m&c biotech report 06 - marks & clerks/… · patenting human embryos.” indeed,...
TRANSCRIPT
BiotechnologyReport 2006
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . page 1
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . page 2
Stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . page 3
Overview
A realistic assessment
The legal position
Developments within the industry
Conclusions
Genetic diagnostic testing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . page 11
The market
The patenting landscape
The key players
Lessons for the future
RNA interference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . page 18
The market
The patent landscape
The key players
Conclusions
The future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . page 22
Marks & Clerk contacts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . page 23
CONTENTS
For us all to derive the significant benefits that should arise from the explosive growth of our basic
scientific knowledge an enormous investment is required from both governments and companies in
many industries over many years. In order for this investment to be viable, commercial and academic
organisations need a framework that supports and encourages openness and innovation; namely a
robust patent system, openly acknowledging the contract between governments and patentees of a
limited market exclusivity for innovations that are fully disclosed to all; and a fair playing field in terms
of regulation.
Over the past year, we have seen growing concern about the ethical aspects of biotechnology research: stem cell therapies raise
profound ethical issues; genetic diagnostic testing continues to raise issues over the appropriate use of genetic test results; and
the spread of H5N1 influenza ('bird flu') has moved governmental use of patented technologies further into the spotlight.
These issues serve to highlight that openness of and investment into biotechnology research and drug development are vital and
should continue to be priorities for governments, and academic and commercial organisations worldwide. They can no longer be
considered just national issues, or solely the concern of industry. Technology must move forward together with the ethical debate,
otherwise we risk stagnation while these questions are settled. The UK has been a good example of this approach working over
the past few years, although Europe as a whole has not.
This report provides an interesting and useful insight into worldwide patenting activity in three of the most cutting edge areas of
biotechnology - stem cell research, genetic diagnostic testing and RNA interference. We can draw a significant amount of optimism
from the report, not least in the rapid growth of patents in the field of RNAi since its discovery in 1998. It is an exciting new area
which could help to cure or treat a wide array of diseases, from HIV to cancer to diabetes.
No less important, but more controversial, are the areas of stem cell research and genetic diagnostic testing. In stem cell research,
the report notes reluctance from commercial companies to invest in R&D, perhaps due to the ethically based opposition to
embryonic stem cell research, continued uncertainty about what is patentable within Europe, and the lack of a clear regulatory
path to product approval.
Regulatory uncertainty can only serve to undermine investment into drug development. Historically the US has been the driver of
innovation; it therefore comes as no surprise that US companies are filing vastly more patents in all three areas of research, and
that the US Patent Office is far ahead in the number of patents granted. With growing competition from China, research and
development in the UK and Europe can not afford to linger in regulatory confusion for much longer.
The interests of industry, academia, and most importantly the public are not served by lack of clarity over ethical and regulatory
issues, nor by a lack of openness such as would result from a drive away from patent protection and hence publication with regard
to sensitive technologies. It is therefore essential that investment and the ethical debate move forward together, and that a
strong and open patent system exists. This report confirms that the patent system is a key driver for innovation leading to
improvements in our health and general economic well-being that we can all look forward to.
Dr. David Chiswell Chairman of Sosei Co. Ltd
FOREWORD
page 1
In 2005, Marks & Clerk published the first Biotechnology Report, in which we investigated patent filing trends in several areas of
biotechnology. This year we are pleased to present the second Marks & Clerk Biotechnology Report.
Once again, we have selected three areas of current interest in the biotechnology field, and have conducted detailed patent
searching in order to identify how many applications are being filed, by whom, and where.
Stem cell technology is perhaps more controversial than when we published the 2005 report, with evidence of scientific
misconduct, controversy over patenting the technology, and calls for aspects of the technology to be outlawed all coming to the
fore. At the same time, promising clinical results are pointing towards practical therapies being available in the immediate future.
Genetic diagnostic testing has the potential to be equally contentious, with outcries over patenting the genome and concerns over
the use and availability of patented tests. Previous studies have considered the patenting of genes per se, but this more specific
field is of considerable interest.
Finally, we also consider RNA interference, a relatively novel technology which has the potential to treat a wide range of disorders.
RNAi is likely to be one of the key therapeutic methods in the near future. As the technology is young, the fundamental patents
in the field are only now being granted, but already there has been considerable market activity as companies seek to establish
their position.
This report was compiled using, in part, patent searching performed on our behalf by CPA Analytics.
page 2
INTRODUCTION
The Marks & Clerk Biotechnology Report 2005 reviewed
patent filing and grant trends in the stem cell field. For
2006, we have decided to revisit and update the data from
last year, to investigate more deeply the stem cell area.
OverviewIn the short time since the 2005 report, stem cell
technologies and controversies have rarely been out of the
public eye. In his State of the Union address in 2006, US
President Bush called for “legislation to prohibit the most
egregious abuses of medical research - human cloning in all
its forms - creating or implanting embryos for experiments -
creating human-animal hybrids - and buying, selling, or
patenting human embryos.”
Indeed, relatively few countries at present specifically permit
the creation of human embryos for research purposes. Within
Europe, the Oviedo convention1 prohibits such activities; the
UK and Belgium have not acceded to this convention, and are
the only EU countries to permit human cloning in this form.
Outside Europe, countries with similarly permissive laws
include India, Israel, Japan, Singapore, and South Korea.
In the UK, the Human Fertilization and Embryology Authority
(HFEA) is actively granting licences for creating cloned
human embryos, and for deriving novel embryonic stem cell
lines from such clones. Perhaps surprisingly, a survey
conducted for the HFEA found that the UK public on the
whole trusted the Authority to be involved in regulating
embryo research, while relatively few trusted politicians or
religious leaders to play a role2. The UK Government is also
reviewing the law in this area, and in particular has called for
a review as to whether the creation of human-animal
chimeras should be permitted3, although even this may be
too late as research groups in the UK are reported as wishing
to carry out such research.
These scenarios are still generally at the level of basic
research, and we are a long way from viable treatments
based on the use of human embryonic stem cells.
A realistic assessmentIn contrast to the general media hype, some notes of realism
have been creeping into the assessment of stem cell
technology, and the likely benefits from such research. A
recent UK report4 contained an upbeat assessment of the
state of stem cell technology, but warned that, globally,
“investment from the venture capitalist community and major
pharmaceutical and healthcare companies will not be readily
forthcoming for stem cell research”, primarily due to the
uncertainties surrounding a return on the investment and the
uncertain reception of such research by the public. For this
reason, much current stem cell research investment is
directed by public bodies, whether national, as in the UK, or
subnational, as in California or New Jersey. However,
recognising the long term nature of these investments, the
report also called for “at least some of the UK's investment in
stem cell research [to be] strategically directed to more
conventional areas of medicine”; that is, investment should
recognise that key returns from the technology are likely to
be in areas other than human cloning or curing genetic
disorders. In particular, the potential of adult stem cell
technology and its application to neural disorders, bone and
cartilage disorders, cardiovascular disease, and lung
disorders, is clearly noted. A trite observation, perhaps, but
evidence that some reality is beginning to appear in the
assessment of the potential of stem cells.
The warnings of the UK Stem Cell Initiative were echoed by
industry leaders at the Reuters Biotechnology Summit in
February 20065. The lack of US federal funding for embryonic
stem cell research was said to be holding back US research,
while venture capitalists are reluctant to invest due to the
political uncertainty. The chief losers from the funding
STEM CELLS
page 3
1 Full title : Convention for the Protection of Human Rights and Dignity of theHuman Being with regard to the Application of Biology and Medicine:Convention on Human Rights and Biomedicine
2 Scientists must be engaged with the public if the UK is to stay a leader instem cell science, regulator warns:http://www.hfea.gov.uk/PressOffice/Archive/1132051010
3 Fifth report of the House of Commons select committee on science andtechnology http://www.publications.parliament.uk/pa/cm200405/cmselect/cmsctech/7/702.htm
4 Report and Recommendations of the UK Stem Cell Initiative, November 2005
5 http://today.reuters.com/summit/SummitInfo.aspx?name=BiotechnologySummit06
restrictions at present, however, are likely to be academics
rather than industry, due to the deterrent effect on
collaborations. In the long term, it is clear that industry needs
the academic research to be carried out, while academics
need industry support to commercialise their research.
Further unwelcome reality has come from the meteoric rise
and downfall of Hwang Woo-Suk, evidence that scientists are
by no means immune to the hype surrounding stem cell
research. Hwang's ongoing story has been told elsewhere, so
need not be repeated here. An interesting twist, however,
comes from the patent application relating to the fraudulent
work6: publication of the application may well limit the scope
for subsequent patents in the same field, despite the lack of
experimental data supporting the application. Furthermore, it
has been suggested that the patentability of the invention in
the European Patent Office (EPO) at least will not be affected
by the fraud, as there is no duty of candour to the EPO, unlike
the position in the US Patent Office (USPTO).
The legal positionThe scientific community is calling for more clarity and
consistency in the legal status of stem cell research. A joint
statement issued by the Hinxton Group7 in February 2006
called for consensus on the ethical framework for research. In
particular, the group expressed concern that legal restrictions
on human embryonic stem cell research in one country should
not affect collaboration with groups based in or travel to
another country with less restrictive laws.
In terms of the patent position, the main development since
the 2005 report has been the referral of the question of
patentability of human embryonic stem cells to the Enlarged
Board of Appeal of the EPO8. This simply switches
uncertainty at one level within the EPO to uncertainty at
another level. Until the Enlarged Board issue their decision,
which could be several years, the prosecution and grant of
European Patents which claim such stem cells, and perhaps
even those that rely on use of such cells for implementing
the invention, will be suspended. In the meantime, industry
will have to continue filing patent applications, without
knowing whether the invention is patentable. The Enlarged
Board decision also has consequences for the patent position
in national patent offices within Europe, although the UK
Patent Office continues to diverge from EPO practice in being
willing to grant patents to pluripotent human stem cells.
The patentability of stem cells in the USPTO is well-
established. Human embryonic stem cells may be patented,
while patents encompassing human embryos9 are not
granted by the USPTO - a practice which seems to be based
on the XIII Amendment to the US Constitution.
Developments within the industryWith these issues in mind, how is the industry reacting to the
concerns surrounding stem cell technology? Figure 1 gives a
summary of the number of stem cell patents10 granted each
year between 2000 and 2005. It is apparent that the USPTO is
by far the biggest granter of patents, reflecting both the
commercial importance of this market, and perhaps the relative
speed with which US patents are granted, particularly when
compared with the EPO. Of the various territories, only the US,
Australia, Europe, and Canada have granted sufficient numbers
of patents to register separately on this figure; the remaining
countries are grouped together as 'other', and in general have
granted as many patents as AU, EP and CA combined for each
year. The trend is consistently that more patents are granted
each year; a slight drop is seen in the 2005 data, but it is likely
that this is simply an artefact due to full 2005 data not yet
being available.
Of course, patent grant activity is only a part of the story, and
while it may highlight key markets (in particular the US), is
equally likely only to reflect the speed of patent prosecution
page 4
6 WO2005/063972
7 http://www.hopkinsmedicine.org/bioethics/
8 Board of Appeal case T1374/04, on EP 0 770 125 to Wisconsin AlumniResearch Foundation
9 The debate as to when a hESC is to be considered a human embryo doesnot yet appear to have taken place, at least publicly.
10 The search strategy was intended to identify patents relating to stem cellsper se, as well as uses, methods, and reagents relevant to the technology.The initial data set was taken through quality assurance procedures toremove any erroneous records based upon IPC outliers as well as obviousnon-relevant patent applicants.
page 5
Figure 1: Patent grants by year
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
in some jurisdictions, and the effect of uncertainty as to
patentability of some inventions (in particular, in Europe).
Accordingly, it is instructive to look at the numbers of patent
applications. The number of stem cell related patent
applications published each year is consistently around three
times the number of patents granted, although the ratios in
each country vary considerably. The US publishes only
slightly more applications each year than it grants, while
European published applications represent around five times
more than the number of granted patents. A large proportion
of the application figures are made up of published PCT
applications, which of course do not directly mature into
granted patents, but which may later become national
patents in numerous territories.
Further information regarding the stem cell industry can be
found in the location of priority filings. These may represent,
for example, the location of key research or of key companies,
although many non-US applicants will file first in the US purely
for commercial reasons. Figure 2 shows the number of priority
filings made in each country over the period 2000 - 2005.
As expected, the US dominates; although countries of the
Asia-Pacific region (China, Japan, Australia) all show significant
levels of priority applications. Europe as a whole is comparable
with China, although priority filings are split between
countries. Canada shows relatively few priority filings
considering its strength in stem cell research, which is likely to
be simply a result of Canadian applicants filing priority
applications directly in the US; such a practice appears to be
less common for European companies.
From the concerns noted earlier with regard to investment in
the industry, it would be expected that government or public
bodies will be key players within the industry. Indeed, the
patent filing data supports this. Figure 3 gives an indication
of those organisations which have filed significant numbers
of patent families in the period 2000 - 200511. Universities
and public bodies dominate the list, although a number of
specialist stem cell companies are present.
11 Note that these data are revised and updated from the data presented inthe 2005 Biotechnology Report; in particular, the identity of the applicanthas been normalised to take account of mergers, assignments, and patentapplications being held by different, but related, entities.
The current predominance of public bodies is also supported
by the UK Stem Cell Initiative Report12, which highlighted
patents considered to be “influential”; of sixteen patents,
seven were held by research institutes, universities, or other
non-profit entities. There are of course also many publicly-
funded stem cell institutes or other bodies in the process of
being established around the world. It is perhaps too soon for
these to have had any real effect on the patent landscape,
but future patent filings are likely to be more heavily
dominated by public bodies, at least until investors feel more
confident that stem cell technology will provide the returns
they seek.
This confidence is likely to be boosted by positive progress
being made by a number of private companies. For example,
Athersys is currently investigating use of their MultiStem™
technology (a non-ES cell technology) primarily for
cardiovascular conditions, and “anticipates the filing of
page 6
Figure 2: Location of priority filings
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
12 See footnote 4.
multiple Investigational New Drug (IND) applications likely in
the cardiovascular area and possibly involving an orphan
disease” in 200613. Stem Cell Therapeutics of Canada are
currently planning phase II clinical trials of their test
compound NTx(TM)-265, intended to promote growth of
neuronal stem cells in patients for treatment of
neurodegenerative conditions14.
In addition to the data given in Figure 3 regarding key patent
applicants, analysis of the rate of patent filing gives an
indication of the “fastest growing” companies in the field.
Figure 4 shows this analysis15.
Several of the emerging players also appear on the list of top
patent applicants, while others although growing rapidly
have not yet built a large enough patent estate to appear on
the list. The companies shown in this figure represent a wide
range of technologies and companies. ES Cell International
are a Singapore company focused on human embryonic stem
cell technology, with patent filings directed to cell lines
page 7
Figure 3: Top patent holders
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
13 http://www.athersys.com/products/regenesys.php
14 http://www.stemcellthera.com
15 The chart is based on a moving average of patent publications limited to1998-2003 comparing the filing rate of selected applicants with the globalaverage for all stem cell applicants.
themselves, and growth, maintenance and differentiation of
hES cells. Japan Science and Technology Agency is a
governmental body; while Monash University is an Australian
research institute. Lexicon Genetics are a US company, who
hold the rights to technology relating to transgenic mouse
knockout ES cell lines. Among other partnerships, Lexicon
have received a $35m contract from the Texas Enterprise
Fund to develop a knockout mouse ES cell library for the
Texas Institute of Genomic Medicine16. Stem Cell
Therapeutics have already been mentioned, while Advanced
Cell Technology, whose technology is intended to produce
pluripotent cell lines compatible with patients, have recently
relocated their headquarters from Massachusetts to
California; an early indication that California's stance on stem
cell research is achieving results. In addition to their own
patent applications, Advanced Cell Technology license in a
broad range of technologies from third parties; an illustration
of the range of technologies which involve stem cell research
is that several of ACT's patents are licensed by Genzyme
Transgenics Corporation (now GTC Biotherapeutics), whose
page 8
Figure 4: Patent portfolio growth rates
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
16 http://www.lexicon-genetics.com/alliances/other.htm
core technology itself relates to expression of proteins in the
milk of transgenic mammals.
Other companies are also relocating: Stem Cell Sciences,
originally founded to commercialise research from Monash
University and the University of Edinburgh, have announced
that they will shortly be moving their headquarters from
Edinburgh to Cambridge, UK, in part to gain access to the
technology available in the Cambridge area. Jeff Solomon,
CEO of ERBI (the regional biotech membership organisation
for Cambridge and the East of England) comments: “In the UK,
a significant number of stem cell and regenerative medicine
companies have set up in the Cambridge area recently. The
area is home to the Cambridge Stem Cell Institute, the UK
Stem Cell Bank and Bourn Hall; there seems to be a clear link
between this concentration of excellence in all areas of stem
cell expertise and the attractiveness of the region to new
and existing companies working in this field. I believe that
this trend will continue over the next few years, as
companies become concentrated in a relatively small number
of areas of excellence worldwide.”
A further illustration of the range of stem cell related
technologies is given by Figure 5. This shows the most-cited
patents against those identified in our research as being
stem cell related patents17. The data have not been
normalised, so patents granted in 2005 have been cited
fewer times than those granted in 2000. Nonetheless, the
data indicate a number of patents of potential significance to
the industry, and also provide a useful snapshot of the range
of technologies under study.
The table on page 10 shows the top five cited US patents.
The two Abgenix patents relate to methods for producing
humanised antibodies from transgenic mice; the mice are
produced by modifying ES cells before allowing them to grow
into an embryo. These two patents are members of the same
large family, which includes eight granted US patents.
Similarly, the NeuroSpheres patent is also a member of a
family having eight granted US patents, as well as six granted
and five pending European filings. This patent family relates
to the culture and proliferation of neural stem cells. SRI's
technology is used in the modification of ES cells for
generation of transgenic organisms, while the ThermoLase
patent covers a wide range of potential treatments for hair
conditions. Of relevance to the stem cell market, the patent
describes the grafting of autologous hair stem cells to treat
alopecia; perhaps an indication that in stem cell technology,
as with many other medical technologies, a key commercial
driver is cosmetic rather than purely therapeutic treatments.
ConclusionsThe sector is still very active, with a prominent role being
played by government and public bodies. This role is likely to
increase in the near future as national and state
governments rush to set up various stem cell institutes and
other research centres of excellence. While private
investment is still nervous of the returns to be made from the
technology, this is likely to continue. However, encouraging
results coming from private companies at present, particularly
in non-ES cell related technologies, should help to reassure
investors and promote the use of stem cell technology.
Consideration of individual companies and specific patents
shows that, at least for now, non-ES technology is likely to
provide best returns for direct patient treatment, while ES
technologies are more likely to be limited to roles in animal
cloning and generation of transgenic lines, at least for the
short term. Growth in the sector shows no signs of falling.
page 9
17 note that the data relates to US citations against US patents only
Figure 5: Citation rates by year
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
Patent Number Title Assignee
US6075181 Human antibodies derived from immunized xenomice Abgenix, Inc.
US6150584 Human antibodies derived from immunized xenomice Abgenix, Inc.
US6071889 In vivo genetic modification of growth factor-responsive NeuroSpheres neural precursor cells Holdings Ltd.
US6074853 Sequence alterations using homologous recombination SRI
US6050990 Methods and devices for inhibiting hair growth and related skin treatments ThermoLase Corporation
Top 5 cited US patents
page 10
"Genetic diagnostic testing will pervade all aspects of
our daily lives in the decades to come. Not only will it
bring diagnostics for debilitating human diseases and
encourage the development of personalised
therapeutics, but it will also service forensic science,
veterinary and sports medicine, paternity and
ancestry tracing and offer a potential antidote to
identity theft".
Professor Christopher. R. Lowe, Director of the Institute of
Biotechnology and Professor of Biotechnology at the University of
Cambridge
The marketThe Human Genome Project, together with spin-offs from
that project such as the SNP Consortium, the International
HapMap Project and the Protein Structure Initiative, have
instigated a new era in medicine. Gene-based diagnostics are
expected to become of increasing importance in healthcare
by enabling early diagnosis of disease, guiding drug
development and testing, and enabling tailoring of
therapeutic interventions based on genetic factors predictive
of drug efficacy and safety.
Along with deepening knowledge of the working of the
human genome, has come development of new techniques
for detecting genetic information. These include DNA “chip”
or microarray technology, and techniques for analysing and
comparing large amounts of sequence information
(bioinformatics). The fusion of technologies underpinning the
pharmacogenomics revolution is reflected by the diverse
range of companies spearheading the commercial utilisation
of pharmacogenomics from specialist genomics and “chip”
companies to major pharmaceutical and electronics
companies. Major universities, including most notably the
University of California, have steadily fed, and continue to
feed, much basic research in the genomics field into the
commercial world with growing associated IP portfolios.
However, application of genomics is quickly moving out from
the university laboratories and specialist companies into the
big providers of diagnostics and therapeutics.
The acquisition in 2005 of Genaissance Pharmaceuticals by
Clinical Data along with an important IP portfolio covering
various genetic tests illustrates well how pharmacogenomics
is moving from being a new field to an increasingly prominent
and necessary part of the business of any company seeking
to be, or remain, a key commercial player in healthcare in the
21st Century.
The patenting landscapeRecent patenting analysis in relation to genomics has been
very much driven by concerns over the issue of ownership of
genes. The effect of such ownership on freedom of academic
researchers to further build publicly available knowledge on
the working of the human genome is a key issue. Such
analysis reported in Science in October 200518, and more
recently in a report by a committee of the National Academy
of Sciences in the US19, has shown that almost 20% of human
genes (4382 of the 23,685 genes logged in the NCBI's gene
database by mid 2005) are the subject of US patent claims.
However, it is also clear that much of the deluge of early DNA
sequence filings made with no firm evidence of function, e.g.
relying on extrapolation of function from homology with
previously available sequence information, has already
languished or may well not survive scrutiny by patent offices.
A major contributor to sequence filings in this category was
Incyte Genomics which has metamorphosed into Incyte
Pharmaceuticals. Such filings are unlikely to comply with the
utility requirement applied at the US Patent Office and face
equally difficult hurdles in Europe as illustrated by Biotech
Appeal Board Decision T1329/04 at the EPO. That decision,
which concerns a Johns Hopkins University patent
application covering a new member of the growth
GENETIC DIAGNOSTIC TESTING
page 11
18 Article entitled “Intellectual property Landscape of the Human Genome”,Kyle Jensen and Fiona Murray, Science, 14th October 2005, 310, 239-240.
19 Report of the Committee On Intellectual Property Rights In Genomic AndProtein Research And Innovation organised under the auspices of theScience, Technology and Economic Policy Board and the Committee onScience, Technology and Law of the US National Academy of Sciences:“Reaping The Benefits of Genomic And Proteomic Research: IntellectualProperty Rights, Innovation, and Public Health” (2006), available on-line fromThe National Academies Press (www.nap.edu).
differentiation factor gene family, highlights that claims to
isolated sequences assigned a function on the basis of mere
extrapolation will be caught at the EPO on the horns of a
dilemma. Either the isolated sequence is obvious, or if post-
published evidence is required to reasonably confirm
function, the attack arises that there was no solution of a
technical problem at the filing date (which the EPO also take
as meaning that the claimed gene sequence fails to meet
the requirement of inventive step).
With a view to getting behind the figures on gene-related
patent application filings and determining the IP activity and
key holders of IP which in 2006 are driving forward
commercialisation of genetic diagnostic testing, we
conducted research to identify relevant patents and patent
application publications on or after January 1st 1998. As for
previous studies of DNA-related US patent claims, the data
not unexpectedly shows that US-originating IP dominates
the genetic diagnostic testing field. This is shown most
graphically by the country mapping of priority data for each
family in the complete dataset of publications (Figure 6).
Outside the US, the UK and Japan are the next biggest
contributors of IP, but the US exceeds the UK and Japan by
around 14 times.
Previous investigation of DNA-related US patents reported
accelerating numbers from the early 1990s, peaking in 2001.
By focusing more specifically on publication of patent
page 12
Figure 6: Location of priority applications
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
applications in relation to genetic diagnostic testing both by
the US Patent Office and elsewhere (Figure 7), particularly
fast growth in the number of publications is seen from 2000
onwards, peaking in 2002. However, the numbers for 2003
are not substantially lower and while complete figures are
not yet obtainable for 2004-2005 they can be anticipated to
reflect a continuing active area of innovation.
Analysis of the grant data (Figure 8) emphasises the
dominance of the US as regards both generation and grant of
relevant IP. Grants peaked in 2001 but after then have
continued at a fairly steady although slightly lower level.
However, the best indicator of innovation activity in the
genetic diagnostic testing field comes from looking at
earliest priority year data of relevant published specification
families.
Figure 9 shows earliest priority year data for all published
families in the dataset. Once again, we see a peak in 2001
which has accompanied maturing of the field and perhaps a
lowering of speculative filing in relation to sequence data.
However, analysis of assignee data reveals a very different
profile from that obtained from previous studies focusing on
who owns what genes.
The key playersFigure 10 shows the top 20 patent assignees in terms of
number of patent families. The University of California
emerges as a key IP holder whether one looks at claims of
DNA-related US patents or one chooses to focus more closely
on published patent specifications relating to genetic
diagnostics and extend the jurisdictions covered. However, in
acquiring Genaissance Pharmaceuticals, Clinical Data also
acquired the highest identified concentration of published
patent families relating specifically to genetic diagnostics.
Much of that portfolio would appear to arise from a
substantial filing programme over a short period of time and
publishing in 2000-2001, although Genaissance's portfolio
of published IP continued to grow subsequently. Genaissance
is joined in the top 10 IP holders by other specialist genomics
companies: Millennium (no. 3), Avalon (no. 4), Genset (no. 8)
and Curagen (no. 9). However, the appearance of Bayer at no.
10 reflects that major pharmaceutical companies are
acquiring relevant IP both internally and through alliances.
Extending the listing to the top 20 IP holders brings in
additionally Novartis, Merck and GlaxoSmithKline.
While there is a high dominance of key players in the US, two
European specialist genomics companies on the basis of
Figure 7: Published patent applications
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
page 13
page 14
Figure 8: Granted patent applications
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
Figure 9: Earliest priority year for patent families
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
patent application filings appear to be significant emerging
players in the genetic testing field, the German company
Epigenomics and the French company Genodyssee. Figure 11
shows the 'emerging players' in the field20 and indicates that
Europe is not being left behind.
The undoubted importance of microarray technology in the
growth of genetic diagnostics is reflected by the presence of
Affymetrix in the top 10. Extension of the listing to the top
20 highlights involvement of the major electronics company
Hitachi, a partner with Roche for the development of clinical
diagnostic systems. Four out of the top five cited US patents
20 The chart is based on a moving average of patent publications limited to1998-2003 comparing the filing rate of selected applicants with the globalaverage for all genetic diagnostic testing applicants.
Figure 10: Top patent assignees
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
in the dataset relate to detection methodology. This reflects
that in parallel with growth of gene sequence IP has come
significant developments in detection of sequences and that
both streams of innovation have been important to the
growth of genetic testing. The top five cited US patents are
listed in the table on page 17 (these relate only to US patents
cited against US patents).
Lessons for the futureIt is notable that while Myriad Genetics have attracted much
controversy in Europe over their licensed European patents
relating to BRCA1 and BRCA2 gene diagnosis of breast cancer
(assignees University Of Utah et al.), others have been far
more prolific developers of IP relating to genetic tests and yet
have not attracted the same adverse attention. The business
model of Myriad Genetics has clearly been a factor in bringing
the company into conflict with both government bodies and
diagnostic laboratories in Europe and elsewhere.
From the patenting perspective, the saga of the Myriad-
licensed patents provides a number of other lessons. Firstly,
the major issue in the oppositions to the BRCA1 gene
European patents (EP0699754, EP0705902 and
EP0705903) was a priority issue arising from the problem
that consensus sequences for diagnostically important genes
are liable to mature with time. The US priority application
filing programme for the Myriad-licensed BRCA1 gene
patents failed to take account of such maturation of the
initial sequence information for the BRCA1 gene such that
the same information deposited in GenBank by the inventors
was citable prior art at the EPO. This resulted in the broad
diagnosis claims of EP0699754 being held invalid for lack of
inventive step.
Equally of note is that Myriad have retained coverage in
Europe via both their licensed BRCA1 and BRCA2 gene
patents for mutations having high prevalence amongst
Ashkenazi Jewish women. This illustrates that commercially
page 15
Figure 11: Emerging companies
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
significant IP relating to genetic diagnosis may be achieved
by identifying key mutations.
Indeed, as also revealed by a previous investigation of gene
patents, others have filed on such findings, including in
relation to the BRCA1 gene21. All of the Myriad-licensed
BRCA1 European Patents are currently the subject of appeal
proceedings and it may be some years yet before their final
fate is known. The Myriad-licensed BRCA2 European Patent
was restricted to testing for the 6974delT mutation in the
Ashkenazi population after opposition but with a related
divisional pending covering detection of various mutations.
This again means that uncertainty over eventual patent
coverage is likely to continue for a considerable time.
However, identification of ethnic differences in genetic
variation looks set to be a fruitful, although sometimes
controversial, source of IP which will have an important
influence on application of genetic testing.
The problem of patent thickets in relation to genetic testing
has been voiced. It is evidently an issue that has the potential
to become more prominent in the future with the growth of
desire for microarray systems able to detect multiple
sequences simultaneously. However, it remains to be seen
whether in practice IP rights will commonly be so widespread
that a real problem arises. It is notable that the second
highest cited patent in the dataset is a US patent entitled
“Biomarkers and targets for diagnosis, prognosis and
page 16
21 Verbeue et al., 'Analysing DNA patents in relation with diagnostic testing',European Journal of Human Genetics (2006) 14, 26-33
page 17
management of prostate disease”. The owner, Urocor Inc., is a
company which has chosen to focus on diagnostics relating
to prostate cancer, bladder cancer, kidney stones and other
urological disorders. Other companies in the genomics field
are also choosing to focus on specific disease states.
The effects of genetic testing patents on the healthcare
industry will be profound. In the US, there will inevitably be
pressure from health maintenance organisations (HMOs) to
reduce costs; perhaps by encouraging service providers to
screen for susceptibility to diseases or responses to
treatment. However, the patchwork of different HMOs may
reduce their negotiating power, and service providers may be
able to resist the drive to use patented technology.
In Europe, state-provided healthcare services add complexity
to the commercialisation picture and we predict that health
service bodies in Europe will increasingly be generators of IP
in the genetic testing field. This will be driven in part by the
wish to secure freedom to use, and in part by the desirability
of provision of genetic tests at minimal cost as a basis for
prescribing decisions on expensive drugs. However, we can
also expect that health service bodies in Europe will come
under pressure to offer their patented tests to patients who
they are not set up to help. This will raise interesting
dilemmas if as must be predicted such outreach is seen as a
means of revenue generation.
A strong prediction must be that health service providers in
both the US and Europe will be forced to respect IP rights of
others in the genetic testing field as they themselves seek to
commercialise genetic tests. While some may continue to
decry the licensing fees sought by those companies seeking
to leverage value out of genetic testing IP, such protest may
become increasingly difficult to sustain.
Furthermore, in relation to certain diseases it may well arise
that testing has to be against a set of key mutations. This can
be anticipated to be a driver for patent pooling if patent
rights cannot otherwise be readily utilised to achieve
commercial value. There will undoubtedly be many more
changes in the ownership of IP underpinning the genetic
diagnostics revolution as companies re-position themselves
to take commercial advantage.
We predict that lessons will be learned from the saga of the
early patent filers, such that future IP protection will be more
specifically targeted, and IP holders themselves will be more
willing to license others to perform the tests rather than
carrying out testing in-house. This will both encourage the
use of patented technology, and will be an engine against
patent thickets; both of which effects will benefit patients
and the industry.
Patent Number Title Assignee
US5784162 Spectral bio-imaging methods for biological research, medical diagnostics Applied Spectral and therapy Imaging, Ltd
US5972615 Biomarkers and targets for diagnosis, prognosis and management of Urocor, Incprostate disease
US5795976 Detection of nucleic acid heteroduplex molecules by denaturing Stanford Universityhigh-performance liquid chromatography and methods for comparative sequencing
US5981180 Multiplexed analysis of clinical specimens apparatus and methods Luminex Corporation
US6013431 Method for determining specific nucleotide variations by primer extension Molecular Tool, Incin the presence of mixture of labelled nucleotides and terminators
Top 5 cited US patents
RNA INTERFERENCE
The market RNA interference (RNAi) has been hailed as one of the most
important recent discoveries in biology. The process was
originally identified in plants and invertebrates although the
usefulness of the technique as a potential therapy for
treating mammalian disease was first proposed in the late
1990s.
RNAi is a process by which short interfering molecules of
RNA (siRNA) are used to silence gene expression. siRNA
molecules induce the sequence-specific degradation of
complementary mRNA, or will specifically interfere with the
translation of such mRNA, and thereby inhibit expression of
the protein encoded by the mRNA. The technique is
considered to be of huge potential because it is possible to
design specific siRNA molecules that will target transcripts of
a selected gene and thereby modulate the expression of the
chosen gene. In principle, it should be possible to design
siRNA constructs to combat almost any known disease of
plant or animal, that is characterised by pathological over-
expression of a protein.
In contrast with other gene silencing techniques, results of
pre-clinical trials have been very encouraging and
consistently suggest that RNAi will be of significant clinical
utility. In May 2005, the US company, Sirna Therapeutics,
published results of clinical trials for an siRNA molecule that
shows promise for treating age-related macular
degeneration. Furthermore, in December 2005, Alnylam
Pharmaceuticals initiated Phase I clinical trials for siRNA
directed against Respiratory Syncytial Virus and
interestingly, in view of the current concerns with avian
influenza, also has siRNA molecules for treating pandemic flu,
in advanced stages of development.
It is anticipated that 2006 will see the publication of the
results of a number of other trials from these companies and
other leaders. Over the next few years, the industry expects
to see a serious race to complete efficacy trials and
ultimately to secure regulatory approval for the use of RNAi
in the clinic.
The patent landscapeRNAi was first published in the literature in 1998 with some
of the platform patent applications filed shortly before this
date. It will therefore be appreciated that the number of
patent applications filed, and in particular, patents granted,
will be somewhat limited compared to more mature technical
fields. Accordingly, it is not surprising that Figure 12
illustrates that only a few patent documents relating to RNAi
were published in the late 1990s, whereas the number of
published cases in 2003 had reached more than 700
published applications. There was nearly a threefold increase
in published applications between 2001 and 2002, followed
by a further trebling in numbers of publications between
2002 and 2003. We envisage that this exponential trend will
continue in the foreseeable future and it will be interesting to
monitor the number of RNAi patent publications that become
available over the next few years.
Figure 13 illustrates the number of patents that have been
granted in this technical field. It is worth noting that it was
only in 2005 that the numbers of applications proceeding to
grant began to gather pace. 2006 appears as if it will be a
busy year for grants in this area. We have already seen the
Notice of Allowance issue in respect of one of the
fundamental patents in the US (US 10/832,248 - the so
called “Tuschl II” patent). This patent is likely to issue soon
after this report goes to press (March 2006) and it is
anticipated that this patent will be a key patent for the Max
Planck Society and its exclusive licencee, Alnylam
Pharmaceuticals. As this and other key patents begin to
issue, and given the commercial interest in this area, it will be
interesting to monitor to what extent competitors will start
to file post-grant oppositions and/or file actions in the courts
against each others patents. It appears that such “patent
wars” have already been initiated. A total of seven opponents
filed oppositions against one of Alnylam's key European
patents (EP-B-1144623 - the “Kreutzer-Limmer” patent). The
Decision of the Opposition Division of the EPO is eagerly
awaited and should issue shortly after the oral proceedings
that are scheduled for June 2006.
page 18
The key playersFigure 14 identifies 30 of the most active patent applicants
in the RNAi field. Many of them are seeking to protect the
platform technologies that underlie RNAi and it is not
surprising to see that many such applicants are academic
institutions (e.g. University of Massachusetts, Max Planck
Society or Cold Spring Harbor) although supply and
development companies such as Dharmacon also feature in
this category. Other applicants are pursuing protection for
treating specified medical conditions with carefully designed
siRNA molecules (e.g. Sirna). It is interesting to note that at
least some of the applicants identified in our analysis
represent those astute patentees that ensure RNAi is
encompassed by their therapeutic patent applications - even
if their main focus does not necessarily relate to developing
siRNA molecules per se (e.g. Rigel Pharmaceuticals Inc).
Sirna Therapeutics, based in California, is clearly one of the
front-runners in this field. It has a significant number of
patents in its own name; has licenced IP from the University
of Massachusetts; and has formed a number of strategic large
pharma partnerships (e.g. with Eli Lilly & Company).
Our investigations identified a number of patents and patent
applications in the name of Alnylam Pharmaceuticals
although the company was not included in the top 30
applicants identified by our search strategy. However, its
position in the market should not be underestimated on the
basis of patent applications standing in its own name.
Alnylam has skilfully acquired rights from many of the key
patentees identified in Figure 14. This has been achieved by
acquisition (e.g. of Ribopharma AG in 2003); through
exclusive licence deals (e.g. with Max Planck or Isis
Pharmaceuticals) and also by means of a number of
partnership deals (e.g. with Novartis).
Intradigm Corporation also feature in the key players list and
would appear to be a company to monitor for the future. It is
actively developing therapeutic siRNA molecules in a number
of areas. One of its lead programmes relates to the use of
siRNA for inhibiting angiogenesis.
page 19
Figure 12: Published patent applications
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
page 20
Figure 13: Patent grants over time
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
ConclusionsRNAi is a rapidly developing technical area and there is huge
optimism that efficacious siRNA molecules will be marketed
as therapeutics in the medium or even short term.
The technology promises much and we fully expect to count
the numbers of patent applications in their thousands in the
coming years. Many of the platform applications may already
have been filed and we anticipate the biggest growth to be
seen in patent applications that include siRNA molecules
within an arsenal of agents that may be directed against a
therapeutic target.
Many companies, in the race to file first, choose to file patent
applications based on the recognition that a particular protein
may have implications for a disease state following the
scientific discovery of an unknown physiological effect of
such a protein. Under these circumstances a medical use-type
application may be lodged that is somewhat speculative. One
of the dangers of filing such speculative applications is that
the application may be weak on the grounds of
sufficiency/enablement because the applicant may not be
able to fully describe the therapeutic agents they would like
to use. For example, the limit of their knowledge may be that
it would be desirable to utilise an inhibitor of the protein in
therapy but unfortunately no commercially viable inhibitor is
known. Many observers of the patent system may argue that
such applications are filed too early.
A number of tactics may be employed to overcome
sufficiency objections from patent offices. It would appear
that RNAi may represent a further way of overcoming
sufficiency objections. After all, if an inventor has the
sequence of the protein available to him or her they should
then be able to design and fully describe a siRNA molecule
for inhibiting expression of that protein and which may be
included in their patent specification.
Furthermore, it is relatively easy to test the effects of such
siRNA molecules on protein expression in a cell-line model
and thereby also fulfil the requirements of providing
supporting data in a patent specification. It therefore seems,
in the case of newly identified medical indications, that RNAi
may well represent a mechanism of rapidly providing a
disclosure that is both sufficient and supported and thereby
accelerating the rate at which a company can file to protect
its latest research.
page 21
Figure 14: Top patent applicants
Source: Computer Patent Annuities Limited Partnership/Marks & Clerk ©2006
This has to be balanced against the danger that simply
suggesting use of RNAi to suppress expression of a particular
gene may be considered obvious by some patent offices,
particularly as the design of effective siRNA molecules
becomes essentially routine as the technology matures.
Accordingly, any patent application covering RNAi in this
fashion should also ensure that the concept of inhibiting the
protein in question should be considered to be a new and
inventive therapeutic proposal. If this is not in itself
inventive, it may prove difficult to obtain protection for
anything other than very specific siRNA fragments which are
shown to be particularly effective.
It is our view that there will be a significant increase in the
number of filings that contemplate therapeutic uses of siRNA
molecules. We predict that the next few years will see
thousands of applications being placed on file that relate to
the use of RNAi for modulating the expression of proteins
that have been discovered to contribute to a disease state.
The very pace of change on the RNAi field will make it an
intriguing exercise to monitor patent activity over the next
few years and to see how the quickly developing patent
landscape evolves.
THE FUTURE
Despite the continued controversies over stem cell therapeutics and genetic diagnostic testing, there is clear evidence that
the patent position remains strong, and that there is significant growth and activity in the market. We predict that this
trend will continue, and that the number of patent filings will increase. However, until the EPO issue their ruling on
patentability of human embryonic stem cells, uncertainty will persist in this particular area. It is difficult to predict on which
side the EPO will rule. Nonetheless, the promising results from non-embryonic stem cell therapies are likely to encourage
industry regardless of the EPO's position, while strong government investment in the technology can only help the
industry. Government bodies are likely to continue to be important players in the field for some time to come.
Recent moves to restrict the scope of allowable gene patents at the EPO are likely to help the industry in the long term,
as patent thickets and broad dominating patents are less likely to occur. The necessity for applicants to demonstrate a clear
utility for a gene before it can be patented will discourage very early stage filings.
RNA interference technology is about to come of age, and there is likely to be considerable movement and consolidation
within this field as the complex overlapping patchwork of IP rights is clarified. There are clear signs that the main players
are willing to license their rights to others, so avoiding the patent thicket problem in this industry as well. As the
development of useful siRNA sequences for specific genes becomes almost routine, we expect that patents will perhaps
become harder to obtain, but the industry itself will flourish.
page 22
If you have any questions about this report, or would like more information, contact one of the authors from our
Bioscience Group:
Dr. Gareth Williams
UK & European Patent Attorney
66-68 Hills Road,
Cambridge, CB2 1LA, UK
T: +44 (0)1223 345520
Dr. Claire Irvine
UK & European Patent Attorney
4220 Nash Court, Oxford Business Park South,
Oxford, OX4 2RU, UK
T: +44 (0)1865 397900
Dr. Paul Banford
UK & European Patent Attorney
Sussex House, 83-85 Mosley Street
Manchester, M2 3LG, UK
T: +44 (0)161 233 5800
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