INFORMATION SYSTEMS FOR BIOTECHNOLOGY

January 2002

COVERING AGRICULTURAL AND ENVIRONMENTAL BIOTECHNOLOGY DEVELOPMENTS

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.pdf version

IN THIS ISSUE:
2001 World Review of Agbiotechnology
The Future of Transgenic Plants
Use of G1 Donor Nuclei Improves Viability of Cloned Cattle
End of the Year Brings Good Tidings For Plant Utility Patents
Battles and Skirmishes in the Biotech Patent Arena
Upcoming Meetings

2001 WORLD REVIEW OF AGBIOTECHNOLOGY

2001 was a year where lessons were learned and decisions were made. This review glances across the last twelve months, highlighting only a handfull of stories from the myriad of press cuttings and column inches devoted to agbiotechnology during 2001. These stories are a few of the milestones worth noting as a New Year begins. They range from `hard-core' scientific discoveries, which may impact the industry for many years to come, to the biopolitical issues that are likely to have equally important effects.

January
The US Food and Drug Administration (FDA) announced it had sent a letter to corn millers and food manufacturers urging them to screen yellow corn for possible StarLink corn comingling. The FDA allegedly explained that it sent the December 27^th, 2000, letter to the corn industry because it may have missed some StarLink corn in the government buyback program established in late September. "The FDA believes that the best strategy for keeping Cry9C protein out of the food supply is to focus on intervention as early as possible in the preparation of yellow corn products for human food use."

The UN Food and Agriculture Organization (FAO) welcomed the mapping of the rice genome. R. B. Singh, FAO Assistant Director-General was quoted as saying: "The mapping of the rice genome is very important because it can influence the world's food security, poverty elimination, as well as the welfare of farmers. What FAO would expect from the multinationals ... is that they make seeds available to farmers at affordable prices. The private sector must understand that [it] has to share the technology and bring the benefits of this new technology to farmers at an affordable price." (Reuters, Jan. 2001)

February
The Royal Society of Canada released its report entitled "Elements of Precaution: Recommendations for the Regulation of Food Biotechnology in Canada." Reaction to the report was mixed. Newspaper headlines in Canada declared that, according to the Royal Society, the Canadian public was effectively being treated as "guinea pigs" by the agbiotech industry.

The European Parliament agreed on proposals that formed the basis of the new EU directive on the deliberate release of genetically modified organisms, now known as Directive 2001/18/EC. The new measures included provisions for the strict labeling and monitoring of GM foods, feeds, seeds, and pharmaceuticals. They also set up a public registry that allows consumers to trace GM products to the market. Under the new rules, any licenses would be conditionally granted, based on documentation that sufficient risk assessment studies were performed and that continuous monitoring for possible hazards associated with the product was ongoing. http://biosafety.ihe.be/GB/Dir.Eur.GB/Del.Rel./2001_18/2001_18_TC.html

March
The New Scientist (March 3^rd, 2001) reported on events unfolding at a meeting of New Zealand's Royal Commission on Genetic Modification that highlighted the need for careful monitoring of the GM food debate. Dr. Elaine Ingham (Oregon State University) was forced to recant claims offered in her testimony and write a letter of apology to the Commission. Ingham testified that a GM version of a common soil bacterium, Klebsiella planticola, could spread and devastate natural plant life if released into the wild. The New Scientist quoted her as saying, "We could lose terrestrial plants. This is an organism that is potentially lethal to the continued survival of human beings."

The US Environmental Protection Agency (EPA) released a white paper examining how the wet milling process affects levels of the StarLink corn protein in finished food products. The paper concluded that wet milling results in no (or essentially no) residues of Cry9C protein in human food fractions and that "… the public can be assured that the numerous foods produced with corn sweeteners, starches, and oils pose no risk of inducing sensitization or allergic response to the Cry9C protein."

A Federal court in Canada ruled that a Saskatchewan farmer, Percy Schmeiser, had violated Monsanto's patent on GM herbicide tolerant canola. Mr. Schmeiser argued unsuccessfully that it was a case of `genetic pollution' and he had not broken any license agreement.

April
Monsanto voluntarily instituted a massive recall of a variety of Roundup Ready^® canola seed in Canada after trace amounts were found in seed batches marketed by Agricore and Saskatchewan Wheat Pool. The contaminated variety was Quest-73, an herbicide resistant canola variety approved for export, and the rogue seed was Quest-200, which does not have export approval. The reason for the recall was purely to prevent international trade problems, as there was no health issue involved. Both varieties have been approved in Canada and have been deemed safe for commercial release.

May
The Food Safety Authority of Ireland (FSAI) announced details of a survey to determine the level of GM maize ingredients in tortilla chips and taco shells, with the aim of ensuring that industry is adhering to food labeling regulations. Results showed that GM maize ingredients were present in 19 of 26 samples tested, with the majority having levels below 0.1%, considerably less than the 1% threshold level that triggers the labeling requirement. According to Dr. Patrick O'Mahony, Chief Specialist, Biotechnology, FSAI, there are no known health implications arising from the presence of the GM ingredients identified in these products. Results of a new round of testing will be made public early in 2002.

In South Korea, the Ministry of Agriculture and Forestry said it was creating a bio-industry department to cover GM agricultural products. The new unit now oversees the development of GM organisms, makes sure products are labeled as GMOs, and suggests policies to boost agricultural engineering. Describing the launch of the new department, an official said, "When the law that allows GMOs to move across borders takes effect, they will be traded freely, so GMO management organization is needed."

An official Chinese report released by the Ministry of Science and Technology should not go unnoticed. It detailed the fact that, to date, China has developed 47 transgenic plant species, cloned goats, and transplanted genes into pigs, rabbits, sheep, and cows. The report said that over the past decade China has made remarkable achievements in pest and disease resistance, quality improvement, herbicide resistance, and security control in genetic engineering of plants.

June
Researchers at Singapore's National University announced that by modifying genes affecting ethylene production they succeeded in delaying fruit ripening by up to four months. The results showed that fruit with the modified genes produced up to 90% less ethylene.

Following their own investigation, the Centers for Disease Control (CDC) in the US announced that StarLink corn was not responsible for human allergies. The results from blood samples taken from 17 people who reported complaints all showed a negative sensitivity to Cry9C. According to the CDC, its "investigation did not find any evidence that hypersensitivity to the Cry9C protein was responsible for the self-reported allergic responses that people experienced last fall [2000]."

In Australia, researchers at CSIRO Plant Industry reported to have developed a technique using `hairpin RNA' that effectively vaccinates crop plants against viruses like Barley Yellow Dwarf Virus. Researchers believe that this new technique will increase food production and reduce the amount of pesticides currently used to control virus-carrying insects.

July
Chinese National Hybrid researchers reported they had genetically engineered a "super rice" that could double the yield of normal grain. The yield of normal rice is about 360 kg per mu, a Chinese land unit equivalent to 0.06 hectares. First-generation hybrid rice, which is feeding half the population of China, provides about 450 kg per mu, while the super rice might reach 900 kg per mu.

A report released by the United Nations Development Program claimed that opposition in richer countries to GM crops might set back the ability of poorest nations to feed growing populations. The report stated that, "The current debate in Europe and the United States over genetically modified crops mostly ignores the concerns and needs of the developing world. Western consumers … are more likely to focus on food safety and the potential loss of biodiversity" but, "farming communities in developing countries are more likely to focus on potentially higher yields and greater nutritional value and on the reduced need to spray pesticides that can damage the soil and sicken farmers."

Japanese Agriculture Ministry (MAFF) researchers announced that feeding StarLink corn had no effect on pig productivity or meat composition. The meat, organs, and blood of pigs eating feed containing 70% StarLink corn for 11 to 13 weeks were examined. There was no evidence that either a gene or the Cry9C protein specific to StarLink was carried over to the pig samples, the Ministry said.

The European Commission unveiled its long-awaited proposals on the labeling and traceability of foods containing GMOs. The new rules require the labeling of all foods and animal feed derived from GMOs and, in the case of processed goods, that records be kept throughout the production process allowing the GMO to be traced back to the farm.

An international research team of scientists from Stanford University and seven European and Canadian institutions announced the complete DNA sequencing of the agriculturally important bacterium, Sinorhizobium meliloti. S. meliloti is one of several bacterial species with the ability to transform atmospheric nitrogen into other chemicals via nitrogen fixation.

After many months of work and hearings, the New Zealand Royal Commission's inquiry determined that genetic engineering holds promise as a way of conquering disease and wiping out pests, but it is risky and should be rigorously tested on a case-by-case basis. The USD$2.6 million inquiry rejected the idea of a GM-free New Zealand by recommending a loosening of restrictions on low-risk GM applications, but also sought a toughening of rules on high-risk ones. The report indicated, "It would be unwise to turn our back on the potential advantages … but we should proceed carefully, minimizing and managing risks."

August
Plant biologists Eduardo Blumwald (University of California at Davis) and Hong-Xia Zhang (University of Toronto) reported in Nature Biotechnology they had successfully inserted a single gene from Arabidopsis into tomato plants to create the first crop able to grow in salty water and soil. The genetically engineered tomato confines salt in compartments within its cells and also removes salt from the soil. The leaves of the GE tomato plants contained very high concentrations of sodium, but the fruit was not tainted by excess salt. Blumwald was cited as saying that commercially useful salt-tolerant tomato plants could be available within three years.

Researchers Linda Gahan, Fred Gould, and David Heckel reported in Science the identification of the gene associated with Bt resistance in Heliothis virescens (tobacco budworm). The researchers showed evidence that disruption of a cadherin superfamily gene by retrotransposon-mediated insertion was linked to high levels of resistance to the Bt toxin Cry1Ac in the cotton pest H. virescens. Monitoring the early phases of Bt resistance evolution in the field has been viewed as crucial but extremely difficult, especially when resistance is recessive. The findings should help enable efficient DNA-based screening for resistant heterozygotes by directly detecting the recessive allele.

Dr. Steve Slater (Cereon Genomics), working in collaboration with Dr. Brad Goodner and his research team (University of Richmond, Virginia), released the genome sequence for Agrobacterium tumefaciens. "Agrobacterium tumefaciens is one of the most important tools for plant biotechnology," said Dr. Slater. "The availability of the genomic sequence can help to improve the process of producing new crop varieties through biotechnology." The DNA sequence for A. tumefaciens strain C58, which includes two plasmids and two chromosomes, has been downloaded to GenBank, the public DNA sequence warehouse of the National Center for Biotechnology Information at the US National Institutes of Health in Bethesda MD. (http://www.ncbi.nlm.nih.gov)

A storm erupted over what Greenpeace called the `mystery DNA' discovered in Roundup Ready soybeans. The European Food Research and Technology paper authored by Marc De Loose (Belgium's Center for Agricultural Research) and others reported that some unexpected DNA was found next to an inserted gene in an herbicide resistant variety of GM soybean. However, De Loose dismissed safety issues raised by Greenpeace, saying he and colleagues found no evidence to suggest that the unidentifiable genetic sequence could lead to unknown and unpredictable results.

September
The monarch butterfly once again made waves in the biotech world when the impact of Bt corn pollen on the butterfly population was assessed in a paper published in PNAS by Mark Sears et al. The study—a collaborative research effort by scientists in several states and Canada—suggested that the impact of Bt corn pollen from current commercial hybrids on monarch butterfly populations is negligible.

France's President Jacques Chirac condemned the wave of GM crop protests that have swept the French countryside by saying, "The savage acts of destruction in recent weeks are not acceptable and should be firmly condemned. There is no justification for people who assume the right to ransack the property of others to assert their arguments. We cannot accept such behaviour. They should be prosecuted and punished." Chirac defended such crop tests as "normal and necessary" and said they should proceed with full transparency.

Reports indicate GM papaya may alleviate the decimation of Jamaica's papaya crop by the virulent ringspot disease. Eight years after the disease began its devastation of farms—killing trees and putting farmers out of business—experts in Jamaica are propagating a transgenic variety of papaya they say resists ringspot. The new disease-resistant variety is now on its third field test.

PhilRice (Philippines) announced that a new biotechnology-derived rice, IR72, described as resistant to major plant diseases, would be tested in two trial sites and released soon for commercial use. The rice, containing the Xa-21 gene, was proven in greenhouse inoculation tests to be resistant to nine kinds of bacterial blight. Researchers at the Philippine Rice Research Institute conducted the development and greenhouse testing of this biotech rice in cooperation with researchers of the International Rice Research Institute.

October
EU Consumer Health Commissioner David Byrne was quoted (Reuters, Oct. 9^th) to say that the EU could resume approving new varieties of genetically modified foods and other products early next year if members sign off on a new plan to end a three-year moratorium. In remarks to reporters in Washington, Byrne said new guidelines mirroring the legislation could be devised "between now and Christmas" with the goal of launching GM approvals early next year.

Researchers at the University of Leeds grew thale cress that lights up when it is damaged or stressed. The team took a DNA section and bonded it with DNA from a firefly's light-producing lantern cells. They then mixed the sample with bacteria that invades thale cress and dipped the plants in it. When the thale cress flowered and produced seeds, they grew into new plants that glow faintly when stressed, such as in poor light or high heat. The researchers hope to use this research to develop hardier stress-resistant crops.

In a vote of 91 to 126, Canadian Members of Parliament voted down a bill that would have required mandatory labeling of GE foods, despite massive public support for such measures. The defeat of the bill, initiated last year by Liberal MP Charles Caccia, came despite statements from the Health Minister that he is in favor of mandatory labeling, saying "The Liberal government clearly believes that the interest of corporations takes precedent over that of 95% of Canadians. They have left the decision on what we eat, and what we have the right to know, to the biotech and food industries and not with consumers."

The US EPA renewed registrations for Bt corn varieties for seven years and took actions to ensure that farmers comply with planting restrictions designed to prevent the development of insects resistant to the toxin. EPA also required additional research on the crops' environmental impacts, including the long-term effect on monarch butterflies. Steve Johnson, assistant administrator of EPA's Office of Prevention, Pesticides, and Toxic Substances, was quoted as saying, "Bt corn has been evaluated thoroughly by EPA, and we are confident that it does not pose risks to human health or to the environment."

November
According to a EU report, GMO safety research has been supported in successive Framework Programmes from 1985 to the present day. The pattern of development shows that over this 15-year period, 81 projects have been supported. These projects have involved over 400 teams from many different disciplines and represent a combined EU community financial contribution of about EUR70 million. Summaries of all these projects are contained in the report, which is available at http://europa.eu.int/comm/research/quality-of-life/gmo/index.html.

A November 28^th press release from University of California, Berkeley, indicated that some of Mexico's native corn varieties grown in remote regions have been contaminated by transgenic DNA. The Mexican Government also confirmed the findings. However it was noted that the reasons for and full impact of such findings remain open to interpretation.

University of Georgia researchers completed the first comprehensive molecular map of the peanut plant. "We have developed landmarks and determined how the landmarks are arranged with respect to one another [within the peanut plant]," said Andrew Paterson, a plant geneticist with the UGA College of Agricultural and Environmental Sciences. "The landmarks enable us to determine what important genes, instead of cities, are nearby."

December
In a high profile move, the Swiss government rejected an application to conduct field trials of GM wheat. The decision, now under appeal, caused widespread consternation among Swiss scientists, who argued that it amounts to a de facto moratorium on field tests of any transgenic plant. Five members of the federal Biosafety Commission resigned in protest, including its president, Riccardo Wittek.

Indian Agriculture Commissioner C. R. Hazra told reporters that the country would allow the field testing of GM rice, maize, tomato, and cauliflower. He said the process of testing would take four years before the crops' commercial value could be assessed. Minister Ajit Singh was cited as saying the government would likely approve commercial production and sale of a GM cotton seed variety, once the extensive tests were completed by February 2002.

The Government of Canada responded to a petition, filed in July of 2001 by Greenpeace, pertaining to StarLink corn and Canada's feed, food supply, and ecosystems. The Government's response provided an in-depth look at the existing regulatory system for biotechnology: aspects covering health, the environment, and trade and socio-economic questions, as they pertain to regulation and sustainable development in the country. http://www.inspection.gc.ca/english/ppc/biotech/tech /greenstare.shtml

According to a Wall Street Journal article on December 20^th, the US FDA sent warning letters to Hain Celestial Group Inc. and five other natural-foods companies that they are misleading consumers with labels touting products as GM free. According to the WSJ, the FDA letters, issued on November 29^th, reflect agency officials' growing concern that some marketers might be trying to play to the public's worries about an unfamiliar technology—which the FDA has declared is safe. It's far from clear, however, exactly what a food company can legally say about its efforts to avoid biotechnology.

Ben Chapman, Shane Morris, and Doug Powell
Food Safety Network
University of Guelph
dpowell@uoguelph.ca

In order for plant biotechnology to survive on an industrial level, we must have "killer" plants for irresistible applications. The first killer plants are actually those that save lives. My lab and others are working on plants that can be used in the war of bioterrorism. Last year at this time, I wrote an ISB News Report article on plants that detect landmines (http://www.isb.vt.edu/articles/feb0106.htm). We have made great strides toward finding genetic elements that are inducible to explosives. We have seen interest from the Department of Defense gradually increase as well. During this time, Neil Bruce and colleagues at Cambridge University have produced transgenic tobacco plants overexpressing a bacterial nitroreductase gene to bioremediate soil containing trinitrotoluene (TNT).¹ As defense and homeland security agencies open their wallets and seek out plant biologists to produce biosensors for wide area detection of biological and chemical weapons and explosives, we should see breakthroughs occur in basic plant molecular biology. Think of where plant biology would be if we had NIH level funding for the past 20 years? Defense-related objectives have the potential to significantly boost plant biology research. Why plants? Plants are the only feasible macroscopic organic platform that can heterologously express plant, animal, and microbial metabolic pathways.

We continue to see the convergence of agricultural biotechnology, human nutrition, and pharmaceuticals. Plant biologists are teaming with immunologists and nutritionists to show how crop plants might deliver drugs, edible vaccines, and nutraceuticals to the world at low costs per dose. Charlie Arntzen and colleagues have been successful in clinical trials of edible vaccines this year. Start-up companies, such as CropTech, that are set to produce drugs in plants, continue to raise money for R&D efforts during economically lean times. As we think about public perception and how we examine risks and benefits, a plant that overtly improves human health, such as the Golden Rice, is more compelling than plants that tolerate broad-spectrum herbicides. When will we have transgenic plants that increase sex drive, produce proteins that block hair loss, and help decrease gas? Grass that does not need mowing? These and other output traits are the future of transgenic plants.

Plant biotechnology has been under siege now for quite some time in the US and elsewhere, mainly on the ecological biosafety front. In 1999, it was the monarch butterfly, whose controversy was laid to rest by six PNAS papers in 2001. This year, it is alleged illicit gene flow from transgenic corn to Mexican landraces.² (I predict, by the way, that the article in which these allegations were made will be retracted). Next year there will be another concern. Ecology is such a vast area that the immature plant biotech industry will be groping in the dark for some years to come. Science (or the lack thereof) seems to be the sidecar of the environmental contingency that is opposed to biotechnology in general. Thus, we will see the agrochemical industry becoming more proactive in their approach to ecology. Technologies such as transplastomics and the Terminator gene (renamed "Safety Gene") will no doubt play a part in proactively maneuvering through not only the EPA regulations but also the public's hearts and minds. We will also see the Monsantos and Syngentas hiring more ecologists to meet a need that was, until recently, not seen as relevant. The consolidating agbiotech industry will begin an expansion in which start-up and midsize companies find new niches as the large multinationals get over the biosafety hump. In five-years' time, though, the killer applications will override relatively small ecological concerns to place socially desirable transgenic plants in the apple of the public perception eye. There will still be no confirmed food safety concerns for foods coming from genetically modified plants. However, as organic producers continue to gain larger market shares, food safety concerns will loom over their products.

Finally, some technologies that I think will emerge will make transgenic plants much easier to produce and cause the transgenes to be produced in a more regulated fashion. It could be that large funding increases and exponential genomics information and bioinformatics technology will drive these efforts toward major breakthroughs in the next couple of years. In planta transformation of Arabidopsis thaliana, first performed on seeds in 1986 and then on plants through the floral dip/vacuum infiltration methods in 1993 [see references in (3)], have opened the imagination of those who would put the tissue culturist out of work. If Arabidopsis is amenable to in planta transformation, then why not tweak this technique for the transformation of soybean, corn, and, in fact, all other economic plants? How many hours (years?) have been spent searching for this grail?

Genomics will hold the key to regulating transgene integration and expression. And it will also provide information about the fine controls of gene expression, especially through expression microarray analysis. Why use a constitutive promoter to express an insecticidal transgene, when a tight, herbivory-inducible system is available? Such control over transgene expression in time and space puts many nontarget concerns to rest. Recall that the rarely-used Syngenta Bt corn event that expressed Bt toxin in pollen was the target for the original monarch butterfly study.⁴ The negative publicity was, no doubt, partly responsible for the company not seeking US re-registration for the deregulated corn event.

In 2002, we will find the maturation of plant biology continuing. Breakthrough papers in gene expression, including gene silencing, will appear. Companies will announce the development of new products with output traits that are truly lovable by the public. Extreme environmental activists will not love them, of course, but thanks to zero tolerance of terrorism, at least ecoterrorism will significantly diminish. Finally, we can hope to see plants being used in non-agricultural applications. If all goes well, plants will detect anthrax, botulinum toxins, and TNT and serve to make the world, truly, a safer place in which to live.

Sources

1. Hannink N, Rosser SJ, French CE, Basran A, Murray JAH, Nicklin S, and Bruce NC. 2001. Phytodetoxification of TNT by transgenic plants expressing a bacterial nitroreductase. Nature Biotechnology 19: 1168-1172.

2. Quist D and Chapela IH. 2001. Transgenic DNA introgressed into traditional maize landraces in Oaxaca, Mexico. Nature 414: 541-543.

3. Bent AF. 2000. Arabidopsis in planta transformation. Uses, mechanisms, and prospects for transformation of other species. Plant Physiology 124: 1540-1547.

4. Losey JE, Rayor LS, and Carter MC. 1999. Transgenic pollen harms monarch larvae. Nature 399: 214.

Neal Stewart
UNC Greensboro
Cnstewart1@juno.com

USE OF G1 DONOR NUCLEI IMPROVES VIABILITY OF CLONED CATTLE

Production of cloned mammals by nuclear transfer (NT) has become an established means of propagating valuable individuals or producing genetically modified animals. Since the landmark study reporting the birth of a sheep cloned by NT from a terminally differentiated cell type,¹ many laboratories have reported production of cloned mice, pigs, goats, and cattle. Cloning of cattle by NT is inefficient because the proper cell cycle phase for donor cells has not yet been determined, the DNA of differentiated donor cells is not effectively reprogrammed, the rate of spontaneous abortion is high, and the health of neonatal calves often is compromised. Recent reports demonstrate progress addressing some of these impediments to cloning cattle. Use of non-quiescent nuclei from fetal fibroblasts improves early viability, and cloned individuals can give birth to healthy offspring.

There has been considerable debate about the most appropriate cell cycle stage of donor nuclei for NT. Wilmut et al.¹ suggested that it is important to induce quiescence at G0 stage by starving cultured cells of serum prior to removal of donor nuclei. However, Cibelli et al.² subsequently demonstrated NT-based cloning in cattle using actively dividing G1 stage fibroblasts. In the current issue of Nature Biotechnology, Kasinathan et al.³ report comparisons of methods for producing G0 and G1 cell populations and subsequent fetal development following NT. High confluence of bovine fibroblast cells was more efficient than serum starvation for arresting development at G0 stage. Dividing fibroblasts can be isolated by shaking the culture dish, and the authors demonstrated that the procedure is effective for isolating a synchronous population of cells in G1 phase. Nuclei from each treatment were transferred into enucleated eggs and implanted into 50 recipients. No embryos derived from confluent G0 cells survived beyond 180 days of gestation. However, five live calves were obtained from nuclei of cells at G1 stage. Hence, use of nuclei from actively dividing G1 cells proves important for producing viable calves using NT.

In a recent issue of Science, Lanza et al.⁴ reported on the health and reproduction of cattle cloned from non-quiescent fetal fibroblasts. The transfer of 496 embryos into 247 recipients resulted in 110 (45%) pregnancies. Eighty pregnancies ended in spontaneous abortions, and 30 (27%) developed to full term. Five calves died shortly after birth and one calf died after 149 days due to cardiovascular, enteric, hepatic, or other problems. Twenty-four calves were viable at birth and remained live and healthy for one to four years. A range of examinations suggested that these cloned individuals were physiologically, immunologically, and behaviorally normal. They exhibited puberty at the expected age and high rates of conception upon artificial insemination. Two of these cloned individuals have given birth to calves that appear normal in all respects.

The possibility of human reproductive cloning has elevated the question of whether cloning can generate "normal" individuals. Some scientists who argue that reproductive cloning is unsafe remain unconvinced by the recent Science article.⁵ Most pregnancies resulted in miscarriage or inviable neonates. Some criticized as simplistic the phenotypic criteria used to conclude that surviving individuals were normal. Rudolph Jaenisch (Whitehead Institute, MIT) noted that subtle abnormalities, such as brain function, would be hard to detect. Further research will be needed to determine whether poor fetal and neonatal viability is due to unrefined cloning methods or to cloning per se.

The US Food and Drug Administration's Center for Veterinary Medicine (CVM) is considering the safety of somatic cell cloned animals and their progeny.⁶ CVM's first priority is to examine the safety of food products from animals developed through somatic cell cloning that are otherwise unmodified. When it became evident that commercial ventures were developing somatic cell clones for use in breeding food-producing animals, CVM contracted with the National Academy of Sciences to conduct a review of the available safety data on cloned animals and foods derived from them. This review, expected to be released this spring, will consider the safety of cloning to animals, the environment, and foods derived from the animals. The review will help CVM determine how these animals should be regulated, including determination of whether there may be circumstances in which CVM ordinarily would not need to exert its authority. Until CVM has scientific information on safety, it has been asking companies not to introduce cloned animals, their progeny, or their food products into the human or animal food supply.

Sources

1. Wilmot I, Schniecke AE, McWhir J, Kind AJ, and Campbell KHS. 1997. Viable offspring derived from fetal and adult mammalian cells. Nature 385: 810-813.

2. Cibelli JB, Stice SL, Golueke PG, Kane JJ, Jerry J, Blackwell C, Ponce de Leon FA, and Robl JM. 1998. Cloned transgenic calves produced from non-quiescent fetal fibroblasts. Science 280: 1256-1258.

3. Kasinathan P, Knott JG, Wang Z, Jerry DJ, and Robl JM. 2001. Production of calves from G1 fibroblasts. Nature Biotechnology 19: 1176-1178, December 2001. http://biotech.nature.com.

4. Lanza RP, Cibelli JB, Faber D, Sweeney RW, Henderson B, Nevala W, West MD, and Wettstein PJ. 2001. Cloned cattle can be healthy and normal. Science 294: 1893-1894. (November 30 2001.) Article and supplemental data available at http://www.sciencemag.org.

5. Kolata G. 2001. 24 cow clones, all normal, are reported by scientists: A challenge to arguments against cloning. New York Times, Friday, November 23, 2001: A17.

6. FDA, Center for Veterinary Medicine. 2001. Update on livestock cloning. CVM Update, July 13, 2001. http://www.fda.gov/cvm.

Eric Hallerman
Department of Fisheries and Wildlife Sciences
Virginia Polytechnic Institute and State University
ehallerm@vt.edu

END OF THE YEAR BRINGS GOOD TIDINGS FOR PLANT UTILITY PATENTS

As described in last month's issue ["US Mulls Over Plant Utility Patents, While Biotech Gets Mixed Support in the EU" ( http://www.isb.vt.edu/news/2001/news01.dec.html #dec0104)], the US Supreme Court recently heard oral arguments on whether the US Patent and Trademark Office can issue utility patents for plants. The Court published its decision on December 10, and the answer is yes: plants are proper subject matter for utility patents. Justice Thomas delivered the opinion of the Court, which tracked Pioneer Hi-Bred's arguments, described previously. Justice Breyer and Justice Stevens, however, dissented, taking J.E.M. Ag Supply's position that Congress had intended the Plant Patent Act and the Plant Variety Protection Act to exclude patent protection under the Utility Patent Statute. A copy of the decision is available at the US Supreme Court Web site http://www.supremecourtus.gov/opinions/01slipopinion.html.

BATTLES AND SKIRMISHES IN THE BIOTECH PATENT ARENA

2001 saw a worldwide escalation in apprehensions about biotech patents. Gene patents appeared to have been viewed with a particularly jaundiced eye. In October, for instance, the International Bioethics Committee of the United Nations Educational, Scientific and Cultural Organization called upon UNESCO to promote the adoption of an international moratorium on the granting of gene patents until any ethical ramifications could be explored. During a 60 Minutes show, Morley Safer warned that "chances are, your genetic structure and mine, our most private property, may well belong to someone else." Although ludicrous, this statement undoubtedly made an impression on many viewers. According to 60 Minutes, one of the major concerns about gene patenting is that it hinders research. Yet in response to a questionnaire issued by the European Parliament, Gugerell Christian, Director of the European Patent Office, stated that, in spite of the large number of gene patents, he is not aware of a single incidence where gene patents hampered research. Still, the perception persists that patents have a chilling effect on basic research.

Agbiotech patents did not escape misgivings. In early November, the International Treaty on Plant Genetic Resources for Food and Agriculture was adopted with two abstentions (the US and Japan). An objective of this treaty is to discourage patents on food crops. During the same month, the Canadian Biotechnology Advisory Committee released its interim report, which recommended the creation of a farmer's privilege within the Patent Act. A concern here is that a patent owner could have rights to seed produced in farmers' fields, an issue that US Supreme Court Justices raised during the recent oral hearing of Pioneer Hi-Bred International Inc. v. J.E.M. AG Supply Inc.

Many found current patent law adequate for fighting or circumventing particular patents.

Waging the Patent Battle at the Source
One popular battlefield is a patent's birthplace—the patent office. In the European Patent Office (EPO), a third party can challenge the validity of a European patent within nine months of the publication of the notice to grant the patent. An Opposition proceeding may result in the patent being upheld in an unchanged or amended form, or the Opposition Division may decide to revoke the patent. Claiming bio-piracy, the Mexican government reportedly filed a request for an Opposition last summer to halt DuPont's European patent on a maize variety called OPTIMUM HOC/HO, which the government claims originated in Mexico.

Although the US does not offer an Opposition mechanism, a third party can challenge a patent by initiating a reexamination proceeding with the US Patent and Trademark Office (USPTO). The International Center for Tropical Agriculture filed such a request for reexamination of a patent owned by Pod-ners LLC, which claims a Phaseolus vulgaris field bean. In January 2001, the USPTO published its intent to reconsider the patent. In yet another case of alleged bio-piracy, India's Agricultural and Processed Food Exports Authority challenged three US patent claims held by RiceTech, Inc. (Alvin, TX). In August, following reexamination, the USPTO reduced the original twenty claims to five.

When reexamination fails, a party can turn to the courts. In 1999, Brassica Protection Products LLC (Baltimore, MD) and Johns Hopkins University sued Sproutman, Inc. (Upper Black Eddy, PA) for infringement of patents relating to the production and consumption of cruciferous seed sprouts. While the litigation was pending, Sproutman initiated a reexamination proceeding, and the USPTO ultimately reaffirmed the validity of the claims. Last summer, however, the court heard arguments in the infringement action and decided that the patents are invalid due to a lack of novelty.

Prior Art: Offensive and Defensive Tactics
These strategies of patent attack relied upon prior art for ammunition. One policy underlying patent law is that the patent grant should not remove something from the public domain, and for this reason, a claimed invention must be novel. That is, an invention must differ from the prior art, which is the sum of publicly available information. In addition, a patent should not issue for a claimed invention that would have been an obvious variation of something in the prior art. A recently created dot-com called "BountyQuest" takes advantage of the patent-busting power of prior art by allowing individuals or companies to challenge a patent for a $2,500 fee plus a cash prize of $10,000, or more. The prize goes to the person who can uncover prior art that could invalidate the patent. As an example, a $20,000 bounty was posted for a Monsanto patent with claims to DNA encoding enzymes that can render plants tolerant to glyphosate herbicide. This bounty apparently closed without anyone collecting. However, a German graduate student won a $10,000 bounty for his submission of documents on an Incyte Genomics, Inc. (Palo Alto, CA) patent that covered a relational database system for storing and manipulating large amounts of genetic information.

Instead of finding prior art, a preemptive strike can be initiated by creating prior art. Meeting for the first time in 2001, a special body of the World Intellectual Property Organization (the Intergovernmental Committee on Intellectual Property and Genetic Resources, Traditional Knowledge and Folklore) considered the topic of a more effective integration of traditional knowledge documentation into searchable prior art. Meanwhile, India is developing a digital library of its traditional knowledge and will provide access to US and European patent offices. Individuals who wish to publicly disclose their invention as a defensive publication strategy can use the services of IP.com, which publishes invention disclosures on the Web.

Taking Aim at Patents on Diagnostics
In May, Myriad Genetics, Inc. (Salt Lake City, UT) announced that it had received eight patents in the US and abroad, covering the BRCA1 and BRCA2 breast and ovarian cancer genes and their use in the development of therapeutic and predictive medicine products. After obtaining their Canadian patent, Myriad reportedly demanded that Canadian provinces route tests involving the patented genes to the company's laboratory or to designated licensees. In response to the higher costs, the British Columbia health ministry halted testing in August. Ontario Premier Mike Harris condemned the Myriad patents and indicated that Canadian laws should be amended to prevent private firms from patenting human genes. Myriad's patent claims were no more popular in Europe, where researchers and clinicians from France, Belgium, Denmark, Germany, the Netherlands, and the United Kingdom filed an Opposition request against Myriad's EPO patents. On October 4, the European Parliament adopted a resolution opposing the Myriad patent.

Compulsory Licenses: Confronting a Patent with a Bludgeon, Not a Stiletto
Instead of clashing with a patent head on, a government can make an end run with a compulsory license, which is a grant of a license without the patent owner's permission. Under the current Trade-Related Intellectual Property Rights (TRIPS) Agreement, Members can issue compulsory licenses that allow local production of generic drugs in the event of a national emergency. Following the recent anthrax deaths in the US, Canada announced its intent to impose compulsory licensing on Bayer's ciprofloxacin (CIPRO), and Tommy Thompson, Secretary of the US Department of Health and Human Services, reportedly used the threat of compulsory licensing to strike a deal with Bayer for the US government to buy 100 million CIPRO tablets at a reduced rate.

According to Representative Christopher Shays (R-CT), Congress would probably back any request from Thompson for permission to bypass the Bayer patent, and after the Bayer deal was finalized, Representative Sherrod Brown (D-OH) introduced legislation ("Public Health Emergency Medicines Act"; H.R. 3235) that would allow the Secretary of Health and Human Services to authorize compulsory licensing of patented inventions relating to health care emergencies. Traditionally, the US has held a dim view on compulsory licenses as shown by another bill ("Comprehensive Trade Negotiating Authority Act of 2001"; H.R. 3005), which declares that one of the principal negotiating objectives of the United States is to make reasonable efforts to address the problem of supplying essential medicines, other than by compulsory licensing.

Selected Sources

1. In re Cruciferous Sprout Patent Litigation (DC MD 2001). A copy of the decision (MDL Docket No. 1388) can be obtained from the Web site of the US District Court for the District of Maryland. http://www.mdd.uscourts.gov

2. Dove A. 2001. Patents not key barrier to AIDS therapy. Nature Medicine 7(12): 1262.

3. Madeley J. 2001. Food patent `bio-pirates' under fire from aid agency. Financial Times (London) 32 (October 25).

4. Young E. 2001. US accused of double standards on drug patents. NewScientist.com (November 2).

Phillip B. C. Jones, PhD., J.D.
Seattle, Washington
phillipjones5939@msn.com

More meetings can be found at http://www.isb.vt.edu

Foods for Health: Potential, Perspectives, and Policy
May 19-21, 2002
Radisson Hotel Metrodome, Minneapolis, Minnesota

Organized by the National Agricultural Biotechnology Council and sponsored by the University of Minnesota, this conference will cover three main dimensions of foods for health: (1) current research directions, (2) application of technologies, and (3) society, law, ethics and public policy. Topics addressed under research directions include proteomics, high throughput analysis of plant-derived products, bioinformatics, and the epidemiology of diet-related disease. Technology application encompasses edible vaccines, nutraceuticals, translation of genomics to applications, and genetic engineering. Topics under society, law, ethics and public policy include public education, consumer preference and acceptance, regulatory issues, values, religious practices and perspectives, and policy implications.

Contact:
University of Minnesota
Email: nabc2002@mail.coafes.umn.edu
http://www.coafes.umn.edu/nabc2002/overview.html

Introduction to Biosafety and Risk Assessment for the Environmental Release of Genetically Modified Organisms (GMOs)
Theoretical Approach and Scientific Background
June 3 - 7, 2002
Trieste, Italy

The workshop is dedicated to those scientists actively involved in environmental releases of genetically modified organisms (GMOs). The main purposes of the workshop are (i) to supply basic information on risk assessment and risk management and (ii) to provide an overview on international biosafety regulations and the main safety issues debated at an international level.

Contact:
Programme and Training Unit, ICGEB
Tel: +39-040-3757333
Fax: +39-040-226555
Email: courses@icgeb.trieste.it
http://www.icgeb.trieste.it/~bsafesrv/bsfn0112.htm

BIO 2002 International Convention & Exhibition
June 9 - 12, 2002
Toronto, ON, Canada
Billed as the world's largest biotechnology event, this Convention will feature 17 concurrent educational tracks; over 250 hours of sessions and symposia; more than 800 speakers and more than 750 exhibitors.

Contact:
BIO Meetings Department
Tel: 202-857-2506
Fax: 202-331-8132
Email: bio2002@bio.org
http://www.bio2002.org

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