular factor in the light of all the relevant
circumstances. These may include such matters as the m
otive to
find a solution to the problem the patent addresses, the number
and extent of the possible avenues of research, the effort
involved in pursuing them and the expectation of success.”


This statement of principle was also approved by the House of Lor
ds in
Medsystems Inc


Angiotech Pharmaceuticals Inc
. One of the important points, to my
mind, is that all these considerations interact with each other.

In short, it all depends.
mmune’s argument proceeded on the basis that Novartis needed to e
stablish (a) a
fair prospect of success (b) within a reasonable time, as if these were two independent
conditions that had to be satisfied. They are not successive hurdles to be jumped; they
are no more than aspects of the statutory question: was the inven
tion obvious? We
should stick to the statutory question, which has to be applied in all sorts of
circumstances and in all sorts of different fields of endeavour.


An invention is, at least usually, either a product or a process. So the statutory
question is
: was it obvious to make the product or to carry out the process? In order to
Judgment Approved by the court for handing down

MedImmune v Novartis

answer the statutory question it is, of course, necessary to decide what the invention
is. As Lord Hoffmann pointed out in
Biogen Inc v Medeva plc

[1997] RPC 1, 34:

Whenever any
thing inventive is done for the first time it is the
result of the addition of a new idea to the existing stock of
knowledge. Sometimes, it is the idea of using established
techniques to do something which no one had previously
thought of doing. In that ca
se, the inventive idea will be doing
the new thing. Sometimes, it is finding a way of doing
something which people had wanted to do but could not think
how. The inventive idea would be the way of achieving the
goal. In yet other cases, many people may have

a general idea
of how they might achieve a goal but not know how to solve a
particular problem which stands in their way. If someone
devises a way of solving the problem, his inventive step will be
that solution, but not the goal itself or the general met
hod of
achieving it.


In many “obvious to try” cases, it is the

of trying that constitutes the inventive
step. It was no doubt this that led Sir Donald Nicholls V
C to say in
Molnlycke AB v
Procter & Gamble Ltd

[1994] RPC 49

“… obviousness co
nnotes something which would at once

to a person skilled in the art who was desirous of
accomplishing the end.” (Emphasis added)


However, in our case, the patentee was not the first to have the idea of phage display
of antibodies or antibody fragment
s and using it to screen an antibody library.
Professor Smith had already had that idea, and made it public, some months earlier at
the Banbury conference. It is plain from the slide that he showed at that conference
that his proposal entailed an experimen
t with antibodies having different binding
properties, which are then exposed to antigen. Nor was the patentee the first to find a
way of doing it. The patentee used the method that had already been described by
Parmley and Smith two years before the prior
ity date. Nor did the patentee solve a
particular problem that stood in the way, because as things turned out there was no
problem. In short the patentee pursued an identified goal with known means. Where,
then, was the inventive step?


In some cases invent
ion can lie in finding out that something that was thought not to
work can in fact work. In
Pozzoli SpA v BDMO SA

[2007] EWCA Civ 588 [2007]
FSR 37 Jacob LJ put it this way:

27 Patentability is justified because the prior idea which was
thought not to wor
k must, as a piece of prior art, be taken as it
would be understood by the person skilled in the art. He will
read it with the prejudice of such a person. So that which forms
part of the state of the art really consists of two things in
combination, the id
the prejudice that it would not work
or be impractical. A patentee who contributes something new
by showing that, contrary to the mistaken prejudice, the idea
will work or is practical has shown something new. He has
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MedImmune v Novartis

shown that an apparent “lion in
the path” is merely a paper
tiger. Then his contribution is novel and non
obvious and he
deserves his patent.

28 Where, however, the patentee merely patents an old idea
thought not to work or to be practical and does not explain how
or why, contrary to th
e prejudice, that it does work or is
practical, things are different. Then his patent contributes
nothing to human knowledge. The lion remains at least
apparent (it may even be real) and the patent cannot be
” (Emphasis in original)


This, I think, is why the judge decided that the patent in suit was not obvious over
Parmley and Smith. That paper thought that expressing large proteins on filamentous
phage would probably not work. But at the Banbury conference Professor Smith’s
on had changed. In the meantime other workers in the field had published
important papers advancing this area of scientific endeavour as Kitchin LJ has
explained; and Professor Smith’s own thinking had developed. Although he may not
have gone as far as say
ing that his idea of phage display of antibodies or antibody
fragments and using them to screen an antibody library
definitely would

work, he
thought it was really worth pursuing; and was selling it as an idea to try. On the basis
of his previous work and
scientific analysis, he was reasonably confident of success,
although he recognised that success was not guaranteed. He was not predicting
problems; but he said that
there were problems, there were ways to overcome them,
which he identified. It cannot
be said that his idea was one which “was thought not to
work”; or that there was a “
prejudice that it would not work or be impractical
”. The
experts also agreed that the skilled addressee would not have expected to take a long
time to put Professor Smith’s

idea into effect, to see whether it did in fact work. In
fact it did. Mr Wyand QC argued that if the skilled addressee had been given
Professor Smith’s idea he would have gone back to Parmley and Smith to find out
how to put it into practice. On reading P
armley and Smith he would have noted the
reservations expressed in that paper, which would have put him off. In the first place,
whether that would have been the case is a pure question of fact, which the judge
resolved against Med
mmune. Second, as Mr Tho
rley QC submitted, if the skilled
addressee went back to Parmley and Smith it would have been to find out how to
implement Professor Smith’s new idea; not to second guess the idea itself.


Professor Smith had, so to speak, invented a weapon. He had fired i
t at a particular
target. At the Banbury conference he suggested that it could be fired at a different
target, which it might well hit. The patentee fired it. It hit the target as Professor
Smith had suggested.


Against that background can it be said that t
he judge was wrong to hold that the
invention claimed by the patent in suit was obvious?

Biogen Inc v Medeva plc

cautions an appellate court against interfering with a trial judge’s multi
factorial value
judgment on whether a claimed invention is obvious.
In this case there is no need for
such caution. In my judgment the judge’s conclusion was amply supported by his
findings of fact. I too would dismiss the appeal.

Judgment Approved by the court for handing down

MedImmune v Novartis

Lord Justice Moore


I agree that the appeal should be dismissed for the reasons given b
y Kitchin LJ. I also
agree with and endorse the observations of Lewison LJ on the question of
obviousness and in particular the proper approach to interpretation of the statutory