4. Mapping
of Rice Patents and Applications Onto the Rice Genome
This landscape is a work in progress and is designed to provide an overview of the policies involved with the patenting of the rice genome. We also provide an analysis of the genes and proteins that are claimed in United States patents and patent applications that have significant homology to the fully-sequenced rice genome.
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Kerry FluhrEmail:k.fluhr@cambia.orgLocation:AustraliaInstitution:CAMBIA[Close]
Kerry FluhrKerry obtained a B.A. in Biochemistry from Ithaca College, followed by a Ph.D. in Biological Chemistry from the University of Michigan, where her research focus was in the area of mechanistic enzymology. Following graduate school, she completed a postdoctoral fellowship at the University of Washington, where she studied Type III-secreted exotoxins in gram-negative bacteria. Kerry is also a USPTO-registered Patent Agent, and prior to joining CAMBIA, she worked for several years at a Seattle-based law firm. Her work involved the preparation, prosecution, and analysis of patents and patent applications relating to biotechnology and medical devices. As a patent analyst at CAMBIA, Kerry focuses on patent landscapes, patent tutorials, and other IP-related projects. Wei YangEmail:wei@cambia.orgLocation:AustraliaInstitution:CAMBIA[Close]
Wei YangWei is originally from China, where he obtained his B.Sc degree in biochemistry from Wuhan University. He worked at China National Rice Research Institute (CNRRI) as a research scientist before joining CAMBIA in 1996 and obtained a PhD in plant molecular biology from the Research School of Biological Sciences, Australian National University. Wei's PhD work on apomixis is shown in the BioForge apomixis project and is available to use under a BiOS license. He then worked as a Research Scientist at CAMBIA on Arabidopsis transgenomics. Wei has now shifted focus from scientific research to intellectual property and is working with the IP group in biotechnology-related patent analysis and assisting in Chinese-related IP issues. Kerry MillsEmail:k.mills@cambia.orgLocation:AustraliaInstitution:CAMBIA[Close]
Kerry MillsKerry studied for her BA and BSc at ANU, completing her honours year working on HIV at the John Curtin School of Medical Research in 1996. She then moved to Melbourne for her PhD at the Walter and Eliza Hall Institute (WEHI), studying surface proteins of the malaria parasite, Plasmodium falciparum. In 2003, she moved to Heidelberg, Germany, where she studied the earliest infection events of the Hepatitis B virus. She has now returned to her home town to work with CAMBIA. Marie Connett-PorcedduEmail:cambia@cambia.orgLocation:Australia (2007), FranceInstitution:CAMBIA (2005-2007)[Close]
Marie Connett-PorcedduMarie was CAMBIA's Deputy Chief Executive Officer 2005-2007. She led CAMBIA's Patent Lens development team, including the addition of biological sequence search tools, status and family information, and expansion from a life sciences database to all patent categories. She also coordinated the launch of the BiOS License and BiOS-compatible agreements covering materials transfer and data access, and the BiOS Initiative. Marie has a PhD from Cornell University where she worked on the molecular genetic and biochemical mechanisms underlying a pollen production deficiency. Her MBA was earned in the Moore Business School of USC. She has a BA in Modern Languages and Literatures, is registered with the USPTO bar as a patent agent, has co-owned businesses in two countries and has experience with intellectual property business rules in an array of different countries. She is now the CEO of A Rocha International. Richard JeffersonEmail:raj@cambia.orgLocation:AustraliaInstitution:CAMBIA[Close]
Richard JeffersonRichard obtained a PhD in Molecular Biology at the University of Colorado, followed by an NIH fellowship at the Plant Breeding Institute in Cambridge where he was responsible for creating and distributing amongst the most widely cited and licensed plant biotechnologies. CAMBIA, an international non-profit institute based in Australia was founded in 1991 and is dedicated to development of tools and enabling technologies to promote equitable life sciences-enabled innovation worldwide. The CAMBIA BiOS Initiative (www.bios.net) - the biological open source movement is an integrated response to increasing science and technology complexity, patent thickets and innovation system inefficiencies. As part of this work, CAMBIA created the Patent Lens, (www.patentlens.net), an independent, public-good global resource for increasing patent transparency. Richard has worked and taught extensively in the developing world, supporting the Rockefeller Foundation's biotechnology network for over ten years, and has worked as senior staff for the FAO, and consultant for other UN Agencies. He has been profiled in media including The Economist, Newsweek, Nature Biotechnology and Red Herring. CAMBIA's work has recently featured in cover editorials in most major life sciences journals. In 2003 he was named by Scientific American to the List of the World's 50 most influential technologists, cited as the World Research Leader for 2003 for Economic Development. Richard is an Outstanding Social Entrepreneur of the Schwab Foundation, for which is a regular panelist at the Davos meetings of the World Economic Forum. View full Curriculum Vitae. Carol NottenburgEmail:c.nottenburg@cougarlaw.comLocation:United StatesInstitution:Cougar Patent Law[Close]
Carol NottenburgCarol holds a Ph.D. in Genetics from Stanford University and a J.D. magna cum laude from University of Puget Sound (now Seattle University) School of Law. She was a biomedical scientist in the academic world for many years before earning her law degree. Her legal focus is patents and their strategic integration with business goals. In private law practice, she often counselled clients on freedom to operate issues and saw the need for more pragmatic learning tools about patents. Carol was the Director of Intellectual Property and Chief Legal Officer for CAMBIA until 2004 and oversaw the creation of the CAMBIA IP Resource. She has now returned to private practice as principal of Cougar Patent Law (www.cougarlaw.com) and is retained as a consultant for CAMBIA. Neil BaconEmail:neil@cambia.orgLocation:AustraliaInstitution:CAMBIA[Close]
Neil BaconNeil is from Hamilton, New Zealand, where he caught a B.Sc (Phys) at Waikato Uni. He did a short stint of seismic surveying in the Bass Strait with Esso and enjoyed a few stormy days of seas rougher than he imagined possible. He worked at the CSIRO Division of Fossil Fuels and did a part-time M.Sc. (Phys) at the UNSW. Since then he's been doing IT work, initially embedded engineering applications and telecommunications and finally more general IT, in the UK, NZ, Belgium and Australia. Neil moved back to Australia from Belgium to be warm and live near a nice surf beach, but something went wrong with the plan and he ended up in Canberra - oh well, it's great for cycling. Neil has worked extensively on CAMBIA Sequence Software |
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CAMBIA is working to redefine the scope and utility of Patent Landscapes by developing a landscaping framework that allows experts to participate in the process. We recognize that many of you, as readers of the rice genome landscape, may have imporant knowledge or insights to contribute. We encourage all interested readers to become involved in this work - with the view to improving the structure and content for all.
By joining our team as a Guest Contributor, you will be able add value to this landscape by creating, editing, and annotating pages in the landscape. We encourage guest contributors to identify themselves on their profiles. Anonymous profiles will only be allowed under extenuating circumstances.
Rice is a hugely important food crop for the world's population. It's importance goes beyond food security; rice plays a large economic and cultural role as well in many countries. Rice production must increase in order to sustain those who depend upon it. Besides traditional breeding methods, biotechnological methods are being applied to improve production. Some of these methods rely upon knowledge of the rice genome and use of genetic sequences.
This landscape is meant to support policymakers in assessing the implact of patent activity affecting access to the genetic material of rice. Lack of coherent information about the current holdings of patents in this field can hamper effective policies and research and development. To this purpose, the patent landscape presented here examines patents and patent applications directed to any part of the rice genome, directly analyzing the degree to which granted and pending patents cover the rice genome.
The landscape was produced by first compiling a comprehensive collection of patent sequences that are recited in the claims of United States granted patents and patent applications. Sequences were compiled from both NCBI and the USPTO. A program (MEGABLAST) was used to identify nucleotide sequences that are highly similar to sequences in the rice genome. To qualify as a “hit”, the sequence had to be at least 150 nucleotides in length and have a a probability value of 1e-200 or less. Matches with such values are highly statistically significant. Major findings include:
While there is relatively low amount of rice gene patenting in the U.S., patenting of rice genome in key rice-growing countries was not assessed. The amount of patenting in these other countries will depend on a number of factors, including whether and to what extent such patents are allowable, the effect of publication of sequences in U.S. patent applications and other publications, and the status of a patent system in these countries. Because of the undisputed importance of rice, further analysis of patenting in other countries is warranted. It is hoped that the information in this patent landscape will guide new analyses.
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With the increasing importance of patents, it is highly advantageous for scientists and business developers to be versed in the field of intellectual property. An understanding of patents is necessary to fully comprehend business opportunities, particularly in the area of agriculture.
In this intellectual property landscape, we analyze the patents, patent applications, claim drafting strategies, and key players in the area of rice (Oryza sativa) genome patents. In particular, we highlight bulk sequence applications and patents and applications with broadening claim language (such as hybridisation and percent identity language). To demonstrate these important aspects of genome patents, we will provide example patents and patent applications from various assignees and discuss their associated claims.
With this landscape and others now present on the Patent Lens, we strive to provide a readable and understandable overview of patents in some key areas of the life sciences. In this way, we hope to contribute to the public awareness of intellectual property issues that surround key research tools. The information in these reports is not exhaustive, but highlights issues that are likely to be of particular importance to those doing work in the area. In this regard, these reports can be used to open the door to the patent world and to provide a platform from which additional self-directed investigation can be performed.
This landscape is NOT intended as a legal opinion or as a substitute for legal advice, nor is it intended to make the user an expert in patents. Furthermore, the nature of the patenting systems worldwide means that new patents and patent applications may appear at anytime. Similarly, patents may lapse or patent applications may expire or be replaced by new applications. So, although we give extensive coverage of the intellectual property surrounding rice genome sequences, this landscape should be viewed as an insight and snapshot of the subject.
CAMBIA is in the process of developing new tools to enable our readers to use and understand patent information. As we develop these tools, we plan to incorporate new functionality into this and other landscapes. In addition, we are working on exanding our analysis of patenting of the rice genome to include amino acid sequences and additional related nucleotide sequences.
The goal of this report is to contribute to public awareness of intellectual property issues surrounding the genetic sequences of rice. Rice is an important economic crop, as well as a major subsistence crop for large populations. Because rice is a close genetic relation of other cereals such as wheat, maize (corn), and sorghum, patent claims over genetic sequences of rice can result in exclusionary treatment of genetic resources of these cereals. Also, as the first cereal genome that has been sequenced, the patenting behaviour of rice sequences may serve as a model for how sustenance crop genes are patented in the future.
Although the rice genome is relatively small compared to other flowering plants, we found hundreds of patent applications claiming rice sequences. As a part of our analysis, we mined the sequences claimed in U.S. patents and patent applications and identified sequences that had significant homology to the rice genome and provide links to these patents.
Because of the volume of patent activity in this area, a detailed discussion of all the patents and patent applications is beyond the scope of this landscape. Though our analysis of patents and patent applications below is not exhaustive, we highlight issues from which users can perform additional self-directed investigation.
Due to a variety of factors, such as drought, climate change, soil erosion, urbanization, and pollution, rice growers are faced with the challenge of producing more rice for more people, but with fewer resources. While government-based rice breeding operations have done extraordinarily well improving rice yield and quality using more traditional breeding methods, biotechnology will likely be a essential component of strategies aimed at meeting this challenge.
In the advent of gene patenting, access to enabling technologies may be impeded by intellectual property, material transfer agreements (MTAs), or other contractual arrangements. Gene patents, in particular, have the potential to monopolize genes and proteins associated with desirable agronomic traits. Patents also impact the gene-based tools needed to improve rice, such as transformation and genotyping techniques.
The inherent relatedness of plant genomes has the potential to expand the reach of patent claims well beyond their expected scope. In particular, the similarity between the rice genome and the genomes of other cereal makes it possible that patent claims to rice sequences will also literally extend to other crops. Similarly, patent claims to the genes of other crops may encompass portions of the rice genome.
Intellectual property also has an impact on a larger scale by shifting the demographics of rice research from publicly-funded organizations to private companies. This shift has changed who solves problems for whom, and who has access to the tools of innovation.
In addition, patent craft has evolved in the era of sequence patents. New patent strategies have emerged, and old ones have been re-tooled to claim biological sequence "inventions" as broadly as possible. For example bulk sequence applications, which we define as those claiming more than 1,000 sequences, are frequently filed although they are likely to issue with claims to only a few sequences. However, during the pendency of the application, the uncertainty of which sequences will be claimed in the final patent may be used to influence contracts and agreements that often have limitations and consequences far greater than an enforced patent.
Access to patent sequence data in the major rice-growing jurisdictions is limited or non-existent, which makes it extremely difficult to fully assess the impact of patents where they matter most. Since the vast majority of rice produced in the world is consumed in the same country that it was produced, domestic patent laws are key for determining access to innovation tools.
For example in India, it is currently not possible to conduct a full-text search of domestic patents or patent applications; only bibliographic information is available. How can anyone assess whether they have freedom-to-operate in India if they cannot access the claims or specifications of Indian patents? The uncertainty regarding the metes and bounds of patents can lead to exploitation of parties not privy to the inner workings of the Indian patent office.
CAMBIA’s goal is to facilitate access to science-enabled innovation by creating tools that promote patent transparency. To this end we have created the Patent Lens, which includes a free patent search tool that allows users to search the full text of patents and applications from the United States, Europe, and Australia as well as world (PCT) applications. In addition, we provide a BLAST-type tool that permits searching of sequences that are disclosed in the specification or recited in the claims of U.S. patents and patent applications.
The rice genome patent landscape outlines many of the key issues associated with patenting of the rice genome. Inspired by the analysis published by Jensen and Murray in 2005 (Science 310: 239-240), we have carried out an analysis of genes that are claimed in both U.S. granted patents and patent applications. Unlike Jensen and Murray, we included patent applications in our analysis.
This landscape cannot provide an exhaustive treatment of rice genome sequences patented in all jurisdictions. Because the U.S. Patent and Trademark Office (USPTO) provides sequence data in electronic form, we were able to do this analysis with U.S. patents and applications, and we have supplemented this with some information we were able to find on counterpart filings in other countries that report to a European Patent Office (EPO) database. Unfotunately, however, many jurisdictions do not make sequence information available electronically. For example, although sequence information for China filings has been discussed in a peer-reviewed journal article, we found it is not actually available.
Our analysis of U.S. patent applications shows that around 74% of the rice genome is recited in the claims of patent applications, but very small percentage ends up in granted patents. Numerous bulk sequence applications claim more than 100,000 rice genome nucleotide and/or amino acid sequences. Bulk sequence applications create uncertainty as to which sequences will issue when the patent is granted. While the application is pending, agreements can be made that benefit from this uncertainty. However, the patent office is stemming the tide on bulk sequence applications by limiting the number of sequences that are claimed in a granted patent to fewer than ten, and in many cases, only one or two sequences.
Our analysis of granted U.S. applications shows that a number of promoters, transcriptional activators and important structural genes are encumbered by patent claims. Pages in our landscape contain tables that provide information about these granted patents, as well as links to the Patent Lens.
One of the most important lessons in compiling this landscape was how difficult it was to access and analyse the data. If it was difficult for us, how difficult would it be for a small business enterprise wanting to enter this research area?
There are three major obstacles in our ability to conduct a thorough analysis of the rice genome; the lack of available patent data in key rice-growing jurisdictions, the lack of public information about patent licensing, and a lack of knowledge of case law in the rice-growing jurisdictions. While it is usually possible to determine who is the initial assignee of a patent application, it is virtually impossible to determine who is the rights holders of a granted patent with any degree of certainty. This makes it difficult to determine how to best conduct any negotiations regarding the patent.
This landscape is a work in progress, as the patent world is dynamic as new patents are filed, published, granted, or abandoned, and continuation applications are filed every day. Also, the landscape is changing as patent jurisdictions are increasing their capacity for search and analysis by individuals outside the patent office. CAMBIA plans to facilitate access to patent data from difficult jurisdictions and create new interactive patent landscaping tools to simplify the creation of new, dynamic, interactive patent landscapes.
Food security, which is the condition of having enough food to provide adequate nutrition for a healthy life, is a critical issue in the developing world. About 3 billion people, nearly half the world's population, depend on rice for survival. In Asia as a whole, much of the population consumes rice in every meal. In many countries, rice accounts for more than 70% of human caloric intake. As seen in Figure 1, the total consumption of rice (expressed as % of total calorie intake) varies widely between different regions. In Asia in total, just over 30% of all calories come from rice.
But within a region, rice intake varies even more widely. Figure 2 shows fifteen of the countries most reliant on rice for energy. The graphs show that although total Asian rice intake is around 30%, people in countries such as Cambodia, Bangladesh and Myanmar rely on rice for over 70% of their calories. Africans as a whole gain less than 10% of their calories from rice, but in countries such as Madagascar and Sierra Leone, people use rice for nearly 50% of their energy needs.
Figure 1: Rice as a percentage of total caloric intake by region (2000).*
Figure 2: Rice as a percentage of total caloric intake (top 15 countries)*
* Data in Figures 1 and 2 was extracted from Table 16 of the IRRI World Rice Statistics.
Rice yields have been increasing since the 1960s, but since the 1990s, growth in rice production has been slower than population growth. Indeed, it is anticipated that rice production will need to increase by 30% by 2025 in order to sustain those who need it for sustenance. However, climate change, especially access to water, soil erosion and other problems threaten rice yields. A study by the International Water Management Institute suggested that by 2020, one third of Asia could face water shortages.
Because of high domestic consumption of rice in rice-producing countries, the economic importance of rice differs from that of traditional exports. Worldwide, only 5-6% of rice is exported. Japan, for example, consumes their entire domestic production and has to import around 8% of their rice each year. However, this imported rice is not released to the domestic market, ensuring a high local price. Thus the pressures of world trade on these countries are not as great as for exported crops. It also makes these countries vulnerable to local catastrophes, such as crop failure due to inclement weather (eg too much or too little rain), pests (such as insect swarms) or diseases (such as rice fungal diseases).
Furthermore, because both rice growers and people who rely on rice for sustenance tend to be poor, there is a constant pressure from rice growers to keep prices as high as possible, and from consumers to keep the price low. This strain is in constant force in all rice-growing countries, but is particularly important in the poorest countries.
For a good overview of this subject, please refer to the United Nations Conference on Trade and Development website.
Beyond providing sustenance, rice plays an important cultural role in many countries. Products of the rice plant are used for a number of different purposes, such as fuel, thatching, industrial starch, and artwork.
Growing, selling and eating rice is integral to the culture of many countries. In Japan, rice was historically a product for the wealthy and is now a highly-prized crop. Many rituals surround the preparation of the rice beds, the sowing of the crop, and the harvest. In China, it has been suggested that rice has been cultivated for 3000 - 4000 years, where it gradually rose to become an important part of aristocratic life. China's rural culture has developed around the growing of rice, and foods made from rice are the basis of festivals such as the Land Opening Festival, which marks the start of the rice cultivation season, and the Spring Festival. Even in Western countries, rice is an important part of culture. Imagine Italy without risotto or Spain without paella!
In order to keep up with the increasing demand for rice, improvements are needed in rice performance parameters such as yield, quality, disease resistance, and other desirable growth characteristics. Conventional breeding methods will not be sufficient to yield the needed improvements in rice, and it is likely that biotechnology methods will be necessary to tap into the significant yield potential of rice.
This especially true in the case of hybrid rice. Many farmers have switched to growing hybrid rice due to the higher yields that it tends to produce. Technically, it is feasible to create intervarietal and intersubspecific hybrid rice strains by conventional breeding methods. However, it is impossible to exploit distant heterosis (the introduction of enhancing genes from other species or genera) without using molecular methods because crosses between plants of different species or genera normally leads to sterile offspring.
Hybrid rice is rice that has been created by crossing two different parental strains. Such crosses generally result in an F1 generation that is more robust than either of the parental strains. The improved qualities of the F1 generation is referred to as "hybrid vigour" or "heterosis". The hybrid vigour may result in superior agronomic qualities such as higher yield, stronger resistance to diseases, more efficient use of soil nutrients, and better weed control. Hybrid vigour and other superior qualities arising from crossing genetically different plants has been well known and used by traditional crop breeders for decades.
In the past, the production of hybrid rice strains was limited by rice's inherent propensity to self-pollinate. In 1974, Chinese scientists overcame this when they developed the first generation of hybrid rice using a three-line hybrid system based on cytoplasmic male sterile (CMS) lines and hybrid combinations. In 1996, an even more efficient second generation of hybrid rice was developed based on photoperiod-sensitive genetic male sterility (PGMS) lines.
Traditional rice production (i.e., non hybrid rice) relies on rice varieties. A rice variety is a rice line that is a group of rice plants distiguished by common characteristics of significance to agriculture and often has been assigned a commercial name. When rice is produced from a variety, a single line is planted and it fertilizes by self-pollination. When a rice variety is reproduced, it retains its distiguishing characteristics, and farmers can keep seeds for replanting next season.
In contrast, hybrid rice is the product of a cross between two distinct rice lines, and due to the difficulty of making hybrids, they are generally only produced by seed companies. Farmers do not save seeds for replanting because self-fertilization will result in genetic segregation of traits. Therefore, farmers need to buy new hybrid seeds every year. This may produce an economic hardship for the farmer, who has to balance the benefits of hybrid vigour with the annual cost of purchasing new seeds.
Hybrid rice for food security (2004). FAO Factsheet.
Yuan L.P. (2002) The second generation of hybrid rice in China. Sustainable rice production for food security, Proceedings of the 20th Session of the International Rice Commission, Food and Agriculture Organization of the United Nations.
Most, if not every, current application of new technology to agricultural productivity requires access to proprietary enabling technologies belonging to others. To actually deliver commercial innovations in agriculture that are derived from modern biotechnology requires "Freedom to Operate". Freedom to Operate refers to the permissive use of technology and materials in the research, development and delivery of products and processes.
Obtaining Freedom to Operate first requires an analysis of the intellectual property surrounding the technology area of interest. Intellectual property, and patents in particular, have potential to impact the production of rice. Patents on rice genes and proteins can have an effect on the research level by affecting access to the biotechnology tools used for rice improvement. It can also have an impact on a larger scale by influencing the structure of the industry that produces rice.
In the area of rice performance, it is straightforward to envision how patents may have an impact. Many of the desirable agronomic traits are controlled by genes, proteins, or regulatory elements that are the subject of patents. In addition, the enabling technologies, such as Agrobacterium-mediated plant transformation, that allow rice researchers to create strains exhibiting desirable agronomic traits are the subject of patent applications or granted patents. With this landscape and other features of the Patent Lens, we hope to enable readers to determine the patent status of the genes associated with important agronomic traits.
Patents can also have an impact on rice production on a larger scale. For example, a thicket of patents or pending patents may actually discourage investment in the downstream innovation often required to convert an interesting invention into a useful product. Patents may shift the demographics of the rice industry and affect who solves problems for whom.
Rice, apart from being a staple food for several billion people, is also a model system for cereals. For the rest of the world, other cereal crops, such as wheat, corn, sorghum and barely (among others) form the basis of most people's "daily bread". Rice is of particular use as a model for these other cereals because of the small size of its genome (430 Mb), its relatively short generation time and its relative genetic simplicity (it is diploid, or has two copies of each chromosome). Moreover, rice is quite easy to transform genetically. Wheat, in contrast, has a genome 40 times as large as rice, and can be diploid, but is more commonly tetraploid (4x), such as in durum wheat, or hexaploid (6x), such as in bread wheat. Each additional set of chromosomes adds complexity to genetic studies. But how can rice act as a model for other cereals? The most striking feature of the cereals is that, despite huge differences in genome size and ploidy, the genomes of rice and the other cereals are highly conserved. This conservation occurs not only in the sequences of the genes present, but in the order of the genes, or "synteny".
Rice and other plants, especially other cereals, are amazingly similar on a genetic level. For example, the genes are often present on the chromosomes in the same order (synteny), and moreover, the genes themselves are very similar at a sequences level (homology). This is important if the granted rice patent covers, through "homology" or "percent identity" language, a gene in other another cereal, such as maize or wheat. This means that when when patents contain broadening language, including percent identity language, they may literally cross-cover other species. That is, a patent on a rice gene with, for example, percent identity language, may actually cover genes in wheat, or barley, or even bamboo! This means that researchers in another field may be unwittingly infringing patents on rice. (Note however, that because of recent changes in U.S. patent law, a court is likely to interpret the claim to cover only rice.)
Patenting and research behavior resulting from rice genome data may have an impact on how other crops are handled in the future. In the years since the rice genome was sequenced, there have been tremendous improvements in high-throughput DNA sequencing. As a result, there has been an explosion in the number and variety of genomes that have been sequenced. It is likely that the disclosures and claims of some of the more recently-sequenced plant genomes will be modeled on the patenting behaviour of the rice genome.
Because many rice genome patents were filed before the related crop species were sequenced, there was relatively little sequence-based prior art to be found by patent examiners. As a result, earlier plant genome patents are likely to be broader in scope than later applications.
CAMBIA is continuously working to develop new tools and functionalities to support innovators worldwide.
The complexity of the patent system, unfortunately, can result in fear, uncertainty and doubt about what valid intellectual property rights exist. The existence of a patent does not necessarily mean that the claims are in force (e.g., maintenance fees or annuities might not have been paid) or valid (e.g., a court may have invalidated one or more claims). For this and other reasons, CAMBIA provides the Patent Lens, a free online resource that aims to increase transparency in the patent system.
The Patent Lens is a fast, free, full-text searchable patent database containing documents from the largest patenting jurisdictions for the life sciences. It holds over 8 million patent documents and is updated regularly.
The Patent Lens provides not only the ability to search and look at technology described in patents, but also to explore where patents may not be in force. The patent status and patent family database allows patent searchers to check for information provided by the national patent offices on the dynamic status of patents and related patent applications in over 40 countries.
Finding nucleotide and amino acid sequences associated with patent applications and granted patents is often a hit-or-miss situation. Sequence listings are not always provided with a published application or patent, and when they are, they are not always in a text format that is compatible with conventional sequence analysis tools such as BLAST. To address this issue, CAMBIA has created a sequence server that allows a user to enter a patent (or patent publication number) and retrieve any sequences associated with that patent or application. The sequence server also provides links to the sequence at GenBank (if available) as well as BLAST.
The Patent Lens facilitates learning about what patent rights apply where, by providing tutorials, IP analyses, and information about patents around the world.
CAMBIA'S technology landscapes provide an overview of the patenting activity in important technology areas. We are in the process of integrating new patent informatics tools and features into the landscapes as we develop them. As such, our patent landscapes are "works in progress" that will continue to evolve with the new tools.
BiOS (Biological Open Source) is a legally enforceable framework to enable the sharing of the capability to use patented and non-patented technology, which may include materials and methods, within a dynamically expanding group of those who all agree to the same principles of responsible sharing, a “protected commons”. Those who join a BiOS "concordance" agree not to assert IP rights against each others's use of the technology to do research, or to develop products either for profit or for public good. BiOS-compatible agreements can support both freedom to operate, and freedom to cooperate.
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Rice is one of the most important cereal crops and feeds more than a third of the world's population (Khush, 1997). Rice is a monocarpic annual plant that usually grows between 1 and 1.8 meters tall with long slender leaves 50–100 cm long and 2–2.5 cm broad. Its small, wind-pollinated flowers are characteristic of grasses. The seed is a grain normally 5–12 mm long and 2–3 mm thick (see "Rice" in Wikipedia).
While rice is believed to have evolved around 130 million years ago (Chang, 1976), it is only considered to have been cultivated within the last nine thousand years (Patarapuwadol, 2005). There are two domesticated species: Oryza sativa, the most common, grown throughout Asia, Australia, the Americas and Africa; and Oryza glaberrima, grown on a small scale in western Africa.
There are three main varieties of Oryza sativa:
Within each variety, there are many cultivars, each favoured for particular purposes or regions. A japonica variety was the first to undergo genome sequencing, and is the focus of this landscape.
Apart from the two domesticated species of Oryza, there are a further twenty-one wild species. Nine of the wild species are tetraploid. The remaining species, inclusive of the two cultivated ones, are diploid. The International Rice Research Institute (IRRI) has registered and preserved over 80,000 varieties of rice. Of these, 76,000 are said to be O. sativa (Jackson 1997). All varieties of rice have 12 chromosomes.
Rice has the smallest genome size of all common cereals (see table below, comparing Oryza sativa against that of other plants).
|
Organism |
Common Name |
Genome Size |
|---|---|---|
| Oryza sativa |
rice |
430 Mb |
| Sorghum bicolor |
sorghum |
772 Mb [1] |
| Lycopersicon esculentum |
tomato |
950 Mb |
| Zea mays |
maize |
2365 Mb |
| Hordeum vulgare |
barley |
5000 Mb |
| Triticum aestivum |
wheat |
17000 Mb |
(Genome sizes were taken from the NCBI's Genomic Biology web pages.)
References
[1] Bowers JE, Abbey C, Anderson S, Chang C, Draye X, Hoppe AH, Jessup R, Lemke C, Lennington J, Li Z, Lin YR, Liu SC, Luo L, Marler BS, Ming R, Mitchell SE, Qiang D, Reischmann K, Schulze SR, Skinner DN, Wang YW, Kresovich S, Schertz KF, Paterson AH (2003) A high-density genetic recombination map of sequence-tagged sites for sorghum, as a framework for comparative structural and evolutionary genomics of tropical grains and grasses. Genetics 165:367-386
[2] Chang TT (1976) The origin, evolution, cultivation, dissemination, and diversification of Asian and African rices. Euphytica 25(1):425-41
[3] Khush GS (1997) Origin, dispersal, cultivation and variation of rice. Plant molecular biology 35 (1-2), 25-34
[4] Jackson MT (1997) Conservation of rice genetic resources: the role of the International Rice Genebank at IRRI. Plant Molecular Biology 35(1-2): 61-67
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No |
Country |
Rice Production |
|---|---|---|
|
1 |
China |
183,354 |
|
2 |
India |
130,513 |
|
3 |
Indonesia |
53,985 |
|
4 |
Bangladesh |
40,054 |
|
5 |
Vietnam |
36,341 |
|
6 |
Thailand |
27,000 |
|
7 |
Myanmar |
24,500 |
|
8 |
Philippines |
14,615 |
|
9 |
Brazil |
13,141 |
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10 |
Japan |
11,342 |
The genome of Oryza sativa consists of 12 chromosomes, one circular mitochondrial DNA, and a circular chloroplast DNA. Additional information about the rice genome may be found at the TIGR Rice Genome Annotation site. Chromosomes are often drawn as in Figure 1 below: with a short and long arm and an intervening centromeric region. Figure 2 depicts the shapes and relative sizes of the Oryza sativa chromosomes. Table 1 shows the size (in Mbp) and predicted number of genes for each chromosome from Oryza sativa ssp. japonica (Nipponbare).
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Figure 1 |
Figure 2 |
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Table 1 |
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Synteny, or preservation of the order of genes on a chromosome, can be a marker for evolutionary history, or a key to functional relationships between genes. Over time, chromosomal rearrangements take place, and therefore the degree of synteny can give us information about shared ancestry. In organisms with a known shared ancestry, synteny can be used to predict the presence of genes in more than one species. Moreover, it means that genes present in one species are likely to be present in closely-related species. For example, the degree of synteny between rice and other cereals means that genes present in one or both rice species may well be present in other species.
But how great is the degree of synteny between rice and other cereals? Very great. In fact, if you look at any rice chromosome, the degree of synteny between it and, for example, maize is astounding (see Figure 1). This principle holds true for all the cereals, and means that genes present in one cereal will almost certainly be present in the same order in another. When Goff et al (2002 Science 296: 92-100) assessed the known proteins from maize, wheat and barley, 98% had homologues in the rice genome.
What is the significance of synteny between cereals? Why is this of concern when talking about patenting the rice genome? Depending on the language used in the patent, this could potentially mean that a patent on an important rice gene could cover, without separate patents, that gene in wheat, in corn, in sorghum, in rye, in sugar cane, etc. But is there significant homology between rice and other cereals at the level of individual genes?
Just because the same "genes" exist in the same order on a chromosome in rice and wheat, for example, does not necessarily mean that the sequences of the individual genes or resulting proteins are identical or highly similar. There are examples of conserved genes that tolerate a great degree of diversity, and others that are virtually identical across a wide evolutionary range. Furthermore, many sequences that "drive" expression of important genes are patented. So what degree of homology exists between rice and other cereals? Homology is usually expressed in terms of "percent identity", although "percent similarity" is also used. Percent identity is more precise, as it means the percent to which two genes or proteins match exactly over a given seqeuence. When we look, as an example, at the homology between rice and wheat (Figure 2), we see that many rice genes are present that share nucleotide identity of 80% or more with wheat.
The same is true for maize. As shown in Goff et al. (2002 Science 296: 92-100), the regions of homology between rice and maize of greater than 80% over 100 bp. Virtually every part of the maize genome finds a homologue in rice, where the sequence identity is greater than 80%.
Figure 1: Comparison of chromosome 3 of the rice variety
japonica with the maize species Zea mays.
Image re-printed from http://www.gramene.org/ Note that to a large extent, the rice genes (centre) are present
in the same order on one or more maize chromosomes.
Figure 2: Comparison of the rice genome (chromosomes 1-12) with the wheat genome.
Each coloured box represents a match of 80% or greater at the nucleotide level with a
wheat gene. The chromosomal location of the corresponding wheat gene is colour-coded
(wheat chromosome 1 is purple, wheat chromsome 4 is yellow and so on).Image kindly provided by Dr Mark Sorrells, Department of Plant Breeding & Genetics,
Cornell, Ithaca, NY
Rice has the smallest genome of all common cereals (Khush GS, 1997). Rice was the first cereal to be fully sequenced, and both the indica and japonica genome sequences were published in 2002 (Yu J, et al. and Goff SA, et al.). The indica genome is 420 Mb in size and contains between 32,000 to 50,000 genes. The japonica variety is larger, at 466 Mb, and contains around 46,022-55,615 genes. For this landscape, we analyzed the japonica rice genome.
The genome was sequenced by both public and private groups, as described below.
In 1997, a consortium of publicly funded laboratories called the International Rice Genome Sequencing Project (IRGSP) was established to map the rice genome. The consortium includes labs from ten countries: Japan, the United States of America, China, Taiwan, Korea, India, Thailand, France, Brazil, and the United Kingdom. The IRGSP adopted the "clone-by-clone shotgun sequencing strategy" so that each specific position on the genetic map was associated with a sequenced clone. IRGSP’s policy is that all rice sequence data must be released into the public domain. In December 2004, the completed rice genome sequence was made available through the NCBI database.
Research such as the genome-sequencing project has provided a wealth of molecular marker data, together with phenotypic, ecological, and archaeological data and has significantly helped our understanding of the evolutionary history of the genus Oryza (Khush GS, 1997). It has also assisted efforts to assimilate useful genes from wild species to cultivated rice through inter-specific hybridisation. Organizations such as IRRI have been using this knowledge to help modify rice in an endeavour to reduce poverty and hunger and to improve the health of rice farmers and consumers.
More information about the IRGSP participants are provided on the next page of the landscape.
Private firms and other interested parties have also contributed to the sequencing of the rice genome. Key players in the private sphere were Monsanto, Syngenta and Myriad Genomics. Monsanto released all of its data into the public sphere, but not before they had filed patent applications on more than 200,000 sequences. Syngenta also released their sequence information, but not exactly in a timely manner. More information about the role of these companies is provided later in this landscape.
Goff SA, et al. (2002) A draft sequence of the rice genome (Oryza sativa L. ssp. japonica). Science. 296(5565):92-100.
Khush GS (1997) Origin, dispersal, cultivation and variation of rice. Plant molecular biology 35 (1-2), 25-34
Yu J, et al. (2002) A draft sequence of the rice genome (Oryza sativa L. ssp. indica). Science. 296(5565):79-92.
The IRGSP is a consortium of public institutions that was established in 1997 to sequence the rice genome using Nipponbare, a cultivar of Oryza sativa ssp. japonica. It consisted of a number of publicly-funded organisations, including:
Rice
Genome Research Program (RGP)
A Japanese-government-funded joint project of the National Institute of
Agrobiological Sciences (NIAS) and the Institute of the Society for
Techno-innovation of Agriculture, Forestry and Fisheries (STAFF). The program
itself was part of the Japanese Ministry of Agriculture, Forestry and Fisheries
(MAFF) Genome Research Program.
The Institute for Genomic
Research (TIGR)
A not-for-profit institute involved in the sequencing and analysis of genomes.
Based in Rockville, Maryland, USA.
National Center for
Gene Research Chinese Academy of Sciences (NCGR)
Established by the Ministry of Science and Technology, the Shanghai
local government, and the Chinese Academy of Sciences (CAS) in 1992. The NCGR
was responsible for sequencing chromosome 4 from rice.
Arizona
Genomics Institute (AGI)
The AGI, CSHL, Washington University and University of Wisconsin (ACWW)
consortium was granted funds in 1999 (from USDA/NSF/DOE/CSREES) to sequence and
annotate the short arms of chromsomes 3 and 10 as part of the IRGSP.
Cold
Spring Harbor Laboratory (CSHL)
A private, not-for-profit, organisation based in Cold Spring Harbor, NY.
Involved in sequencing chromosomes 3, 5, 9, 10, and 11 from Oryza sativa L.
ssp. japonica cv. Nipponbare.
Plant Genome
Initiative at Rutgers (PGIR)
PGIR was established to participate in the international efforts to sequence the
rice genome. It is a high-throughput sequencing facility, of medium capacity,
also involved in sequencing the maize genome. Based at the Waksman Institute,
Rutgers University, The State University of New Jersey, New Jersey.
Genoscope
(France)
The French National Sequencing Center, founded in 1997 in Evry, near Paris.
Involved in sequencing chromosome 12 from rice.
Academia Sinica
Plant Genome Center (ASPGC)
Based at the Institute of Botany, Academia Sinica, Taipei, Taiwan. Support
derived from National Science Council, Council of Agriculture, Academia Sinica
and the Institute of Botany. This group was involved in the sequencing of
chromosome 5.
Indian Initiative
for Rice Genome Sequencing (IIRGS)
Founded through efforts of the Department of Biotechnology, and the Indian
Council of Agriculture. The Initiative is based in New Delhi and was involved in
sequencing of the long arm of chromosome 11
Korea
Rice Genome Research Program (KRGRP)
Sponsored by the Rural Development Administration, Suwon, Korea, under direction
of the Science and Technology Policy Institute. The program was responsible for
generating more than 100,000 rice ESTs.
National
Center for Genetic Engineering and Biotechnology (BIOTEC)
Thai component of rice sequencing efforts.
Wisconsin
Rice Genome Project (GCOW)
Based at the University of Wisconsin-Madison, within the University of Wisconsin
Biotechnology Center. Involved in sequencing chromosome 11.
John
Innes Centre (JIC)
An international centre of excellence in plant science and microbiology, based
in the Norwich Research Park, Norwich, UK. Funded by both local and
international funding bodies, including the Biotechnology and Biological
Sciences Research Council (BBSRC).
Brazilian
Rice Genome Initiative (BRIGI)
Involved in sequencing of chromosome 9.
IRGSP adopted an incremental (clone-by-clone) shotgun process so that each sequenced clone can be associated with a specific position on the genetic map. This sequencing process was therefore slower than the whole-genome shotgun sequencing strategy adopted by other rice sequencing projects, but the result was the most complete sequence of the entire rice genome. The project was completed 3-years ahead of schedule in 2005 with help from the Monsanto draft rice genome sequence data. Total international funding was ~US$150 million (CSREES figures).
In addition to the public rice genome sequence efforts, there have been several notable commercially-funded efforts to determine the nucleotide sequence of rice. For additional information, see the NCBI Oryza sativa (rice) genome view.
Monsanto
Syngenta and Myriad Genetics
The Rice Full-Length cDNA Consortium (Japan)
Beijing Genomics Institute (BGI)
In April 2000, Monsanto was the first private company to announce a working draft of genetic map of rice (japonica type). Monsanto’s sequencing had been done under contract by universities that received both public funds and funding from Monsanto. Although Monsanto's sequencing was carried out simultaneously with the public sequencing initiative, the Monsanto data were not released to the public until June 2000, when Monsanto launched the now-defunct rice-research.org database to provide access for publicly funded researchers to its draft rice genome sequences. Shortly before Monsanto released the rice sequence data, they filed U.S. patent applications claiming more than 200,000 rice genes, promoters, and other sequences. See the Monsanto page in Chapter 10 for more information about Monsanto's patenting of the rice genome.
In January 2001, Myriad Genetics and Syngenta announced that they had also completed DNA sequencing of the entire rice genome. Excerpts from Nature News 5 April 2002:
"We can use the rice genome to help improve wheat and corn right now. The genes are interchangeable," says a member of the commercial sequencing team, Stephen Goff of the Torrey Mesa Research Institute, San Diego….
The publicly funded International Rice Genome Sequence Project, is set to deliver a complete sequence based on a slower, more expensive, but more complete, technique in 2004.
"This will be gold standard", says plant biologist Michael Bevan of the John Innes Institute, Norwich, UK. "These papers are landmarks, but they're only part of the story.”….
In the end, Syngenta has made its sequence freely available, through its own website, to non-profit institutions…
Bevan is sanguine about this arrangement. "Syngenta put a lot of resources into the project, and they need to see returns," he says. "Hopefully they will have extracted all the juice they want from the genome in a year or so and will make it fully accessible."
New Scientist (Coghlan, A., New Scientist Print Edition 14:19, 2001) also published an article about Syngenta and Myriad Genetics' sequencing project. Quote from the New Scientist article:
"Rice has become the first crop plant to have its entire genome sequenced. Syngenta, the Basel-based multinational that funded the breakthrough, expects the rice genome to unlock genetic secrets of all cereals, from wheat and barley to maize and sorghum."
In this project, 28,469 full-length complementary DNA clones from Oryza sativa were sequenced by a consortium in Japan. The research team was led by Dr. Shoshi Kikuchi at the Department of Molecular Genetics, National Institute of Agrobiological Sciences in Ibaraki, Japan. The results of this sequencing effort were published in Science (Science 301:376-379, 2003). Other participants included the Foundation for Advancement of International Science Genome Sequencing and Analysis Group, and RIKEN.
The consortium collected 3'- EST sequences of 175,642 cDNA clones from rice, clustered them into 28,469 nonredundant groups, and sequenced all representative clones from each group. Through homology searches, they assigned protein functions to roughly 75.86% of the clones.
Shortly before the Science paper was published, the consortium filed a patent application claiming 28,469 cDNA sequences. Later in this landscape, we show a claim analysis of this patent application. Note, however, that any of the sequences filed earlier by Monsanto would constitute prior art against RIKEN's claims.
A related scientific publication was authored by Nagata et al. in 2004 (Mol Biol Evol. 21(10):1855-70). This publication disclosed a comparative analysis of plant and animal calcium signal transduction element using plant full-length cDNA data.
All above rice sequencing projects used Nipponbare, a cultivar of the rice subspecies japonica (Oriza sativa ssp. japonica), as the target rice cultivar. Beijing Genomics Institute, however, chose to sequence Oryza sativa ssp. indica, the major rice subspecies cultivated in China and many other Asian-pacific regions. Sequencing a different type of rice is important because it aids in understanding of the differences between different rice species.
BGI's sequencing project was initiated in May 2000, and used 93-11, a cultivar of Oryza sativa L. ssp. indica, as target material. This particular cultivar of indica is the paternal cultivar of a "super" hybrid rice breed called Liang-You-Pei-Jiu or LYP9, which has 20 to 30% higher yield per hectare than the average of other rice crops in the fields. A working draft of the 93-11 genome sequence was completed in October 2001 and published in Science 296: 79-92, 2003.
BGI then launched a Rice Information System (BGI-RIS) to host the rice sequence data from 93-11. In addition, the sequence information of japonica rice from Syngenta has also been included in this system based on an agreement between BGI and Syngenta. More detailed information about BGI-RIS can be found in Nucleic Acids Research, 32: D377-D382.
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There are many issues associated with genome patenting that make it different from patenting articles of manufacture. This chapter discusses some of the issues relating to the patenting of genes, for example, why gene sequences are patentable, how patent craft has evolved in the post-genomic era, and how to search for biological sequences that are the subject of a patent or patent application.
The mantra is that "anything under the sun made by man" is patentable. Using this criteria, it would appear that genes and proteins, which exist naturally within living organisms, would not be patentable. However, patent laws in many jurisdictions, including the United States, Europe and Australia, allow patent applications to claim nucleotide and amino acid sequences as compositions of matter as long as they have been isolated from their cell of origin. Isolated nucleotide and amino acid sequences claimed under "composition of matter" claims in a U.S. patent are like any other patented technology in this respect. If used in a way that is covered by the claims of a patent that is in force, the user may be subject to being stopped by injunction or be required to pay royalties.
The road to allowing patents on sequences began with a U.S. Supreme Court case involving a genetically-engineered bacterium for cleaning up oil spills. In this oft-cited case of Diamond v. Chakrabarty (447 U.S. 303 (1980)), the Supreme Court had no difficulty finding that a living, genetically-altered organism may qualify for patent protection. From there, patent law in the U.S. evolved to allowing patents on many types of biotechnology products, including transgenic plants and eventually for DNA and protein sequences. The rationale for concluding that DNA sequences - and by extension, protein sequences - are patentable is that the claimed sequences are human-made; they are "purified and isolated" sequences (Amgen, Inc v. Chugai Pharm. Co. Ltd., 13 U.S.P.Q. 2d 1737 (D. Mass. 1989), aff'd in part, rev'd in part, vacated in part, 927 F.2d 1200 (Fed. Cir. 1990), cert. denied, 502 U.S. 856 (1991)). This view is very controversial and at times contentious, even within the U.S. courts.
In the 1990s, the U.S. Patent Office granted many patents claiming "purified" or "isolated" nucleotide and amino acid sequences. The year 2001 however, brought a change that severly limited the ability to obtain claims reciting sequences. The U.S. Patent Office released the "Utility Examination Guidelines", which set out procedures for ensuring that patent applications complied with the utility requirement of patent law (Federal Register, Vol. 66, 1092-1099). A claimed invention now had to have a "specific and substantial" or a "well-established" utility. The impact was huge for claims to sequences. Under these rules, a claim to "A cDNA consisting of the sequence set forth in SEQ ID No: 1." is unpatentable unless there is a known function for the sequence. In addition, more restrictive rules may well be implemented in the near future.
Thus, in the United States, after a period of granting expansive patent claims, it has become increasingly more difficult to obtain patent claims to DNA or amino acid sequences.
The claims define the scope of a patent. There are different types of claim language that are used in gene-based patents and patent applications that broaden the scope of the claim beyond the actual sequences that are disclosed in a specification. For the purposes of this landscape, we refer to this type of claim language as "broadening language".
Examples of different types of broadening language include the following:
Hybridisation language in claims allows an applicant to claim a particular nucleotide sequence, as well as any nucleotide sequence that hybridises to that sequences under a given set of experimental conditions. See a tutorial on the basis for hybridisation language for a more detailed description. An example of a claim with hybridisation language is claim 1 from US Patent No. 5747327:
A cloned DNA which encodes phospholipase D originated from a plant, wherein said DNA comprises a nucleotide sequence selected from the group consisting of nucleotides 182-2617 of SEQ ID NO:1 and nucleotides 107-2542 of SEQ ID NO:3 or a sequence complementary thereto or a sequence which specifically hybridizes to said cloned DNA or said complementary sequence in a hybridization solution containing 0.5M sodium phosphate buffer, pH 7.2, containing 7% SDS, 1 mM EDTA and 100 mg/ml of salmon sperm DNA at 65° C. for 16 hours and washing twice at 65° C. for twenty minutes in a washing solution containing 0.5×SSC and 0.1% SDS.
Percent identity language, which is also sometimes expressed as percent similarity language, allows an applicant to claim not only the sequence of interest, but any sequence that is for example, 70, 80, or 90% identical to that sequence. This dramatically broadens the scope of the claim by increasing the number of individual sequences that meet the criteria of the claim. Percent identity or similarity language may be used with either nucleotide and amino acid sequences.
A potential difficulty with determining the meaning of a claim with percent identity language is that applications do not always specify the parameters for calculating the percent identity. There are many different algorithms that may be used to determined how similar sequences are to each other. Many algorithms assign different values for gaps in sequences that can affect the overall percent score in a variety of ways.
Such claims are not often granted these days. Unless examples of related sequences are specified in the patent and furthermore are shown to have similar function, they are not usually allowed.
For example, the first claim of US Patent No. 6821764:
- An isolated nucleic acid fragment encoding a serine O-acetyltransferase comprising: (a) a nucleotide sequence encoding a polypeptide having serine O-acetyltransferase activity, wherein the polypeptide has an amino acid sequence of at least 95% sequence identity, based on the cluster, when compared to SEQ ID NO: 8 or (b) a full complement of the nucleotide sequence of (a).
Some applications include claim language reciting particular amino acid substitutions. For example, claim 1 from US Patent No. 7057088:
An isolated DNA encoding a protein selected from the group consisting of
(a) a DNA encoding a protein comprising the amino acid sequence set forth in SEQ ID NO: 1,
(b) a DNA comprising the nucleotide sequence from position 54 to 1199 set forth in SEQ ID NO:2, and
(c) a DNA encoding a protein comprising the amino acid sequence set forth in SEQ ID NO:1,wherein one to 10 amino acid residues are substituted, deleted, added, and/or inserted and wherein said protein:
(i) has gibberellin 2β-hydroxylase activity; and
(ii) conserves amino acids corresponding to His-241, Asp-243 and His-302 in the amino acid sequence set forth in SEQ ID NO:1.
One common way to capture a nucleotide sequence is provide the SEQ ID NO of an amino acid and word the claim such that any nucleotide sequence that encodes that amino acid sequence is claimed. Because the genetic code is degenerate, such a claim encompasses a very large number of nucleic acid sequences.
For example, the first claim of US Patent No. 7268271
A method for increasing LEC1 expression in a plant cell, wherein said increase is measured against a control plant cell, said method comprising introducing an isolated LEC1 nucleic acid into the plant cell to produce a plant cell that exhibits increased LEC1 expression, wherein the isolated LEC1 nucleic acid comprises a member selected from the group consisting of (a) a polynucleotide which encodes a polypeptide of SEQ ID NO: 2;(b) a polynucleotide of SEQ ID NO: 1; and(c) a polynucleotide complementary to a polynucleotide of (a) or (b).
SEQ ID NO:2 is purely an amino acid sequence, and thus all nucleic acids coding for this sequence are covered by this claim.
As discussed in Chapter 2 of this landscape, rice has significant homology and synteny with other plant species. This leads to the possibility that composition of matter claims for rice sequences and related sequences (related by a specified percent identity or by hybridization) will encompass similar sequences in other plants. We refer to this as "cross-coverage".
For example, a claim that reads:
An isolated nucleic acid sequence that has at least 80% sequence identity to SEQ ID NO:10.
may “literally” cover more than one species if there are sequences from more than one species that fall within the 80% sequence identity range.
In the U.S., there is a presumption of validity for patent claims, but there are a number of other factors that may actually limit the scope of claims that at first glance appear to literally cover other species. Some of these factors include:
There are a number of ways that the claim language itself may limit the number of species covered. For example:
An isolated nucleic acid sequence that has at least 80% sequence identity to SEQ ID NO:10, wherein the isolated nucleic acid sequence is from maize.
Because this claim specifies maize, it would likely not cover rice.
An isolated nucleic acid sequence that has at least 80% sequence identity to SEQ ID NO:10, wherein the isolated nucleic acid sequence encodes a polypeptide of a monocot.
In this case, a polypeptide that was more than 80% identical that encoded a dicot polypeptide would likely not fall under the scope of the claim.
An isolated nucleic acid sequence that has at least 80% sequence identity to SEQ ID NO:10, wherein the isolated nucleic acid sequence encodes a soluble starch synthase.
With this claim, if there were a sequence that was more than 80% identical that encodes an insoluble starch synthase, it would probably not fall under the scope of the claim.
While it may initially be alarming to find a patent application that claims thousands, or tens of thousands of sequences, it is highly unlikely that the application will be granted with more than one, or possibly a few. The United States Patent Office currently only examines one claimed sequence in each patent application. However, it is important to note that policies limit the number of sequences examined, but not the number of sequences in the claim set as initially filed. The limitation to one sequence occurs in the inital stage of the examination process, which often takes place long after the application (with the initial bulk claim set) has published.
According to a notice issued by the USPTO (1316 O.G.13, 27 March 2007), for new applications, an examiner has the option to restrict claims such that only a single nucleotide sequence will be examined per application. The examiner, however, does retain the option to examine more than one sequence if he or she deems it appropriate.
This notice rescinded a 1996 notice (1192 O.G. 68, 19 November 1996) on the subject. In that notice (see Section 2434 of the MPEP), the USPTO issued a partial waiver of 37 CFR 1.141 to permit examination of up to 10 independent and distinct nucleotide sequences claimed in a single application. A similar revision was also made for search and examination of applications filed under the PCT, as a partial waiver of 37 CFR 1.475.
Despite the 1996 Notice, PTO examiners usually examined only a single nucleotide sequence. The 2007 Notice simply eliminated the opportunity for applicants to argue that claims to multiple nucleotide sequences should be examined together.
While these notices do not specifically mention polypeptide (amino acid) sequences, polypeptide sequences are also generally limited to one sequence per application.
For PCT patent applications, the number of sequences examined in an application is limited by Rule 13, Unity of Invention. Rule 13 requires that "the international application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept". For applications claiming multiple nucleic acid sequences, "unity of invention will exist when the polynucleotide molecules, as claimed, share a general inventive concept, i.e., share a technical feature which makes a contribution over the prior art." Therefore, for applications filed in the United States through the PCT process, more than one sequence can be examined in an application.
It is not always a straightforward task to determine if a sequence of interest is already patented, or is the subject of a pending patent application. Sequences in claims are referred to by a number designator - e.g., SEQ ID NO: 1. The sequences themselves are in a separate section called the Sequence Listing. Unfortunately, in the Sequence Listing, there is usually little annotation of the sequences. Annotation, such as it is, must be teased out of the patent text.
To compare sequences in the Sequence Listing and claims to a selected sequence, there are options. Free search options include BLAST and CAMBIA's patent sequence search tool, and pay options include a number of proprietary or subscription based services, such as Thompson-Derwent and Genome Quest.
BLAST
BLAST is a program that finds regions of similarity in biological sequences. It can be used to search for similar nucleotide or amino acid sequences, and also allows searches of a translated nucleotide database using both nucleotide and amino acid queries. To search for patent sequences in BLAST, the patent database must be selected. An oft-used patent database is provided by GenBank, and it contains sequences from granted U.S. patents as well as sequences in published PCT applications and Japanese patents. This search collection currently lacks sequences in U.S. applications, however. Searching with BLAST will identify many patents that contain sequences that are similar to a sequence of interest, but does not differentiate between sequences that are in the Sequence Listing from sequences referenced in claims.
CAMBIA's Patent Sequence Search Tool
CAMBIA offers a free patent sequence search tool that uses the BLAST search interface. The search collection includes sequences from granted U.S. patents as well as U.S. patent applications, all of the sequences in the GenBank collection, as well as many more sequences that are provided by the USPTO in a different format, e.g., sequences from bulk sequence applications. An important feature of our search tool is that it allows users to search for patent sequences that are claimed in patents and patent applications rather than sequences that are simply disclosed in the specification.
Claim language is complex and quite variable, and does not lend itself well to automated analysis via software solutions. If a sequence of interest is recited in a patent claim, it is the claim language that ultimately determines if the sequence is patented or not.
Below is an example where a sequence mentioned in the claims is actually claimed as a composition of matter:
An isolated nucleic acid segment comprising the sequence of SEQ ID NO:2.
Alternatively, here is an example of a claim that recites a sequence, but where that sequence is not claimed:
A vector construct comprising the sequence of SEQ ID NO:7 operatively linked to a nitrogen-responsive promoter.
The claim states that the sequence of SEQ ID NO:7 must be "operatively linked to a nitrogen-responsive promoter". Therefore, the claimed nucleotide encompasses both SEQ ID NO:7 and the promoter, and if your sequence was linked to a different type of promoter, then the use of your sequence would not infringe upon this patent.
A granted U.S. Patent gives a patentee the right to exclude others from making, using, selling, or offering to sell the claimed invention in the U.S. In addition, a patentee may exclude others from importing the claimed product or product of a claimed method, even if it is not patented in the originating country.
Patent applications are not the same as granted patents. If there is no granted patent, there is no infringement. If a patent owner has a good faith belief that you are infringing her patent, the patent owner may request that you "cease and desist", demand licensing fees or royalties, or sue you in court.
So, what if you have discovered that a nucleotide or amino acid sequence that you are working on in your laboratory is claimed in a U.S. patent or pending application? Don't panic! There are a number of options available to you.
First, take a careful look at the claim language to see if the sequence that you are concerned about is indeed claimed in a patent or patent application. Remember that a patent in the U.S. only applies to the U.S. If you are in another country, a U.S. patent or patent application does not apply to you (unless you plan to import the patented subject matter into the U.S.). Refer to the last section of the previous page in this landscape paper for examples of sequences that are simply recited in a claim as opposed to claimed as compositions of matter.
Submit prior art to the examiner as a "third party submission". If the application is a U.S. application, and if you have evidence that the sequence was published prior to the patent filing date, and the application of interest was published less than two months prior, you (as a third party) may submit patents or publications for consideration in a pending published application, pursuant to 37 CFR 1.99 (rule 99). With these types of submissions, the third party is not allowed to comment or provide explanation as to what they are submitting. See section 1134.01 of the MPEP for more information about this option. The downside to this approach is that the examiner is not obligated to consider your submission.
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CAMBIA has produced a patent landscape for the Oryza sativa genome. Our analysis included both granted U.S. patents and pending patent applications. In addition to structural genes, our study encompassed non-coding nucleotide sequences such as promoters.
This chapter shows the results of our analysis. In addition to static plots, we have incorporated the Gbrowse genome browser to enable interactive visualization of the patent and patent application sequences relative to the rice genome.
Surprisingly, only 0.26% of the rice genome is recited in the claims of granted U.S. patents.
This fraction represents the actual, non-redundant coverage of the genome by the sequences that were identified in our analysis. The analysis included all sequences recited in claims, whether they encoded proteins or not. In contrast, the Jensen and Murray analysis reported that around 20% of the coding sequences of the human genome were claimed in granted U.S. patents (Science 310: 239-240). This is a different metric than we used for determining the overall percent coverage. An approximation can be made of the fraction of coding sequences claimed in U.S. patents, however, by estimating the number of claimed coding sequences (213) and dividing by the total number of rice genes (coding sequences) (37,544 according to Nature, 2005, 436: 793-800). Using this formula, the percent coverage is roughly 0.57%, but still remains below 1% of the rice genome.
Patent applications show a different picture as to the fraction of the rice genome recited in claims. Due largely to “bulk sequence applications”, roughly 74% of the rice genome is recited in claims of U.S. patent applications. But due to patent examination policies in the U.S., it is unlikely that very many of these sequences will become part of the claims of granted patents.
These numbers are our best estimate based on our chosen methodologies. In some ways, they are an overcount of the number of patents that recite rice sequences in the claims, because a number of these patents and patent applications are directed at plants other than rice. Therefore, the claims may not actually encompass the rice gene. Also, some of the claims that are included in this analysis are method or product claims that don't directly claim a rice sequence as a composition of matter.
On the other hand, the numbers presented here are an undercount because we did not include nucleotide sequences that are claimed based on the amino acid sequences that they encode. A common practice is to claim "any nucleotide sequence that encodes the amino acid sequence of SEQ ID NO:X". This type of claim will not be picked up in our current analysis because it is an amino acid sequence rather than a nucleotide sequence that is recited in the claim. In future revisions of this landscape, we plan to incorporate amino acid claims to provide a more complete picture of the rice genome.
In this landscape, we have determined the extent to which the rice genome nucleotide sequences are recited in the claims of both issued U.S. patents and U.S. patent applications. Our process entailed a number of informatics steps that are outlined below.
In summary, we compiled a database of patent nucleotide sequences that are recited in the claims of granted U.S. patents and U.S. patent applications, and compared these sequences to the published rice genome using MEGABLAST. We determined which sequences were highly homologous to sequences in the rice genome and mapped these sequences to the corresponding location on the rice chromosome. We only included sequence matches that yielded a BLAST E value of 1e-200 or less, which is highly statistically significant. The results of our analysis are shown in the subsequent pages of this landscape.
It is important to note that the patent and patent application sequences used in this analysis were selected without reference to which genome they are from. For example, if a maize sequence is nearly identical to a rice sequence, then it will be included in our list of results. We have chosen to include such sequences because the inherent similarity of plant genomes makes it possible for patents that claim one species to dominate another. For example, it is possible that a patent claiming a maize sequence can result in exclusionary treatment of the corresponding rice sequence. Chapter 3 discusses this concept in more detail.
We started with the most recent rice genome sequences from the TIGR Rice Genome Annotation web site and then used the formatdb program from NCBI to convert the data to a searchable BLAST database.
Applications
For patent applications, we acquired the sequences of the bulk sequence applications from the Publication Site for Issued and Published Sequences (PSIPS) web site. This web site provides sequence listings for U.S. patents and patent applications with sequence listings that are longer than 300 pages. We also acquired the sequence listings for the non-bulk sequence listings (fewer than 300 pages in length) that are published by the USPTO as an XML document. For each of the listing types (bulk sequence and non-bulk sequence), there was a separate file for nucleotides and amino acids. Data for U.S. applications are available since 2001, when patent applications began to be published.
The bulk and non-bulk sequence listings were then converted to a common data format (FASTA) and combined to create one database for nucleotide sequences, and one database for amino acid sequences. Additionally, each of these combined databases was converted to a searchable BLAST database for use with CAMBIA's patent sequence search tool.
Granted (Issued) Patents
For granted U.S. Patents, we had a data source that wasn't available for the applications; GenBank at NCBI has a searchable patent database of sequences disclosed in granted patents. To create our granted patents sequence database, we started by acquiring the U.S. patent sequences from GenBank. This required removing all sequences that originated from non-U.S. patents.
We then acquired the sequence listings from the bulk and non-bulk patents in the manner described above in the Applications section. The data from all three sources (GenBank, bulk, and non-bulk) were converted to a common format. We then carried out a filtering step that removed any duplicate sequences in the data provided by GenBank, and the sequences provided by the USPTO (bulk and non-bulk).
The identical process was carried out for nucleotide sequences and amino acid sequences, however, our analysis currently is confined to nucleotide sequences. As with the patent applications, each of these combined databases was converted to a searchable BLAST database for use with CAMBIA's patent sequence search tool.
A key feature of our analysis is parsing out the sequences that were recited in the claims of patents and patent applications, rather than just disclosed in the specification. The goal is to ultimately identify sequences that are claimed in patents and applications, but normally a review of the claim language by a human being is required to determine whether sequences that are mentioned in claims are actually claimed. To this end, we created four databases that contain only the sequences that are mentioned in the claims of patents and patent applications. These four databases correspond to nucleotide sequences in applications, amino acid sequences in applications, n
