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Patents
in Animal Biotechnology: Roslin’s experience
to date
Dr
Harry Griffin
Roslin
Institute (Edinburgh)
Roslin
Midlothian
EH25 9PS
Scotland
UK
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- Roslin
Institute is the leading centre for research on the
genetics of farm animals in the UK, with internationally-recognised
programmes of research in animal breeding, genome
analysis, reproduction, growth and development, poultry
science, animal welfare and nutrition. Roslin Institute
has also pioneered the development of methods for
genetic modification of farm animals. Roslin Institute
was formally created on 1 April 1993 from the Edinburgh
Research Station of the Institute of Animal Physiology
and Genetics Research. This in turn was formed by
the amalgamation in 1986 of the Agricultural and Food
Research Council’s Poultry Research Centre and
Animal Breeding Research Organisation.
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- Roslin
Institute has more than 320 staff, visiting scientists
and PhD students. It is located close to the village
of Roslin about 7 miles south of Edinburgh city centre.
The Bio-technology and Biological Sciences Research
Council (the BBSRC; the successor of the AFRC) and
the Ministry of Agriculture, Fisheries and Food are
the major funders of Roslin’s research, contributing
approximately 30 and 45% of its annual turnover of
£10M. The remainder comes from a variety of
sources, including the EC, the Scottish Office, the
Department of Trade and Industry, industry organisations
such as the Meat and Livestock Commission and British
Poultry Federation and individual companies, particularly
in the animal breeding and feed compounding sectors.
The Institute’s staff are employees of the BBSRC.
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- Roslin
Institute’s traditional remit has been the improvement
of productivity and welfare of farm animals and this
continues to be a major focus of our research. In
the past, the expectation of sponsoring government
departments and the agricultural industry was that
the results would be freely available to everyone,
usually via the scientific literature. Encouragement
of a more ‘entrepreneurial’ attitude in
the public sector by successive governments, overall
reductions in funding for agricultural research and
new opportunities provided by advances in molecular
biology have produced some significant changes in
our relationships with sponsors and customers. Contracts
and collaborations with individual companies have
increased and last year we created Rosgen,
a specialist genotyping company which has first option
on results from the Institute’s farm animal genome
programme (i.e. any molecular markers linked to commercially
important traits).
- Nevertheless
the opportunities for major innovation in conventional
agriculture are limited and this is reflected in our
current portfolio of patent applications: 14 of the
patent applications filed by the Roslin Institute
are currently active, but only two have their primary
application in conventional agriculture. The remaining
applications cover techniques for genetic modification
of livestock and poultry. In these instances, the
immediate applications are in biotechnology and medicine,
where commercial rewards are potentially much larger.
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- This
paper will focus on our experience with patent applications
covering two inventions: (1) the use of the b-lactoglobulin
(BLG) promoter to direct expression of human proteins
in the milk of transgenic sheep and cattle (2) the
creation of cloned animals by nuclear transfer from
cells in culture. One important lesson from our experience
is that an appropriate vehicle for exploiting an invention
is at least as important as protection of intellectual
property.
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- BLG
promoter
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- Human
proteins are needed in large quantities for treatment
of a variety of human conditions, including relatively
common genetic diseases such as cystic fibrosis and
haemophilia. Some of these proteins are already purified
from blood, but this is expensive and runs the risk
of contamination ( e.g. by AIDS, hepatitis C or nvCJD).
Blood supplies are also limited. The idea of producing
therapeutic proteins in the milk of transgenic sheep
originated in early 1980's from the then Animal Breeding
Research Organisation (ABRO). Dr John Clark and his
colleagues at ABRO then showed, firstly in mice and
then in sheep, that the b-lactoglobulin (BLG) promoter
could be used to direct expression of transgenes specifically
to the mammary gland. Patent applications to protect
their invention were filed in 1986.
-
- Lack
of interest from the major pharmaceutical companies
prompted ABR0 to seek venture capital to create a
new company to exploit its invention. The company
now known as PPL Therapeutic was established in 1987
with one employee: it now has over 120 staff and is
one of three leading companies in its field. In 1991,PPL
produced ‘Tracy’ the first sheep to produce
large quantities of a human protein in milk (35 g
per litre). In 1996, PPL became a publicly quoted
company with an initial valuation of over £110M.
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- At the
time PPL was created, publicly-funded organisations
such as the Roslin Institute were not allowed to hold
equity in private companies and PPL is wholly independent
from the Institute. Scientific collaboration between
PPL and the Institute has continued and the Roslin
Institute has assigned a total of four patents to
PPL: two covering the use of original b-lactoglobulin
(BLG) promoter and two covering improvements to transgene
expression. US patents covering the use of the BLG
promoter and the specific construct were granted in
1994 and for transgenic animals carrying BLG transgenes
in 1995. European patents for the BLG promoter and
construct, but not for the transgenic animals themselves,
were granted in 1997.
-
- The
US patents will last until 2011; the European patents
until 2007. PPL’s lead product, alpha-I antitrypsin,
(AAT) is a protease inhibitor that is a normal component
of the lung’s defences against bacteria but one
which can be overwhelmed by persistent infection.
AAT from PPL’s transgenic flock is now being
used in phase II clinical trials to treat children
suffering from cystic fibrosis, a condition that afflicts
1/2500 of Caucasians. If clinical trials are successful,
AAT is expected to be on the market in 2001 (i.e.
some 15 years after the key patents were filed).
-
- Two
other companies are producing therapeutic proteins
in milk using similar technology. Genzyme Transgenics
in the US initially focused on using the whey acidic
protein ( WAP) promoter to direct transgene expression
to the mammary gland. Pharming in the Netherlands
have used casein promoters. This may appear to be
simply three companies based on the use of three different
milk protein promoters, but the situation is more
complex than this. For example, PPL & Genzyme
and Pharming & Genzyme have cross licence agreements
to each other’s technologies and broad claims
in a European patent granted to Genzyme to all casein
and milk serum protein promoters are being disputed
by Pharming.
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- Nuclear
Transfer
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- Recent
attention at Roslin has focused on Dolly, the first
mammal cloned from an adult cell and on the prospects
for the cloning of humans. Our reasons for doing the
work were to develop better methods for the genetic
modification of farm animals and -in the longer term-
to provide ways of multiplying elite cattle and pigs
in farm animal production. Until recently the only
way of producing transgenic farm animals was by a
technique called pro-nuclear injection. This involves
the introduction of 200-300 copies of the transgene
into recently fertilised eggs which are then transferred
to surrogate mothers. Only 1-2%of the offspring are
transgenic and only a proportion of these express
the transgene at commercially interesting levels.
Pronuclear injection can also only add genes.
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- The
ability to carry out more sophisticated genetic modification
is important to several biomedical applications of
genetically modified farm animals. In therapeutic
protein production, for example, there is a need for
large quantities of human serum albumin for a range
of clinical uses, including treatment of burns patients.
Annual demand is estimated at 500 tonnes, which at
a cost of $3 a gram translates into a world market
of over $1.5 billion a year. Cow’s milk already
contains a similar albumin and simply adding the human
gene to transgenic cows would require an expensive
purification step to separate the two proteins. The
more radical solution would be to replace the gene
coding for the cow’s albumin with the human serum
albumin gene. More sophisticated genetic modifications
are needed in xenotransplantation. There is a large
shortfall in the availability of human organs for
transplant to human in all countries and genetically-modified
pigs are being developed as an alternative source
of organs. At present it is only possible - by pronuclear
injection - to add genes to pigs and the ability to
also remove genes would greatly improve the chances
of preventing immune rejection.
-
- Experience
with bacteria, yeast and mammalian cells has shown
that very precise genetic modifications can be introduced
into cells in culture, including the removal or replacement
of specific genes or the introduction of the single
base pair changes into the whole of the genetic code
that are typical of many human genetic diseases. In
mice, the availability of embryo stem cells has allowed
genetically modified mice to be derived from genetically
modified cells. To date, however, no group has isolated
embryo stem cells in livestock.
-
- Nuclear
transfer provides an alternative approach. The technique
involves the fusion of individual cells with unfertilised
eggs from which the genetic material has been removed.
The ‘reconstructed eggs’ are activated by
a low voltage electric pulse and then implanted in
surrogate mothers. Cloned sheep and cattle were produced
in the 1980's by nuclear transfer of cells directly
from early embryos, but for nuclear transfer to be
used for genetic modification, it has to be successful
with cells that have been cultured for extended periods
in the laboratory.
-
- The
major technical breakthrough in our nuclear transfer
research was made by Ian Wilmut, Keith Campbell and
their colleagues in 1995 with the production of live
lambs - Megan and Morag - from an established cell
line. This success followed the use of serum starvation
to induce quiescence and patents were filed by Roslin
Institute to protect their invention in August 1995.
Subsequent work produced lambs from other embryo-derived
cells, from foetal cells and - in collaboration with
PPL Therapeutics - one lamb (Dolly) from an adult
cell. Roslin Institute and PPL subsequently announced
the production of the first transgenic lambs by nuclear
transfer. In December 1997, the editors of the prestigious
US journal ‘Science’ voted Dolly ‘Science
breakthrough of the Year’ ahead of NASA’s
Mars pathfinder mission and advances in cyclotron
design.
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- The
patent applications filed by Roslin Institute on August
1995 are described in PCT/GB96/02098 and PCT/GB96/02099.
Patents will be jointly owned by the Roslin Institute,
the BBSRC and MAFF and are unlikely to be issued for
at least 3-4 years. In the meantime, Roslin Institute
has been moving as quickly as possible to capitalise
on its invention. In considering commercial opportunities,
we have separated the possible applications by field
of use and then, within each field, considered the
relative merits of licensing, joint ventures or the
creation of a new company.
- The
Institute has concluded a licence agreement with PPL
Therapeutics that will cover two specific fields:(1)
the production of human therapeutic proteins in the
milk of livestock ruminants and rabbits (2) the modification
of milk composition for nutraceutical applications
such as infant formula milk.
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- All
other biomedical applications of genetic modification
of livestock, including xenotransplantation are covered
by a licence to Roslin Bio-Med, a new company
formed by Roslin Institute in collaboration with venture
capitalists 3i. The chairman of Roslin Bio-Med is
Ian Kent, formerly of Dalgety and Imutran and its
chief executive officer is Simon Best, formerly of
Zeneca Plant Science. 3i will be providing a £6M
investment over the first three years. One main advantage
of the creation of a company over a simple licencing
agreement is that it ensures the continuing involvement
of the Institute’s existing research team, but
the Institute also retains 42% of the equity and has
been able to bring in management with the experience
and skills to ensure commercial as well as scientific
success.
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- Conclusions
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- Timely
filing for patent protection is essential for protecting
the commercial value of inventions but our experience
over the past 10 years has shown that an appropriate
vehicle for taking the initial invention to commercial
reality is equally important. If a suitable commercial
partner does not already exist, it may be necessary
to create one. Moreover, given the time taken to grant
patents, the main use of the patent application is
to convince potential investors that their investment
will be worthwhile.
-
- Dr Harry
Griffin B.Sc., MBA, Ph.D is Assistant Director (Science)
at the Roslin Institute. He can be contacted by tel:<44>(0)131-5274478
or Fax:<44>(0)131 4400434 or by E-mail harry.griffin@bbsrc.ac.uk.
Further details about Roslin Institute can be obtained
from our web site on www.ri.bbsrc.ac.uk.
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