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Life Sciences Report 2014 Genome 2.0
Life Sciences Report 2014 2
Contents
Foreword 3
Introduction 4
Overview of research findings 6
Sequencing technology 7
Personalised medicine 12
Synthetic biology 18
Methodology 24
Contacts 25
Life Sciences Report 2014 3
As we finally emerge from the financial crisis, the word “recovery” can be seen everywhere. The life sciences sector is beginning to enjoy better times again – which is good news for patients seeking treatments around the world – but, as medicine continues to develop and industry focus moves from chemical compounds to biologics, any future “better times” will look very different to those we knew in the 80s and 90s. We are entering the age of personalised medicine.
Since the human genome was successfully mapped in 2003, we have seen incredible advances in sequencing technology. This in turn has revolutionised medical practitioners’ understanding of their patients and has enhanced their ability to select and even tailor treatments for specific conditions to specific patients. As an inventor in the area of sequencing technology, I am particularly excited by the opportunities that disruptive technologies can afford to patients. The ability to identify individuals’ predispositions to hereditary diseases or their susceptibility to particular treatments in a cost-effective and convenient way will ultimately mean that we can get the right therapies to the right people in more locations than ever before.
As we see in this report, patent filing figures in the areas of sequencing technology, personalised medicine and synthetic biology tell the contrasting stories of three relatively modern technologies at very different stages in their own narratives.
Intellectual property plays a central role in the development of new genome-based medical advances. Any entities looking to make a place for themselves in any of these markets need to consider how to best harvest their IP and how and where to protect it. This is important not only for large organisations, but also for SMEs and start-ups – as investors are so keen to see decent IP protection in place.
The opportunities offered by this new era of genomic research – “Genome 2.0” – are extraordinary. If the industry makes the right moves over the coming years, therapies for medical conditions both common and rare will successfully reach significant numbers of patients in need.
Prof Christofer ToumazouFounding Director, Institute of Biomedical Engineering, Imperial College London
CEO, DNA Electronics
Winner of the EPO’s European Inventor Award 2014 (Research category)
Foreword
Prof Christofer ToumazouProfessor Christofer Toumazou is Regius Professor of Engineering, Chair in Biomedical Circuit Design, Director of the Centre for Bio-Inspired Technology and Founder and Chief Scientist for the Institute of Biomedical Engineering at Imperial College. He is also Founder, Chairman and CEO of DNA Electronics and Chief Scientific Advisor to GENEU. In 2014, Christofer won the EPO’s European Inventor Award (Research category) for his microchip for quick DNA testing which can be inserted into a USB stick and provide results viewable on a computer within 20 minutes.
Life Sciences Report 2014 4
Welcome to the 2014 Marks & Clerk Life Sciences Report.
Since we published our 2013 report, there has been further significant change in the life sciences sector and the intellectual property landscape. The full impact of the US Myriad and Prometheus rulings is beginning to be felt, not least with the issue of the USPTO’s “Guidance For Determining Subject Matter Eligibility Of Claims Reciting Or Involving Laws of Nature, Natural Phenomena, & Natural Products”, which has provoked much unrest and even horror among IP practitioners. The Guidance goes to the heart of the patentability of “natural products”, which can include genes, peptides, or chemical entities; as well as of “natural phenomena” including therapeutic regimes. It is fair to say that there is much pushback from the industry, and we can expect legal challenges in the months ahead.
At the same time, there is renewed investment and energy in the sector. Governments across the world are actively funding a range of research, with the EU investing in personalised medicine and the UK and elsewhere in synthetic genomics. Private investment and industry acquisitions too are proceeding: Editas Medicine has raised US$43m of series A funding; San Francisco-based synthetic DNA company Twist Bioscience has raised $26 million in series B funding; and Roche has recently acquired the sequencing company Genias for up to US$350m.
This activity all takes place against the backdrop of continuing significant advances in the underlying genomics technologies. Since the end of the first era of genome sequencing with the conclusion of the human genome project, the challenge has been to apply the knowledge and the data generated to practical applications. It is not enough to simply identify a particular gene associated with a disease, or to identify a gene coding for a particular cellular pathway. Rather, we now have the ability to pinpoint a specific genetic variation in a specific patient which can predict sensitivity to certain drugs. Cancer genomes can be sequenced to determine which therapeutic will be most effective for a given patient. The US$1000 genome is becoming a reality, giving rise to the ability to rapidly and easily study an individual’s genome in its entirety. The UK’s NHS is leading the 100k Genome Project to obtain 100,000 individual genomes with a view to providing a dataset for advances in personalised medicine. There is also growing interest in sequencing and using the microbiome to generate advances in therapies. These developments are made possible by the new sequencing and analysis technologies which are now available, and by the ability to easily manipulate the massive datasets which will be acquired.
We are also at the beginnings of a new era in genome manipulation. RNAi, which allows selective gene silencing, is still a powerful research technique despite having lost some of its early lustre. The technique is gaining traction in therapy, with a number of RNAi therapeutics having completed clinical trials, and many more still in trials. Potentially more explosive are the CRISPR-Cas genome editing system and TALENS, which allow targeted cutting and editing of the genome.
Meanwhile, synthetic biology is growing. The first commercial applications of this have been in the industrial and fuel space, but designed drugs and entirely novel synthetic products are not far behind. Perhaps unlike other biotechnology sectors, there is also a growing army of enthusiastic “DIY” or “garage” synthetic biologists. It may be from here that the biotechnology equivalent of the Silicon Valley garage startups will come.
Introduction
Dr Gareth Williams
Life Sciences Report 2014 5
Introduction (cont.)
Together, these three key fields define “Genome 2.0”, the new era of genomics, medicine, and industrial biotechnology we are now entering. For this reason, our Life Sciences Report this year focuses on these three fields. We have reviewed patent filing data and geographical trends in the sectors to determine where the industry has been, and where it is going. Key players are identified from the data.
I am sure you will find the results of our research into Genome 2.0 interesting and that it will prove a useful guide to the technologies which will shape our biotechnology future. It has certainly thrown up a few surprises.
Dr Gareth Williams Partner, Marks & Clerk LLP
Life Sciences Report 2014 6
Our research into Genome 2.0 is based around patent analytics conducted in three selected areas: sequencing technology, personalised medicine, and synthetic biology and related technologies. Our methodology is discussed further at the end of this report and the results are analysed by individual sector.
We see that the total number of filed applications grew year-on-year until 2007, after which it has dropped slightly (Fig. 1). This dip is mainly owed to the decrease in applications related to personalised medicine (as is discussed in the later section on personalised medicine).
When we look at which organisations have filed the most patents across our three technology areas, we see that different applicants are unsurprisingly active in different sectors. There are however some entities which are strong in all three; these are generally public sector bodies, including the US National Institutes of Health (NIH) and the University of California, both of which have a broad research base. The NIH is also the biggest filer of applications in total, by quite some way, with 360 patent families filed. Roche, whose portfolio is primarily made up of personalised medicine inventions, is in second place with 154.
Sequencing technology is perhaps the most distinct of the three sectors, being dominated by Life Technologies and Illumina, which have little involvement in the other two sectors. Many applicants
active in synthetic biology and personalised medicine have no involvement in sequencing technologies, further differentiating this sector. It would, however, be wrong to call sequencing a niche sector. It is an enabling technology, fundamental to the progress of personalised medicine and synthetic biology, which requires specialised knowledge and skills to advance in.
The dataset highlights the role of public and private sector organisations distinctly. US public organisations feature heavily on the list of top filers, but France also appears to be a strong player in the market, with both the Centre National de la Recherche Scientifique (CNRS) and the Institut National de la Santé et de la Recherche Médicale (INSERM) appearing. Overall, the gap between the number of patent applications filed annually by public organisations and by private ones has grown since 2006. Public bodies are the main drivers of innovation.
These differences reflect the early stage that research into synthetic biology and (to an extent) personalised medicine are currently at, in which research organisations can still make significant contributions and advances to the technology. Even in sequencing technology, there is a strong showing from research organisations such as Stanford University, University of California, and Riken.
For a more detailed view of the results, we now turn to examine the dataset by sector.
Fig. 1: Total patent applications for sequencing technology, personalised medicine and synthetic biology inventions
Overview
Organisation Patents*
1National Institutes of Health 360
2 Roche 154
3 University of California 127
4 Life Technologies 102
=5 Illumina 89
Johns Hopkins University 89
7Institut National de la Santé et de la Recherche Médicale
84
8 Novartis 81
9US Department of Health 77
10 Oncotherapy Science 61
11 Bristol-Myers Squibb 54
12 Siemens Healthcare 51
13 Stanford University 50
14 Russian Government 49
=15 Merck 47
Mayo Foundation 47
University of Southern California 47
Centre National de la Recherche Scientifique 47
19 University of Texas 46
=20 Bayer 45
Riken 45
*Patent applications since 2003, one entry per patent family. Data for 2012 and 2013 incomplete due to 18 month delay in publication after filing.
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Table 1: Top filers of patent applications for sequencing technology, personalised medicine and synthetic biology inventions between 2003 and 2013
Life Sciences Report 2014 7
Since the discovery of the double helix, we have had an insatiable desire to decode and understand the complex chemical signatures of the genome. Not only has this furthered our understanding of the genomic structure and function of a wide range of different organisms, but it has driven the development of a raft of sophisticated techniques for nucleic acid sequencing.
Sequencing nucleic acids (DNA and RNA) underpins not only a large number of analytical and diagnostic procedures, but it is a whole area of research and service in itself. Sequencing technology now finds application not only in medical diagnostics but also in personalised medicine, forensic science and agriculture. The ability to determine a patient’s genome can help to diagnose a particular disease, can indicate susceptibility to numerous disorders, and can determine the likely response to a given drug or therapy. All of these uses contribute to the personalised medicine revolution. The first viral and mitochondrial genomes/sequences were determined in the 1970s using the laborious two-dimensional chromatography sequencing technology available at the time. The technique of Sanger sequencing propelled sequencing into a new era with more and more genome sequences being decoded through the 1980s and 1990s.
The first non-viral genome (Haemophilus influenzae) was sequenced in 1995 and since then many thousands of viral, bacterial and eukaryotic genomes have been fully elucidated.
While the human genome project used the established Sanger sequencing technology, innovation has been driven by a desire for faster and quicker sequencing techniques with the ultimate prize being the “US$1000 genome”. By 2007, the cost of sequencing an average human genome had fallen to about US$10 million and further development and research saw that cost fall to about US$5000 by 2013. Although Sanger’s methods are still used today, the process is best suited to small-scale projects and the elucidation of short sequences.
Through the 1990s and early 2000s, Sanger sequencing was gradually replaced by an array of faster, more reliable and cost-effective techniques, one of the most significant being the pyrosequencing
technique developed by Mostafa Ronaghi and Pål Nyrén at the Royal Institute of Technology in Stockholm in 1996, commercialised though the formation of Swedish company Pyrosequencing AB and further developed and refined by 454 Life Sciences.
In addition to overall improvements in efficiency and reduced cost, sequencing techniques have now developed improved sensitivity and so can be applied to trace samples and still reliably report detailed and accurate sequence information.
Disruptive companies
Oxford Nanopore TechnologiesIn 2005, Oxford Nanopore Technologies was born out of Oxford University. Their technology allows the direct electronic analysis of single molecules and can be used to detect and/or sequence nucleic acids. The technology exploits biological nanopores and enzymes capable of ratcheting a single strand of nucleic acid through the nanopore enabling the identification of the bases as they pass through. Particular advantages of this approach include the ability to directly detect the individual nucleobases without the need for amplification procedures or fluorescent labelling.
SequenomSequenom (Laboratories and Bioscience) are another innovator in the field of sequencing. Their technology exploits MALDI-TOF mass spectrometry to achieve nucleic acid analysis and is capable of delivering accurate and specific data from biological samples and from trace quantities of genetic material.
Helicos BioSciencesHelicos BioSciences provide single molecule fluorescent sequencing methods in which target sequences are hybridised with a series of fluorescent probes which are periodically imaged. Using the data from multiple images, gradually the sequence information is determined.
The number of patent filings in the field of sequencing technology has shown a general increase from 62 patent families in 2003 to 108 in 2009 (Fig. 2). The growth in filings made since 2010 appears to have
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Life Sciences Report 2014 8
accelerated, with 93 patent families in 2010 and 142 in 2011.
The notable dip in the number of filings in 2010 is likely because of the impact of the global financial crisis.
Further analysis shows that despite fluctuations in the total number of applications filed each year since 2003, there has been a relatively steady increase in the number of patents granted each year (Fig. 3). We therefore expect to see the number of patents granted continue to increase.
The correlation between the increase in total number of patents filed each year and the number of patent families implies that filing behaviour among applicants remains steady.
Unlike the other areas of technology analysed in this report, private companies appear to be the leading patent applicants in sequencing technology (Table 2). Public research institutes and universities do not figure heavily among the top applicants. The NIH and Harvard University have submitted applications for 23 and 20 patent families respectively since 2003, but the interest of the former appears to have peaked in 2007 (when it applied for six patent families) with only one patent family applied for in 2011.
The two largest players in the sequencing technology field are Illumina and Life Technologies (now Thermo Fisher Scientific). Predictably, they are the most prolific patent filers in our dataset. These two companies are clearly the driving force in this field and the data shows that both companies have consistently filed many patents since 2003/4 (Fig. 4).
However the data also illustrates the emergence of smaller companies with disruptive technologies. Oxford Nanopore Technologies began to protect their innovations with the first patent filings being made in 2009/10. Since then, our analysis shows two patent applications in 2010/11 and five already published from 2012. Helicos Biosciences are slightly less prolific having filed patents only in the period between 2007 and 2010. However, in 2009/10, they filed as many patent applications as Roche and Harvard University combined. In comparison, Sequenom has more consistently innovated over a longer period filing a small number of patents almost every year since 2003/4.
Intel is also a significant filer in this area, although not often regarded as a life sciences company. Since 2003/4, the American semi-conductor chip maker has filed a total of 20 patent applications directed to a variety of sequencing methods and consumables, with particular emphasis on techniques using enhanced Raman spectroscopy.
BGI ShenzhenFormed in 1999 BGI Shenzhen (BGI) has a broad remit to develop science and technology, build strong research teams and promote scientific partnership in the genomics field. It now promotes itself as “the world’s largest genomics organisation” and to date it has been involved in a number of major projects, including sequencing one per cent of the human genome; the complete rice, silkworm and potato genomes; and contributing vital expertise and data facilitating the completion of many hundreds of other genomes.
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Fig. 3: Total patent applications and patents granted for sequencing technology inventions
Organisation Patents*
1 Illumina 80
2 Life Technologies 70
3 Pacific Biosciences 35
4 Roche 24
5National Institutes of Health
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=6 Harvard University 20
Intel 20
BGI Shenzhen 20
9 Abbott 17
=10 University of California 15
Columbia University 15
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Oxford Nanopore Technologies 12
=16 Helicos BioSciences 10
Keygene 10
Sequenom 10*Patent applications since 2003, one entry per patent family. Data for 2012 and 2013 incomplete due to 18 month delay in publication after filing.
Table 2: Top filers of patent applications for sequencing technology inventions between 2003 and 2013
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Fig. 4: Patent applications (families) for sequencing technology inventions by top applicants
Life Sciences Report 2014 10
One of the most significant developments is the emergence of the Chinese company BGI as a major force in the sequencing field. Analysis of patents filed since 2003 shows that in 2007/8 BGI began to innovate in this area and since then has amassed at least 20 patent applications covering a range of methods and consumables for use in sequencing. Among their most recent patent filings are applications directed to new PCR sequencing methods which extend the capabilities of sequencers, methods of constructing digital gene expression profiling tag libraries (based on Illumina’s Solexa Single End sequencing platform), improved methods for nucleic acid identification and detection (using fragmented target nucleic acids amplified to create nucleic acid nanoballs) and consumable wash solutions for solving problems associated with the discordance
rate and mapping yield in nucleic acid sequencing reactions.
Additionally, BGI has developed and protected a range of techniques for sequencing methylated DNA, improving sequence analysis through the assembly of individual sequenced segments and diagnosing genetic abnormalities in nucleated red blood cells.
While companies such as Illumina and Life Technologies have been developing and protecting sequencing technologies for longer, BGI’s filing statistics are comparable to those of Roche, the NIH and Harvard University over the same period.
Analysis of the favoured first filing territories places the US at the top with the UK and Japan placed second and third respectively (Fig. 5).
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Fig. 6: Total patent applications since 2003 by geography for sequencing technology inventions
Life Sciences Report 2014 11
A large number of the Japanese first filings can be attributed to Hitachi, but in the UK, the numbers comprise a large number of smaller companies as well as the likes of Solexa (since acquired by Illumina).
Chinese and Korean companies have begun filing patents in their respective territories fairly recently and so the number of priority filings in these territories is, not surprisingly, low. However in the case of China, 50 per cent of the priority filings can be attributed to BGI.
When we look at the key territories for total patents filed, again, the US is a long way in front with a total of 2871 publications since 2003 (Fig. 6). However, Europe and Japan feature strongly too with 739 and 520 publications respectively. China is yet to match these territories but this is perhaps not surprising given the fairly recent emergence of BGI.
With the US$1000 genome almost a reality, there are increasing expectations that new methods of sequencing should further lower the cost – perhaps to US$500, perhaps even to US$100. There is clearly a considerable amount of continuing innovation in this field and if sequencing were to rely on a few well established protocols, costs could be expected to plummet over time. With any new technology comes initial cost, however, and thanks to the constant development of new and advanced sequencing methods, the cost of sequencing may have plateaued.
The developing field of personalised medicine (discussed in the next section of this report) is likely to drive further development in the field of sequencing technology – the ultimate goal being to provide systems capable of designing bespoke treatments based on the analysis of a patient’s genome. It is likely we will see developments aimed at the provision of cheap, portable and reliable equipment that can be used to analyse trace biological samples (for example small volumes of blood, saliva or cheek cell scrapings) for the relevant sequence data. We have already seen the emergence of Sequenom’s technology that can extract accurate sequence data from trace samples and improved nanopore technology is beginning to emerge.
The past 40 years have seen the emergence of a number of distinct sequencing techniques and there is every reason to believe that the next 40 years will see similar advances. Of the applications published in 2013, many concern new and/or improved nucleic acid sequencing methods. A closer look at the applicants shows that the likes of Abbott, the University of Washington and Roche are the principal filers of new sequencing technology with Sequenom, Siemens Healthcare and Philips contributing methods of analysing genetic variations, sequencing-by-synthesis techniques and devices for optically controlling nucleic acid sequencing respectively. Between them, we can expect these and similar advances to continue to improve the availability and versatility of sequencing technologies, and ultimately to reduce the cost still further, making a whole host of future applications possible.
Life Sciences Report 2014 12
Many drugs that have been approved for patient use are only effective in treating small proportions of the population. The effectiveness of cancer treatments is particularly low. Not only is this extremely wasteful, but it leads to prolonged morbidity for patients, and in certain instances increased mortality.
Personalised medicine has developed to help doctors screen patients to ascertain if they are likely to respond favourably to a particular treatment and tailor drug therapies to patients. This helps improve effectiveness of particular treatments and/or enable more informed choices of treatment to be made.
In one form, personalised medicine involves analysing a patient’s particular genetic make-up to help a doctor to identify the best treatment or preventative measures for a patient. In another, diseased cells or tissue may be removed from a subject and tested in vitro with a variety of drugs in order to determine the most efficient drug or dosing regime.
Historically, analysing a patient’s genetic make-up has often meant focusing on a particular genetic marker or markers associated with a particular disease and/or response to treatment. Certain drugs have been approved for use depending on specific mutations. Zelboraf ®, for example, has been approved for use in the EU for
the treatment of late-stage melanoma in patients with a BRAF V600 mutation.
While treatments based on the detection of single mutations are extremely important, diseases are often very complex and so identifying only one or a few markers may not always be sufficient to determine the best form of treatment. What is more, even though these tests are becoming simpler, they often have to be carried out in specialised laboratories remote from the patient.
In part the growth of personalised medicine relies on sequencing technologies (discussed in the previous section). With the advent of new techniques, machines such as the Illumina MiSeqDx platform are making rapid, cost-effective and on-site sequencing of patients’ DNA possible.
Advances in personalised medicine are reflected in the number of patent filings for related technologies in the field. Following the completion of the human genome project in 2003, there was a sharp increase in the number of published patent applications from 2003 (234 patent families) to 2005 (524 patent families), followed by a more gradual increase with a peak in 2009 (650 patent families) (Fig. 7). After a dip in 2010 (602 patent families) numbers recovered slightly, but unlike sequencing technology filings, have not yet returned to 2009 levels.
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Life Sciences Report 2014 14Life Sciences Report 2014 13
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Centre National de la Recherche Scientifique
Fig. 9: Patent applications (families) for personalised medicine inventions by top applicants The overall decline after 2009 contrasts with a continued increase in the number of PCT filings across all technologies, according to WIPO statistics. Despite a slight increase in the number of patent families, total filings have seen a drop from 2010 (2942) to 2011 (2570), suggesting that applicants are focusing on a smaller number of key jurisdictions. As sequencing becomes quicker and cheaper, one might expect this trend to reverse with an increase in filings in the field.
Despite a general decline in the number of filings in the area of personalised medicine, the number of granted patents has been increasing year-on-year since 2003 (Fig. 8). This could be due to a reduction in the number of highly speculative applications that never reach grant, indicating a greater understanding among applicants of where to focus research efforts as well as how to navigate the legal obstacles to patenting inventions in this field. However, taking into consideration the four to five (or more) year period between filing and grant, we may soon start to see a tail-off in the number of patents being granted in personalised medicine, mirroring the decline seen in published individual applications since 2007.
Of the top 22 applicants (based on the total number of published patent applications from 2003 to 2013), over half are public bodies, and ten of those are US research agencies, hospitals or universities (Table 3). The NIH leads the way in the field, applying for more than twice as many patent families as the second largest applicant (Roche). While the number of patent families applied for by the NIH has fallen over recent years, others (notably the French organisations INSERM and CNRS) have become more active in the field.
The US has large public research organisations, going some way to explaining the US public sector’s strong position. There may also be a defensive motivation for public bodies to protect IP to prevent the private sector from blocking access to diagnostic and treatment options, which could also explain the presence of two French public organisations in the list. In other countries, such as the UK, we often see patent ownership spread more widely across a number of smaller organisations.
Of the major pharmaceutical companies, only Roche, Novartis and Bayer are in the top 10 applicants, with Merck and GSK further down the list. Given that blockbuster drugs – often considered the ‘Holy Grail’ of the pharmaceutical industry – is a concept contrary to personalised medicine, this is not wholly surprising.
Organisation Patents*
1National Institutes of Health 304
2 Roche 127
3 University of California 85
4Johns Hopkins University 81
5Institut National de la Santé et de la Recherche Médicale
80
6 Novartis 72
7US Department of Health 68
8 Oncotherapy Science 61
9University of Southern California 46
10 Bayer 45
=11 Mayo Foundation 44
Siemens Healthcare 44
13 Amgen 40
14 University of Texas 39
15 Epigenomics 37
16 Merck 36
17Dana Farber Cancer Institute 35
=18Centre National de la Recherche Scientifique 31
Janssen Diagnostics 31
Stanford University 31
=21 Ohio State University 30
GSK 30
*Patent applications since 2003, one entry per patent family. Data for 2012 and 2013 incomplete due to 18 month delay in publication after filing.
Table 3: Top filers of patent applications for personalised medicine inventions between 2003 and 2013
Life Sciences Report 2014 15
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Fig. 10: Key geographies of first filing for personalised medicine inventions since 2003
Due to the specific nature of personalised medicine, research bodies and private companies will inevitably have to focus their resources on particular sub-types of patients, diseases and medicaments. Collaboration between large and small companies, public and private entities, and even between countries will become increasingly important, bringing with it issues surrounding the ownership of the resulting IP.
Consistent with the nationalities of the top assignees, the vast majority of applications were first filed in the US (Fig. 10). Filings at the EPO have lagged a significant way behind, with PCT, Japanese and British applications following. France is equal to Germany in terms of first filings which, together with the activity of INSERM and CNRS, reflects the support in France for research in this field.
The apparently anomalous presence of Iceland in the top 12 geographies can be explained by the activity of deCODE genetics. The company, a subsidiary of Amgen headquartered in Reykjavik, utilises the local population to identify genetic risk factors for common diseases such as cancer, asthma, stroke and heart attacks.
Between 2003 and 2011 over half of each of the top five applicants’ patent families related to cancer. Given the number of types of cancers and the complex genetic aspects of the disease, and the recent regulatory approval of some drugs being restricted to specific genotypes, this is unsurprising. The financial motivation to identify the best cancer treatment for a given patient as soon as possible will undoubtedly be driving public health bodies, particularly in the US where over 1.5 million new cases of cancer
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1052674 451 403 396 392 355 350 247
Fig. 11: Total patent applications since 2003 by geography for personalised medicine inventions
Life Sciences Report 2014 16
Enterome – an interview with Pierre Belichard, CEOEnterome, based in Paris, is pioneering the development of innovative disease management solutions based on a deep understanding of changes in the microorganisms, known as the microbiome, in the gut during disease and in response to therapeutic interventions. The company has identified this as an entirely new and untapped opportunity to impact medicine. Enterome is using its expertise and proprietary technologies to develop novel diagnostic products to support patient stratification, personalised therapies and the clinical development of new drugs for the treatment of microbiome-related diseases such as inflammatory bowel diseases and metabolic diseases (diabetes and obesity). Enterome’s unique Metagenotyping® process has enabled the development of biomarkers for treatment response prediction, disease activity monitoring and as potential companion diagnostics.
IP strategy“Enterome’s IP is generated through an approximately equal mixture of in-house discoveries and in-licensing. Like all companies that are creating a new industry, Enterome tries to maintain a competitive edge by keeping its overall, complex patenting strategy in-house. Gaining the IP rights to naturally occurring bacteria is relatively straightforward and Enterome produces patents in this area using standard procedures; however, since 90% of the bacteria in the human gut have not been identified and are ‘non-speciable,’ identifying and filing patents for the microbiome’s genes represents a potential gold mine.”
Emerging technologies“There are multiple technologies used in the microbiome field. Many microbiome researchers are trying to use old 16S rRNA sequencing technology, however more and more academic teams are using NGS and shotgun sequencing – this is also what Enterome is using. Unlike companies in the US, Enterome is developing a scalable, standardised technology platform that integrates stool collection, microbial DNA extraction technology and a robust sequencing platform. Increasingly, however US companies are starting to recognise the value of a standardised platform of this kind.
“ Sequencing the full gut metagenome is challenging and costly as it produces over 200 times more data than the human genome. In the discovery phase, technologies such as ion torrent™ from Life Technologies are supporting long and some difficult to handle sequences; however these technologies will evolve further to handle regions that can be tough to sequence or increase throughput and decrease costs. Also a lot of effort is being applied to bioinformatics and the handling of large volumes of data and improvements in biostatics and biometry are occurring on a daily basis.
“ Once metagenomic signature sequences have been identified they need to be validated and developed into a new biomarker/diagnostic/product that is standardised to enable regulatory approval. This involves technologies such as qPCR or the Nanostring® technologies, which have been the most promising, gaining FDA approval.”
“ Enterome, with its pioneering technologies, is leading the development of new industry standards in gut microbiome quantitative and functional analysis. The medical potential for the microbiome is enormous, providing a gold mine of opportunities for innovation and IP. Our Metagenotyping® platform is enabling the characterisation of a patient’s microbiome in association with their disease phenotype. This will allow development of novel diagnostic tests and enable new drugs to treat a range of important medical conditions based on the microbiome biology.”
are expected to be diagnosed in 2014 according to the NIH’s own statistics. While the recent focus of personalised medicine has been in cancer, we can expect to see an expansion in other fields, in particular respiratory and circulatory disease, neurology and infectious diseases.
More patent publications were made in total in the US than in any other jurisdiction, followed by Europe, Japan, Canada and Australia (Fig. 11). Clearly these are the jurisdictions in which patent protection is considered most important by applicants. Healthcare systems with clinicians able to put new diagnostic and treatment methods into practice make these geographies attractive markets.
Newer markets such as China and South Korea show low numbers of filings. Although patent filing numbers are high in China and, as identified in our report last year, China is an attractive market for the life sciences industry, the vast majority of patents filed there are from domestic companies. Foreign organisations are clearly yet to consider China a key geography for personalised medicine.
Since 2007, the EU has committed over €1 billion of research funding to personalised medicine through its Seventh Framework Program for Research and Technological Innovation. The Centre for Genome Science in South Korea is conducting three core projects, worth US$500 million, aimed at obtaining genomic and epidemiological information to develop customised medicines. In Japan, personalised medicine is seen as a priority area within healthcare, which is considered core to the country’s growth strategy. Riken, the Centre for Genomic Research in Japan, has been conducting the BioBank Japan Project on the implementation of personalised medicine since 2003. These initiatives, combined with the changing legal landscape in the US, may narrow the filing gap between US and these key jurisdictions over the coming years.
Life Sciences Report 2014 17
Patent eligibilityThe hardware or test kits providing an initial diagnosis or determination step prior to the patient being administered with a chosen drug therapy have not generally given rise to any patentability issues. However, patents claiming the genetic information necessary for making informed decisions have led to significant debate and new legal doctrine being developed.
The US has most notably considered this at some length, causing some considerable concern for the industry.
In the widely-reported Myriad case, the US Supreme Court held that an isolated DNA sequence which is identical to a naturally-occurring sequence is not patent eligible because it is a “product of nature”. This decision overturned previous practice at the USPTO, and goes against the position in most other countries. European law specifically states that an isolated gene sequence is patentable, even if it is identical in structure to that occurring in nature, provided that the function of the sequence is disclosed in the patent application at the time of filing. Similarly, the Australian Federal Court has ruled that Myriad’s patent is valid because isolated DNA sequences would not exist naturally outside the cell and thus constitute an “artificial state of affairs”. This decision is currently under appeal.
Meanwhile in China, no courts have yet dealt with the issue. It is unlikely that patents like Myriad’s will be allowed, however, because of the current SIPO Examination Rules relating to the use of human genetic materials and the exclusion of methods of diagnosis. That said, a kit which itself does not contain human genetic material, but which detects errors in a human’s genetic material, may be patentable with extensive prosecution and argumentation at the SIPO.
Returning to the US, the Supreme Court dealt a further blow to personalised medicine patents in Mayo v Prometheus. In this case, the patent claims related to a method of optimising drugs’ efficacy based on the correlation between drug metabolite levels and the likelihood of adverse side effects or ineffectiveness of treatment. The Court found that since this correlation exists independently of any human interaction, it is a natural process and, as such, not patent eligible.
In light of Myriad and Prometheus, the USPTO recently issued new guidelines for determining the patentability of claims which involve laws of nature, natural phenomena or natural products. Product claims are only allowable if there is a “marked difference” in structure between
the claimed product and a product occurring in nature. Most crucially, the guidelines extend the Court’s ruling in Myriad to all natural products. As such, medicinal formulations containing naturally occurring agents such as antibiotics, antibodies or peptides, all of which have traditionally been patentable, may become more difficult to protect. Unsurprisingly, concerns have been raised over the apparent change in the law, but it remains to be seen whether the courts themselves will adopt a similar position to the USPTO. In the meantime, the increased burden in obtaining and defending patent rights may have a negative impact on patent filings in the US, particularly from public entities. However, patent rights will continue to be central to the success of small and medium-sized biotechnology companies. As a result, a shift from the public to the private sector and a decrease in the dominance of the public sector may be seen in the US. Elsewhere, however, the public sector is expected to remain strong.
It will be interesting to revisit the personalised medicine field in 24 months’ time to determine the impact of the Supreme Court decisions on filing and publication trends.
Fortunately, the USPTO’s stance on natural products is not followed in other jurisdictions, including Europe, although it is well known that European law places other restrictions on the patentability of methods of treatment and diagnosis. The EPO has also recently hinted that it may adopt a stricter stance on inventions based on the identification of a new patient sub-group. This would bring the EPO into line with the UK, where the finding that a known drug is particularly effective for treating a specific group of patients is considered a mere discovery of an advantageous property of the drug, and not an invention (Bristol-Myers Squibb v Baker Norton Pharmaceuticals).
What is clear is that careful drafting of patent specifications will be required to navigate around the continually evolving and diverging laws in the field of personalised medicine.
Life Sciences Report 2014 18
Humans have been deliberately modifying genomes for at least ten thousand years, from the earliest domestication of plants and animals. The process has accelerated as understanding of first genetics, then molecular biology, and then the genome itself has developed. The human and other genome projects have given us the complete sequences of many genomes, and comparative genomics permits genes and proteins to be optimised for particular applications, and protein domains swapped and engineered to open up new uses. With modern tools, we are now at the beginnings of a revolution in our ability to shape and create life for our own purposes.
The first synthetic life has been developed – “Synthia”, produced by the J Craig Venter Institute in 2010, and in 2014, the synthesis of a complete replacement chromosome (synIII) for yeast. Genome editing tools such as TALENs (transcription activator-like effector nucleases) and more recently the CRISPR system (clustered regularly interspaced short palindromic repeats) promise to allow precision engineering of genomes.
Synthetic biology refers to the engineering of existing biological systems, and the creation of new systems, for various purposes. For example, new biological pathways may be created in order to synthesise particular desired products, or existing pathways may be optimised. In extreme forms, entirely new organisms
may be developed. Currently, the main commercial application of synthetic biology is arguably in the biofuels space, but other uses (e.g. pharmaceuticals, materials science) are not far off, with some more distant prospects including biosensors and others.
Genome engineering refers to the specific and precise targeting of genomic sequences in an organism, often for gene replacement or gene excision. The key technologies are the CRISPR system, TALENS, and ZFNs (zinc finger nucleases), although MAGE (multiplex automated genomic engineering) has also been used.
Together, these technologies promise a lot. While CRISPR has already been used to demonstrate targeted replacement of a faulty gene in adult animals, synthetic biology is being used commercially in the production of biofuels. Beyond this, a host of companies have sprung up to research synthetic biology, or to exploit the new genome engineering products. Synthetic biology is even being discussed for its potential role in culture and entertainment (think whistling termites and lily pad speakers). What is more, there is substantial government and public investment in the fields – for example, the UK Government announced in early 2014 an investment of £40 million to establish a number of synthetic biology research centres.
Synthetic biology
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Fig. 12: Total patent applications and patents granted for synthetic biology inventions
Life Sciences Report 2014 19
Where there is commercial interest, there is a role for IP to play. Given the huge promise of the technology, and the early stage of some of the core technologies, we can expect a crowded and uncertain IP field. Indeed, it would not be surprising at some stage to see a repeat of the RNA interference IP battles between various key players. Conversely, there is pressure to keep certain areas free of IP constraints – in particular, the various modular synthetic biology libraries are often open source.
Of course, there are obstacles to obtaining IP protection. With the new USPTO guidelines in relation to “natural products” (discussed in our earlier section on personalised medicine), how will these affect IP on key elements of the various systems, such as CRISPR, or synthetic biology modules (bearing in mind these are often generated from naturally occurring sequences)? How will other patent offices see these technologies? Will there be a flight of companies to more biotechnology-friendly jurisdictions?
The total number of patent filings for synthetic biology and genome engineering inventions by year appears unexceptional, with the number of granted patents rising from 99 in 2003 to 557 in 2012, indicating the general growth of the technology (Fig. 12). However, the number of filed applications appears to have sunk from an initial high in 2003 (1309) and 2004 (1407), and has not yet regained the original high levels.
The number of patent families shows a slightly steadier trend. Although there is the same fall after 2003 – 04, this recovers rapidly (280 families in 2004 to 282 families in 2011) (Fig. 13). This indicates that, although patent applications for inventions
are being filed, patent families are now being filed in fewer jurisdictions to give less global coverage.
One reason for this becomes apparent when considering the top applicants in the sector (Table 4). At first glance, the figures are dramatically different from the other sub-sectors analysed in this report. The top applicant is the Russian Government, with 49 families, and the Russian Department of Science and the Russian Department of Higher Education and Research follow closely behind with 28 and 24 families respectively. Similarly, Chinese universities and institutions are heavily represented in the rankings, for example Nanjing, Zhejiang, Jiangnan, Tsinghua, Chongqing, and Beijing Science and Technology Universities all making the top 21. However, digging deeper into the data suggests that these Chinese and Russian entities do not tend to file widely outside their home country. For example, of the 49 families filed by the Government of Russia, all of these were filed only in Russia (or Eurasia, in a few cases). Similarly, of the Nanjing University filings, only one was filed outside China, as a PCT application. This strongly suggests that, as is the case in other fields of technology, these applications are being filed for reasons other than simply protecting the technology.
The Russian Rusnano Corporation is a government-supported fund for investing primarily in nanotechnology, but also in fields such as synthetic biology. Recent figures suggest the corporation’s loss in 2013 was US$1.1 billion1. This is not the sign of a buoyant industry. In China, meanwhile, academics and inventors are assessed in part on the numbers of patent applications filed, with financial support available for making such submissions.
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Organisation Patents*
1 Russian Government 49
2National Institutes of Health
33
3Russian Department of Science
28
4 University of California 27
5 Bristol-Myers Squibb 25
6Russian Department of Higher Education and Research
24
7 Nanjing University 23
8 Zhejiang University 21
=9 Riken 20
University of Jiangnan 20
11 Tsinghua University 17
12Centre National de la Recherche Scientifique
15
=13Japanese Science and Technology Agency
13
Kyoto University 13
=15 Chongqing University 11
Corning 11
US Department of Defense
11
US Department of Energy 11
=19Beijing University of Science and Technology
10
Merck 10
National Science Foundation
10
Table 4: Top filers of patent applications for synthetic biology inventions between 2003 and 2013
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Fig. 14: Key geographies of first filing for synthetic biology inventions since 2003
1 ‘Rusnano Losses Rise 82%’, The Moscow Times, 6 May 2014
21Life Sciences Report 2014 20 Life Sciences Report 2014
Fig. 15: Patent applications (families) for synthetic biology inventions by top applicants
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However, there is no requirement that the technology be useful or even that the patent application be taken beyond the initial filing stage.
Synthetic biology is the only technology analysed in which the US is not the most common geography of first filing (Fig. 14). China leads the way, with the US in second place. Russia and Japan are almost equal in third (and fourth) place. Discounting the Chinese and Russian filings, the picture is more similar to other areas of technology, with the US and Japan being significant sources of innovation.
In fact, the main split in the dataset seems to be the distinction between private corporations and public bodies. By far the majority of applications are made in the name of public bodies.
Private organisations file relatively few applications. This could indicate that the technology is still at a relatively early stage, coming primarily from research institutes and universities, which would mirror the trends we saw in the early days of RNA interference technology in our 2006 report, where the majority of fundamental patents were from public bodies; later developments shifted towards companies such as Alnylam, Sylentis and others.
As synthetic biology technology develops, we expect to see a shift towards private companies.
Considering the list of top synthetic biology inventors, rather than applicants, we see that only one inventor from a Chinese institution is represented (Li Jun, from Zheijiang University, the inventor on a number of applications concerning synthetic liver cells and organs), and one from a Chinese corporation (Guozhong Zou, from Shanghai Hongbao Green Aquatec, the inventor on a number of applications concerned with holothurian [sea cucumber] farming and microorganism engineering in that context) (Table 5).
In contrast, there are five inventors from Bristol Myers Squibb, three from Japanese organisations (Riken and Kyoto University), and one from the US-based Scripps Research Institute. This indicates that the Russian and, to a lesser extent, Chinese, applicants are making many applications across a whole spread of technologies, which is consistent with the concept that protection of IP is perhaps secondary to other reasons for making these applications.
Some of these applicants appear no longer to be active. Bristol-Myers Squibb, for example, has no cases in the dataset since
Top Inventors Organisation
John N FederBristol-Myers Squibb
Peter G SchultzScripps Research Institute
Yokoyama Shigeyuki
Riken
Chen Jian Bristol-Myers Squibb
Guozhong ZouShanghai Hongbao Green Aquatec
Chandra S Ramanathan
Bristol-Myers Squibb
Thomas C Nelson Bristol-Myers Squibb
Wu Shujian Bristol-Myers Squibb
Hirao Ichiro Riken
Li Jun Zhejiang University
Yamanaka Shinya Kyoto University
Table 5: Top inventors of synthetic biology inventions since 2003
Life Sciences Report 2014 22
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Fig. 16: Total patent applications since 2003 by geography for synthetic biology inventions
2008, suggesting that it used to be active in synthetic biology but has since refocused on alternative technologies.
China perhaps has the potential to become a big player in the synthetic biology area, with the US Government recognising it as “a major component of China’s national technology and innovation strategy […] a centerpiece of the new, twelfth, five-year science and technology program”2. The US Government has also noted “the breadth and depth with which China is approaching synthetic biology as a means to address a broad range of Chinese needs and interests.” Perhaps this is simply not reflected in the patent filing figures, due largely to the difference in emphasis on IP as a driver of innovation in China and elsewhere.
Looking now at the total number of publications in each jurisdiction, even with the Russian and Chinese data included, the US is – as we see in other technologies – the major target for patentees. A key difference to other technologies, however, is that China comes second. This may be because many of the Chinese patent applications proceed to publication, despite not being filed elsewhere, but it may also represent Chinese investment in the field.
However, political engagement in itself is not enough to create an industry. For example, according to the US Government, the UK has perhaps “the most advanced program” in government support for synthetic biology, with some US$190 million recently invested. When we look at patent filings, though, the UK as the country of first filing is still lagging behind competitors such
as Germany, Japan and South Korea (not to mention China and the US), and is on a par with France. Of course, these figures are somewhat skewed because many patents effective in the UK are filed at the EPO, where patenting levels come close to Japan.
Synthetic biology is one of the key fields alongside computer software in which the conflict between open source and IP protection is being played out. For example, the iGEM registry, the BioBricks foundation and the Pink Army Cooperative are all proponents of the open source approach, with libraries of parts available for use. These open source components would obviously not be represented in our data shown here.
While the full ramifications of the US Myriad decision and subsequent revised guidelines on patenting of “natural products” in the US have still to become clear, it is undeniable that they will have an impact on IP protection of modules and components used in synthetic biology. Although, by definition, synthetic organisms are not “naturally occurring”, this may not in itself be sufficient to allow patent protection. For example, the Roslin Institute’s US patent application on Dolly the sheep, “a live born clone of a pre-existing … mammal”, was recently held to be unallowable in part on the basis that the clone was identical to a naturally occurring organism.
2 ‘The Evolving Nature of Synthetic Biology: A Panel Discussion on Key Science, Policy, and Societal Challenges Facing the International Community’, US Department of State, 16 August 2013
Life Sciences Report 2014 23
Synthetic biology is clearly still at an early stage of IP protection, with many of the related patent filings driven by academic and governmental institutions in the US and Japan, and in the emerging economies of China and Russia. While a significant proportion of the filings in these latter two appears perhaps to be politically driven – or at least, by factors other than the desire to protect the IP – it is undeniable that China at least has the drive and capability to become a significant developer of the technology, and that this is emerging largely from its universities.
We are also beginning to see the signs of a transition in the originators of the research, with private corporations (such as BMS or Merck) having been historically active in related technologies, but which are now falling behind public and governmental research institutes. Undoubtedly these will be eclipsed in their turn by newer startups founded to develop the latest technologies.
Life Sciences Report 2014 24
The patent filing data analysed in this report was provided by CPA Global.
Patent landscaping was carried out for patent applications filed around the world between 1 January 2003 and 31 December 2013 relating to three separate areas of technology: sequencing technology, personalised medicine, synthetic biology.
The search criteria used to identify patents relevant to each area of technology were as follows:
Sequencing technology Cooperative Patent Classifications
• C12Q1/6869
• C12Q1/6872
• C12Q1/6874
Personalised medicine Cooperative Patent Classifications
• C12Q-2600/106
• C12Q-200/112
• C12Q-2600/118
• C12Q-2600/136
• C12Q-200/154
• C12Q-2600/178
Synthetic biology Cooperative Patent Classifications and International Patent Classifications
• B01*
• C12N*
• C12P*
• C12Q*
• C12S*
• C40B*
*These classifications were filtered by specific keyword
strings and combinations relevant to synthetic biology
Analysis on top filers in each technology type was run in order to make the data set manageable. Reliable analysis could not be run for data from 2012 and 2013 due to the 18 month delay in publishing all patent filings. Some filing in this range may not be yet published.
Assignee (“Applicant”) data has been cleaned and consolidated to include patent reassignments and takes into account subsidiaries of the parent companies.
Assignee (“Applicant”) data has been cleaned and consolidated to include patent reassignments and takes into account subsidiaries of the parent companies.
Figures 2, 4, 5, 7, 9, 10, 13, 14 and 15 represent data with one entry per patent family (which may contain more than one related patent application in multiple countries).
Figures 1, 3, 6, 8, 11, 12 and 16 represent data with one entry per patent application (which may represent more than one entry per patent family where related patents were filed in multiple countries).
Methodology
Life Sciences Report 2014 25
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If you would like more information about this report, contact the authors from our life sciences group.
Dr Gareth Williams (Editor)Partner, European Patent AttorneyMarks & Clerk LLP, Cambridge (UK)e: [email protected]
Dr Paul ChapmanPartner, European Patent AttorneyMarks & Clerk LLP, Edinburgh (UK)e: [email protected]
Dr Richard GibbsPartner, European Patent AttorneyMarks & Clerk LLP, Glasgow (UK)e: [email protected]
Mike Gilbert Partner, UK Solicitor Marks & Clerk Solicitors LLP, London (UK) e: [email protected]
Michael LinPartner, US Patent AttorneyMarks & Clerk Hong Kong, Hong Kong (China)e: [email protected]
Virginia Beniac-BrooksPartner, Australian Patent AttorneyMarks & Clerk Australia, Melbourne (Australia)e: [email protected]
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