JOURNAL O F MOLECULAR RECOGNITION, VOL. 5 , 19-39 (1992)

Abstracts Bio-Recognition-International

Industrial Biotechnology Conferencet

Montreal, Canada, 1-4 June 1992

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RNA ENZYMES AND RNA AS THERAPEUTIC AGENTS Sidney Altman Department of Biology, Yale University, New Haven, CT,USA

A brief survey of the nature of catalytic RNAs and their importance in biological systems will be presented. Ribonuclease P, an enzyme essential for tRNA biosynthesis that has a catalytic RNA component, will be described in more detail. Studies of the substrate recognition mechanism of this enzyme have led to a general scheme for the targeted cleavage of any RNA in oifro or in uiuo. The specific cleavage of a targeted RNA using RNase P has been achieved with mRNAs expressed in Escherichia coli and in mammalian tissue culture cells. The prospects of this method for disease therapy will be contrasted with techniques using other catalytic RNAs and with ‘antisense’ methods.

BIO-SCIENCE

1. Ribozymes THE DESIGN OF OPTIMAL RIBOZYMES Olke C. Uhlenbeck Department of Chemistry and Biochemistry, University of Colorado at Boulder, Campus Box 215, Boulder, C O 80309-0215, USA

Ribozymes, or catalytic RNAs, may prove to be an important extension of the antisense gene inactivation strategy. Five quite different ribozyme reactions have been adapted so that they can potentially cleave a messenger RNA inside cells. In each case, the specificity of cleavage is achieved by the formation of an RNA duplex with the mRNA target. In this lecture, we draw from our extensive experience studying the hammerhead ribozyme in uifro to address a number of questions: (i) Which ribozyme reaction has optimal catalytic properties? (ii) How long a helix is required for optimal specificity? (iii) How should the site on the target RNA be chosen? By combining a simple kinetic model of the ribozyme reaction with what we know about the stability of RNA helices, considerable insight into the design of an optimal reaction can be obtained.

USE OF RIBOZYMES TO CONFER VIRUS RESISTANCE W. L. Gerlach CSIRO Division of Plant Industry, GPO Box 1600, Canberra, ACT 2601. Australia ‘These abstracts are also available in French from Hazel Strouts, Conference Coordinator, Biotechnology Directorate, Industry, Science and Technology Canada, 235 Queen Street, Ottawa, Ontario KIA OHS, Canada.

Ribozymes have potential to provide enhancement upon or alternative to antisense technology for the modulation of gene activity. One area of application which is being examined is that of virus and viroid diseases of plants. We have produced transgenic plant lines expressing antisense and ribozymes targeted against tobacco mosaic virus and potato leafroll virus. Some transgenics show significant protection against virus infection while others do not. When present, the phenotype is correlated with the inheritance of the gene construction. Similar gene constructions are also effective against viroid pathogens of plants. While these approaches involve genetic transformation of experimental material, other laboratories are investigating the exogenous delivery of ribozymes to affect virus. infection of mammalian cell cultures.

2. Antisense A BACKGROUND FOR OLIGONUCLEOTIDE BASED CHEMOTHERAPEUTICS Paul. C. Zamecnik Worcester Foundation for Experimental Biology, Shrewsbury, MA 01545, USA

During the past half-dozen years the chemotherapeutic possibilities arising from complementary hybridization of specific oligonucleotides with larger pieces of DNA or RNA have grown into an experimental reality. Modulation of the message of the gene has become an ‘enabling technology’ with potentiality reaching into numerous stubborn corners of animal and plant disease. Nearly 40 years have passed since the

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double-stranded DNA helix opened the door to molecular genetics. Shortly thereafter, transfer RNA appeared on the scene, pointing a compelling finger at complementary nucleotide base pairing as the mechanism for translation of the language of the gene into that of the protein. It required two important advances in the late 1970s and early 198Os, however-a dramatic improvement in sequencing of DNA from Maxam and Gilbert, and from Sanger; and the development of solid phase synthesis of oligodeoxynucleotides from Letsinger-to bring oligonucleotide therapeutics onto the scientific stage. Since then a variety of viruses, such as HIV, Influenza, and Herpes, of protozoa such as Trypanosomes and Malaria, and of intrinsic human cell diseases such as leukemia and solid cancer have been the targets of promising ‘antisense’ oligonucleotide therapy in tissue cultures. Few reports have as yet, however, come from a successful similar therapy in animals, in part due to difficulties in synthesizing sufficient quantities of nuclease resistant oligodeoxynucleotides for use in animal model studies.

CONTROL OF GENE EXPRESSION BY ANTISENSE AND ANTIGENE OLIGONUCLEOTIDES ~~~

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carried out with the gene for chalcone synthase (chs; van der Krol et al. (1988), Nature, 333, 866-869). In addition to uniform reduction in pigmentation, specific patterns were obtained. Today many different plant genes acting in a variety of metabolic pathways have been successfully downregulated (e.g., genes acting in fruit ripening, hormone metabolism, starch synthesis, photosynthesis, cell wall synthesis, etc.). Addition of a limited number of sense chs gene copies sometimes leads to the disappearance of chs mRNA and pigmentation (The Plant Cell (1990), 4, 279-290, 291-299). This phenomenon is termed co-suppression or transinactivation and has been found for a large variety of genes. Co-suppression is a post-transcriptional event. I will discuss the question whether antisense and co-suppression are related phenomena. Antisense experiments have provided more insight in the function of flavonoids. From the literature it is evident that besides the role in flower pigmentation, flavonoids may protect the plant against UV-light, can act as phytoalexin and induce nodulation genes in legumins. Furthermore, flavonoids have been implicated in hormonal regulation. Expression of antisense chs cDNA in tapetum cells results in white anthers and white pollen (wp). Surprisingly, w p are arrested in their maturation and consequently are sterile. This provides a novel way to engineer nuclear male sterility, an important trait in hybrid seed production. Finally, I will give some examples of the use of antisense genes to identify the function of kryptic genes.

Claude Helene Muskurn National d’Histoire Naturelle, 7523 Paris Cedex 05, France

Synthetic oligonucleotides can be used to control gene expression. In the ‘antisense’ approach, the oligonucleotide binds to messenger RNA and blocks its transcription into protein. In the ‘anti-gene’ approach the oligonucleotide either intercalates into the furrow of the DNA or forms a triple helix and blocks transcription. The oligonucleotides can be modified to make them more resistant to nucleases. Addition of intercalation groups or hydrophobic groups can increase the affinity for the target sequence and increase the penetration into living cells. Antisense oligonucleotides can discriminate between a normal and an abnormal gene. The ras oncogene which is activated by a point mutation in a number of tumor types will be used as an example of the application of a new therapeutic strategy against these tumors. The development of ‘anti-gene’ oligonucleotides is more recent than that of ‘antisense’ nucleotides. The possibility of selectively blocking the expression of a single gene at the level of a living cell opens new perspectives for therapeutic applications for synthetic oligonucleotides.

(MECHANISM OF) ACTION OF ANTISENSE AND SENSE GENES IN HIGHER PLANTS Joseph Mol Department of Genetics, Free University, De Boelelaan 1087, 1081 HV Amsterdam, The Netherlands

Flower pigmentation is an ideal system to study the regulation and manipulation of plant gene expression. We chose to work with Petunia hybrida because it has a well developed genetics, many mutants are available and it can be transformed and regenerated very easily. Using cloned genes from the pathway we introduced antisense versions in order to downregulate the endogenous genes. The initial experiments were

3. Genome studies MAPPING AND SEQUENCING THE HUMAN GENOME Norton Zinder The Rockefeller University, 1230 York Avenue, New York, NY 10021-6399, USA

The human genome initiative is a world wide effort to develop the procedures and the technology to map both genetically and physically the human genome, to sequence its nucleotides and then use the technologies developed to accomplish it. Though originally started through discussions in the USA in the mid 1980s, there are by now at least a dozen national or regional efforts in this area. These efforts are supported by the national governments probably as a world wide total to about 250 million US dollars a year. In the US the effort is managed by both the Department of Energy and the National Institute of Health. Together in 1990 they produced a plan for the first 5 years of the program, written as if the total effort was to be a US one but always realizing costs and rates of progress would be related to efforts in other countries. The plan sets up a number of goals for this period. These goals have as their purpose to obtain a genetic and physical map of the human genome with well characterized markers first at an average distance of 5-10 centimorgans and than 1-2 centimorgans. Production sequencing is not to begin for this period but rather development of technology to increase the efficiency and reduce the cost would be promoted. Also, and meanwhile, programs supporting mapping and sequencing efforts in a number of model systems, E. coli, yeast, fruit flies, C. elegans, and the mouse could begin. Sensitive to the relationship of genetic information to societal and legal problems a substantial program, at ca 5% of budget, will study problems such as the impacts of genetic screening and the privacy of genetic information.

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THE HUMAN GENOME PROJECT: INSIGHTS INTO GENETIC DISEASE BUT CHALLENGING QUESTIONS FOR SOCIETY Ronald G. Worton Department of Genetics, Hospital for Sick Children, University of Toronto, Ontario M5G 1x8, Canada

Until about 1975 research on human genetic disease was based primarily on examination of the physiological and biochemical phenotype, and for the vast majority of genetic diseases the basic defect remained unknown. With the development of recombinant DNA technology the cloning and characterization of genes encoding well-characterized proteins such as globin, growth homone, insulin, etc., became possible. By the 1980s genetic library screening made it possible to clone and characterize genes encoding purified low abundance proteins such as metabolic enzymes responsible for inborn errors of metabolism. The development of genomic approaches in the mid 1980s made it feasible to clone a gene based only on the knowledge of its position in the chromosome, allowing the clone of disease genes responsible for Duchenne muscular dystrophy, retinoblastoma, cystic fibrosis, and others without any prior knowledge of the protein product of the relevant gene. The impact on human genetics has been dramatic. It is now possible to identify carriers and do definitive prenatal diagnosis for a large number of genetic conditions, allowing pregnancy termination for those conditions that are lethal, or have a high burden. For many genetic diseases work is progressing to the point where new approaches to treatment are on the horizon, and for some, gene therapy is being considered as part of the treatment protocol. In the future, there will be further dramatic escalation in the knowledge base as the Human Genome Project identifies and sequences all the genes in the human genome. This means that each of the 4000 or so genetic diseases will be amenable to study. It means that genes involved in determining susceptibility to heart disease, cancer, neurological dysfunction, and resistance to infectious agents will all be available for detailed analysis. The challenge for society will be to decide how this new knowledge should be applied, particularly in the time period when prevention by prenatal diagnosis will be available but cure will not. Very soon society will be expected to deal with the question of prenatal testing for those individuals who would have a higher than normal susceptibility to cancer, Alzheimer’s disease, schizophrenia, or heart disease. Before genetic testing becomes commonplace, society must think about who has the ‘right to know’ when it comes to such sensitive information. Will employers be able to discriminate on the basis of genetic testing that suggests susceptibility to those conditions listed above? Will insurance companies be able to deny insurance based on similar information? These and other questions are not hypothetical, nor are they premature for discussion at this time. It is only through an enlightened public that we will be able to find our way through the maze of difficult questions posed by the new technology.

HUMAN GENOME INITIATIVE: THE MAPPING PHASE Helen Donis-Keller Department of Genetics, Washington University School of Medicine, St Louis, MO, USA

The Human Genome Initiative has as its ultimate goal determination of the DNA sequence of the entire human genome,

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a formidable task considering that lo7members) cloned for display on the surface of a phage. Rare phage with antigen-binding activities were selected by four rounds of growth and panning with a variety of antigens. Human antibodies have been isolated against a wide range of

Biomira Inc., Research Centre One, Edmonton Research and Development Park, 941 1-20 Avenue, Edmonton, Alberta T6N 1E3, Canada The concept of targeting cancer tissue for the purpose of specific diagnosis and therapy is not new. The realization of that dream is now around the corner because of recent understandings of tumor biology and the development of specific probes through biotechnological innovation. To address the problem of specificity, monoclonal antibodies in a variety of forms have been developed to recognize certain cancer-associated differentiation antigens. In turn, these same antibodies have been modified through genetic engineering methods into humanized forms for better tolerance. This concept was taken one step further by reducing the size of the probe to a Molecular Recognition Unit (MRU) which has the promise of totally revolutionizing the cancer targeting approach. These MRUs, when conjugated to appropriate chelators or drugs will enhance the signal and concentration ratios in the tumor regions, thus providing the treating physician with new diagnostic and therapeutic tools unheard of a few years ago. The elements of this technology are now at various stages of testing and validation.

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6. Carbohydrate technology SYNTHETIC AND ANALYTICAL TECHNIQUES

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CHEMICALLY MODIFIED POLYSACCHARIDES AS HUMAN VACCINES Harold J. Jennings

Raj Parekh Oxford Glycosystems Inc., Unit 4, Hitching Court, Blacklands Way, Abingdon, Oxon OX14 IRG, UK

Analysis of the carbohydrate moieties of glycoconjugates is proving of increasing value in numerous contexts, including the development and production of recombinant glycoproteins, the identification of carbohydrate ligands of natural lectins, and in the refinement and development of vaccines. Such analysis generally involves the release and subsequent recovery of carbohydrate moieties from conjugate, the fractionation of released carbohydrates and finally, if necessary, detailed structural analysis of individual carbohydrates(s). In this presentation, strategies will be reviewed which have begun to allow the total automation of each of the three stages of analysis. It is anticipated that the resulting instruments will allow the routine analysis of the glycosylation of proteins and lipids, and consequently revolutionize our understanding of the biological significance of glycosylation. By analogy with proteins and nucleic acids, it is expected that a natural consequence of the availability of such analytical instrumentation will be the need for a ‘carbohydrate synthesis’. Chemical and enzymatic approaches suitable for automated carbohydrate synthesis are at present poorly defined. However, some recent advances suggest that such a synthesis capable of yielding small oligosaccharides containing natural linkages may indeed be practical and this subject will also be discussed.

AMINOSUGAR INHIBITORS OF GLYCOPROTEIN PROCESSING: WHY DO THEY DISPLAY ANTIVIRAL ACTIVITY? Gary S. Jacob Monsanto Corporate Research, 800 North Lindbergh Blvd, St Louis, MO 63167, USA

During the past few years, a number of aminosugar inhibitors of the mammalian endoplasmic-reticulum exoglycosidase, aglucosidase I, have been found to display antiviral activity. Cumulative data, to date, suggest that these compounds have a hierarchy of effects, with reduction in syncytia formation being the predominant feature. These inhibitors act by altering the normal post-translational processing of viral envelope surface glycoproteins. The envelope surface glycoproteins, such as the gp4Ugp120 complex of HIV, mediate virus binding and fusion events, and are highly glycosylated proteins typically derived from a common glycoprotein precursor which must be processed by a host cellular endoprotease. Consequently, there are a number of different ways in which aminosugars may be exerting an antiviral effect. This presentation will review what is known about these compounds, and describe recent efforts to establish the antiviral mechanism of action. This will include: (i) characterization of changes in glycosylation and endoprotease processing; (ii) effects on the V3 hypervariable loop of gp120; and (iii) studies on SC-48334 (N-butyl-1-deoxynojirimycin),a compound which is presently undergoing clinical testing for the control of HIV infections.

National Research Council of Canada, Institute of Biological Sciences, 100 Sussex Drive, Ottawa, Ontario, K1A OR6, Canada

The use of capsular polysaccharides as immunoprophylactic agents in human disease caused by encapsulated bacteria is now firmly established. However, despite the many advantages of using purified capsular polysaccharides as human vaccines, a serious limitation to their general applicability is the poor immune response of all polysaccharides in infants and some of the polysaccharides in adults. This limitation can be overcome by chemical modification of the polysaccharides. Enhancement of the immunogenicity of many of the polysaccharide e.g. type b Haemophilus infiuenzae, groups A and C Neisseria meningitidis and types In, Ib, I1 and 111 group B Streptococcus, can be achieved by covalently coupling them to protein carriers, and this technique has already resulted in the production of commercial vaccines against meningitis caused by the former bacteria. However, this technique failed to significantly enhance the immunogenicity of the capsular polysaccharides of Escherichia coli K1 and group B Neisseria meningitidis. The capsular polysaccharides of both meningitis-causing bacteria are identical in structure both being homopolymers of a2+ 8-linked sialic acid, and the poor immunogenicity of this polysaccharide is due to the fact that it shares common epitopes with human tissue. In this case, direct modification of the basic structure of the polysaccharide was explored. N-proprionylation of the polysaccharide prior to its covalent coupling to tetanus toxoid gave a conjugate which was able to induce high levels of protective antibodies in mice. The N-propionylated polysaccharide mimics a unique epitope on the surface of both E. coli K1 and group B N . meningitidis not expressed in the exogenous native polysaccharide. These observations could be important in the development of a vaccine against meningitis caused by E. coli K1 or group B N. meningitidis.

7. Drug delivery THE GREATEST CHALLENGE FOR THE TECHNOLOGY OF POTENTIALLY THERAPEUTIC RECOMBINANT PROTEINS IS OVERCOMING THEIR IMMUNOGENICITY Alec H. Sehon Department of Immunology, University of Manitoba, Winnipeg, Manitoba R3E OW3, Canada

Most recombinant proteins are immunogenic. Therefore, (i) they are eliminated faster from circulation than their natural prototypes, (ii) they induce antibodies which intercept their reaching their targets, and (iii) the resulting antigedantibody complexes may lead to untoward physiological effects e.g., serum sickness and, on readministration, occasionally even anaphylaxis. We developed in 1976 the technology for conversion of immunogenic proteins to tojerogenic derivatives by coupling onto the former an optimal number of molecules of

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monomethoxypolyethylene glycol (mPEG). Although the tolerogenic products may be devoid of the biological activity of their progenitors, this is of no consequence for the therapeutic regimen for which the tolerogenic derivatives are intended in the strategy developed by us i.e., the function of our mPEG conjugates is to induce suppressor T (Ts) cells which recognize antigenic epitopes shared by the original and the pegylated proteins. Once the Ts cells have been induced, which takes c a 7 days after administation of the pegylated derivatives, subsequent repeated injections of the unmodified proteins do not break the induced state of antigen-specific tolerance. The potential application of this strategy to a broad spectrum of diseases will be discussed.

ARTIFICIAL CELLS AS A VEHICLE FOR BIOTECHNOLOGICAL MATERIALS

transdermal patches. In each case the drug is either solubilized or dispersed in a micronized state throughout the formulation. Various ingredients have been added to these formulations in an attempt to enhance the penetration properties of drugs. Such ingredients range from simple solvents such as alcohol and propylene glycol to more potent and as yet to be approved enhancers such as dimethyl sulfoxide. However none of these enhancers are capable of targeting the drug to specific skin tissue but rather act to expedite passage of drug through the skin to the blood stream-thus resulting in greater toxicity potential. These shortcomings of conventional dosage forms have now been circumvented with the advent of liposomes. With these miniature vesicles, it is now possible to encapsulate and deliver intrinsically active drugs to their tissue targets. By varying the size and lamellar characteristics of these vesicles, it is now possible to achieve either enhanced cutaneous or percutaneous absorption. A brief overview of the current literature pertaining to topically applied liposomes will be presented with special emphasis on in vivo studies conducted in animals and humans. Recent investigations conducted in our laboratories on efforts to determine drug entrapment efficiency of multilamellar liposomes will also be discussed.

Thomas M. S. Chang Artificial Cells and Organs Research Centre, McGill University Montreal, PQ, H3G 1Y6 Canada

Artificial cells mask their contents from bio-recognition. In this way artificial cells prevent the body from rejecting or destroying their contents. This allows foreign cell cultures, micro-organisms, enzymes, hemoglobin, polypeptides and other useful biotechnological products inside artificial cells to act as therapeutic agents. For example, the following materials enclosed inside artificial cells are not rejected or destroyed, but can carry ollt useful therapeutical functions. Micro-organisms can remove cholesterol from lipoprotein in plasma. Liver cells secrete useful products and also carry out metabolic functions. Islets can control blood glucose level by secreting insulin as required. Enzymes can remove unwanted substances from the body. Complex enzyme systems can convert wastes (e.g., urea and ammonia) into essential amino acid needed by the body. Modified hemoglobin can be used for blood transfusion. Artificial cells. containing other biotechnological materials (protein, polypeptides, growth factors, hormone, etc.) can be implanted to release these therapeutically over a control period of time. Artificial cell research was initiated some time ago (Chang, T. M. S . , Science (1964), 146, 524-525). It has been successfully used to mask bio-recognition of activated charcoal. In this way it is now a routine clinical treatment to remove poisons from patients’ blood perfusing through such a column. It is only in the last 5 years that its potential in biotechnology has been extensively explored internationally (Chang, T. M. S. Artificial cells in Encyclopedia of Human Biology, ed. by R. Dulbecco, pp. 377-384, 1991).

LIPOSOMES AS TOPICAL DRUG DELIVERY VEHICLES Don L. Simmons Lipopharm Inc., 5929 Trans Canada Highway, Suite 30, St Laurent, QuCbec H4T 1A1, Canada

To date, topical drug treatment has been accomplished by conventional pharmaceutical preparations e.g., solutions, creams, lotions, gels, ointments, pastes and more recently by

8. Environmental applications DETECTION AND MONITORING OF POLLUTANT DEGRADING BACTERIA USING CATABOLIC GENE PROBES AND REPORTER GENES Charles W. Greer Biotechnology Research Institute, National Research Council of Canada, 6100 Avenue Royalmount, Montreal, Quebec H4P 2R2, Canada

The role played by bacteria in the biodegradation of a variety of environmental pollutants has been characterized biochemically and genetically. This information has provided the basis for the development and application of catabolic gene probes to detect and monitor these important micro-organisms in polluted soils. Gene probes derived from genes encoding key enzymes in the degradation of petroleum hydrocarbons (alkB, xylE and ndoB) have been used to monitor and isolate bacteria from polluted soils, and to enhance the overall rate of bioremediation by increasing their biomass ex situ and reintroducing them into the soil. Gene probes from the biodegradation pathway for polychlorinated biphenyls (PCBs) and chlorinated benzoic acids have also been used to monitor and isolate biodegrader strains from PCB contaminated soils. Although these gene probes have demonstrated their usefulness for strain isolation and monitoring, the limited genetic information available for the biodegradation of many pollutants suggests that their full potential has not yet been realized. A reporter gene system has been developed to study the fate of environmentally introduced bacteria. The genes for lactose utilization (lucZY) and for bioluminescence (luxAB) have been integrated into the chromosome of a 2,4dichlorophenoxyacetic acid (2,4-D) degrading soil bacterium. The modified bacterium can be easily detected as light emitting blue colonies on a medium composed of 2,4-D as the sole carbon source and the chromogenic substrate XGal. The strain is being used to study its survival and persistence when introduced into different soils, where it can be detected at levels as low as 10 viable cells per gram of soil.

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MICROBIOLOGY AND BIOTECHNOLOGY IN THE OIL INDUSTRY

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9. Biosensors A CRITICAL OVERVIEW OF BIOSENSORS: WHERE HAVE WE BEEN? ~~~

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David L. Gutnick Department o f Molecular Microbiology and Biotechnology, George S . Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel

A number of microbial processes and properties have long been recognized or are currently being considered for specific applications in the oil industry. Subjects of major interest include: (i) the capacity of naturally occurring organisms to break down components of hydrocarbon wastes such as alkane and aromatic hydrocarbons of various sizes and compositions: (ii) the recent discovery of anaerobic processes leading to the breakdown of complex aromatic materials without the requirements for oxygen supplementation; (iii) the capacity both for adherence to and detachment from liquid oil/water interfaces as well as from hydrophobic surfaces; and (iv) the production of surface active detergents, emulsifiers and biopolymers by a number of such organisms. The activities associated with (i) and (ii) suggest major applications in bioremediation of oil pollution in a variety of polluted environments. Technological developments may include the development of specific bioreactors, the conversion of closed contaminated containers into fermentation vessels for bioremediation, the development of new sources of nutrients for supplementation in open environments to stimulate bioremediation in situ, the development of ‘tailormade’ microbial inocula, or the preparation of specific biofilters. Items (iii) and (iv) can lead to the production of a variety of new bioproducts for a number of industrial applications. Technological innovations in these areas may include the use of genetic engineering for strain and product improvement as well as product modifications and new formulations.

REMOVAL OF PHENOL FROM WASTE WATER USING PEROXIDASE IMMOBILIZED ON WASTE CHICKEN BONE

Frank V. Bright Department of Chemistry, Acheson Hall, State University of New York at Buffalo, Buffalo, NY 14214, USA The term chemical sensor is used to define the general class of self-contained, reversible probes that are used to quantify species within a complex sample. In the simplest configuration, some type of chemical recognition element (i.e., a reagent phase) is used in concert with a transducer system. When the recognition element interacts with the analyte of interest a proportional change is induced in the recognition element which is sensed by the transducer. The analytical signal of interest is thus the transducer response. Today’s modern sensors must simultaneously offer superior detection power and selectivity for a particular analyte. To a first approximation detection power is determined by the mode of transduction. For example, with modern fluorescence-based techniques one can easily perform analyses on samples containing 1O-l’ moI of material. Selectivity is a bit more complex issue and is a function of the transducer type and physicochemical properties of the recognition element. In practice one gains selectivity when the recognition element can more effectively discriminate one species over another. Thus, in order to realize the full potential of any chemical sensor, one must have superior detection power (from the transducer) and high selectivity (determined by the recognition element). Of the many recognition elements used for chemical sensing, those based on biological components (intact cells, antibodies, enzymes, proteins, lipid membranes, etc) have resulted in the greatest selectivity. Sensors based on biological recognition elements are termed biosensors. Over the past decade the biosensor field has expanded at an enormous rate. However, in spite of significant growth, there are few examples of commercial sensors based on this technology. In this presentation, we will attempt to critically evaluate biosensor science and technology. Specifically, this talk will focus on their advantages and limitations.

Chris Findlay Cornpusense Inc. 173 Woolwich St, Suite 201, Guelph, Ontario N l H 3V4, Canada Biobone is a novel solid support for practical immobilization of a wide range of enzymes and cells. It is composed of clean granular chicken bone. This material is extremely porous and is made up of crystals of the mineral hydroxyapatite (calcium phosphate) imbedded in a protein matrix of connective tissue. The strength, porosity and ease of attachment has led to the demonstration of Biobone in a wide range of immobilized fluid processes. Research has demonstrated the effectiveness of peroxidase immobilized on Biobone for the polishing of phenolic compounds from waste water streams. Initial levels from 10 to 1OOOppm phenol have been reduced by over 99.99% to ppb levels. The process involves polymerization of the free phenolics into insoluble and practically harmless polyphenols that are collected on the Biobone. Leachate testing has shown that the phenolic polymer remains on the Biobone, permitting its disposal in landfill. The choice of enzyme system permits the targeting of specific compounds, while the mass transfer advantages of Biobone permit practical polishing of large volumes.

DNA HYBRIDIZATION DETECTED BY ACOUSTIC ENERGY TRANSMISSION-A NEW BIOSENSOR MECHANISM ~~

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Michael Thompson, M. Damha, H. B. Su, M. Yang, K. M. R. Kallury, A. L. Kipling, L. Tessier and W. C. Duncan-Hewitt Department of Chemistry, University of Toronto, 80 St George Street, Toronto, Ontario M5S 1A1, Canada Hybridization of nucleic acids to produce double-stranded DNA is one of the most important phenomena to be exploited in analytical biochemistry in recent times. In addition to general use in the gene technology laboratory, there is a rapidly growing interest in the application of DNA probes in the diagnosis of human, animal and plant pathogens and in the detection of human genetic disorders. However, the technology at the present time involves time consuming and expensive fluorescence or radiolabelling of the probe, usually

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involving enzymatic methods. This paper describes the development of a sensor signal which links together the known interfacial viscosity perturbation of acoustic energy transmission with known changes in hydrodynamic properties that occur when DNA duplexes are formed from single strands. Our research involves study of the surface physical chemistry of single strand DNA species together with thorough interfacial characterization. Also being considered are the theoreti-

cal aspects of the flow of acoustic energy from the DNA probe biosensor into water. This is being performed in conjunction with electrical measurements of device parameters by the network analysis method. Finally, a flow-through configuration has been constructed and tested which allows the highly automated introduction of sample to a FIA-incorporated DNA probe-acoustic wave sensor combination.

BIO-BUSINESS 1. Vision 2020 VISION 2020 Glen Cureton SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USA

A futuristic panoply will be presented of what could be expected in products and services resulting from 40 years of genetic engineering. This wide range of options will then be weighed against marketplace realities as shaped by numerous constraints, including economic, social, ethical and political forces. The presentation will then address the probable commercial impacts of r-DNA, proteins, and monoclonal antibodies, as well as that of their derivatives such as gene implants, biosensors, and abzymes. The marketplaces of interest will include pharmaceuticals, diagnostics, agriculture, food, specialty chemicals, and biomaterials.

2. What investors are looking for BIO-BUSINESS - WHAT INVESTORS ARE LOOKING FOR: HOW THE INVESTOR CAN DIFFERENTIATE HYPE VS ACCURATE INFORMATION ON BIO DEALS/HOW TO AVOID GETTING SUED FOR MISSTATEMENTS IN PROSPECTUSES Joel S. Marcus Brobeck, Phleger & Harrison Attorneys at Law, 444 South Flower St., Los Angeles, CA 90017, USA

My presentation will focus on how the investors should analyse and review the prospectus and be able to differentiate very promising companies with excellent technology and management vs those that seem to be ‘hyped’. I will then compare and contrast the investor view with that of the company and how the company needs to position itself in order to avoid lawsuits should its stock decline from an initial public offering price to a point where investors file lawsuits.

3. How to pitch to the financial community FINANCING BIOTECHNOLOGY COMPANIES IN CANADA.. THE ALLELIX STORY

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Graham Strachan Allelix Biopharmaceuticals h c . , 6850 Goreway Drive, Mississauga, Ontario L4P 1P1, Canada

Mr Strachan will describe the financial strategy adopted at different stages of growth since its formation in 1983 by Allelix Biopharmaceuticals, now a publicly traded Canadian company. The presentation will address such issues as: (i) the critical differences in the investment climate for biotechnology between Canada and the USA; (ii) the financial services accessible to Canadian biotechnology companies as they evolve from start-up to mature, public companies; and (iii) the experiences gained and lessons learnt from the Allelix initial public offering successfully completed in December 1991.

AFFYMAX Alan D. Frazier Frazier and Company I.P., Fourth Avenue, Plaza Suite 4020, Seattle, WA 98154, USA

This presentation will be a reflection on how Affymax successfully ‘pitched’ to the financial community for a large private placement and a recent initial public offering. The private placement was a challenge due to the large amount to be raised before proof of concept had been reached. The initial public offering, which was the third largest ‘biotech’ IPO ever, was challenging because the company and the investment story was more of a technology play than the more product-oriented IPO’s that were occurring at the same time.

4. Regulations and harmonization BIOTECHNOLOGY REGULATION IN AN INTERNATIONAL ENVIRONMENT Mark F. Cantley

Concertation Unit for Biotechnology in Europe (‘CUBE’), Directorate-General for Science, Research & Development (DG XII), Commission of the European Communities, Rue de la Loi 200, B-1049, Brussels, Belgium

Seventeen years after Asilomar and fourteen since the Commission first proposed a strict Community Directive on the containment of rDNA work, the debate on whether and how to regulate biotechnology is still intensifying and spreading, worldwide; the beneficial management of biotechnology is on the ‘Earth Summit’ agenda in Rio, in parallel with this conference. The Community has had, since 1983, an explicit, multi-part policy for biotechnology, a policy reviewed and restated last year. The evolution of that policy has seen an intensification of debate about regulations, but also increasingly a focus on public perceptions and opinions of biotechnology. For through the political process, public perceptions drive the legislative system which determines the framework and parameters for regulation. Science and industry have then to live with the consequences. A system combining risk assessment by scientists and risk

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management by the political and regulatory system, should ideally result in a logical and cumulative societal learning process, aided and accelerated by the natural internationalism of scientific exchange. This picture has for biotechnology, and in some countries particularly, been complicated by the divergence from scientific opinion of popular risk perceptions, requiring of science, industry and government, an increased attention to risk communication. This in turn raises fundamental issues of trust, integrity, transparency, accountability, and the legitimation of political or scientific authority. As a result of deep cultural differences, reflected in diverse attitudes towards biotechnology, our regulatory systems in Europe as elsewhere are under tension. They are torn between those aspects which are rooted in particular localities, histories and perceptions, and those relatively straightforward aspects of open and rational science which are the basis for international exchange-of goods and services, as of ideas-and hence for economic and social progress. To the resolution of those tensions, international debate such as this conference can significantly contribute.

BIOTECHNOLOGY AND REGULATION John J. Cohrssen President’s Council on Competitiveness, Office of the Vice-president, Washington, DC 20501, USA

Biotechnology oversight has been unique because certain regulatory schemes have been developed in advance of evidence that would indicate a need for regulation specific to biotechnology. The US has sought to ensure that limited oversight resources are applied only where risk is unreasonable and where they will accomplish the greatest net beneficial protection of public health and the environment. The extent and type of oversight measure(s) should be commensurate with the gravity and type of risk being addressed, the costs of alternative oversight options, and the effect of additional oversight on existing safety incentives. States and localities have relied mainly on federal oversight although a few have sought to regulate recombinant DNA processzs. In contrast, the US policy reaffirmed in February 1992 is a riskbased, scientifically sound approach to the oversight of biotechnology products that focuses on the characteristics of the biotechnology product, not the process by which the product is created.

REGULATIONS AND INTERNATIONAL HARMONIZATION-AN INDUSTRIAL PERSPECTIVE

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common regulations for drugs and biological products including vaccines for the EC, USA, Japan and possibly beyond. The will on the part of the regulatory authorities of Europe, USA and Japan to actively pursue these goals is encouraging. However, many obstacles remain, including overcoming reservations of individual nations to renounce sovereignty over their own regulations. Issues such as how to merge the diverse recommendations arising from the regular and continuous review procedures of regulatory agencies (Canadian Regulatory Systems are now under review of Dr Denis Gagnon of the University of Laval; Australia has just completed its 5th Annual review, etc.) within the framework of global harmonization require urgent attention. How to ensure that the unique (and for some, vital) characteristics and advantages of the regulatory process in countries such as Canada and Australia are included in the Harmonization Programme also needs to be fully addressed. A process through which the views of other stake-holders such as the World Health Organization, the newly emerging states formerly in the Eastern Block, together with other nations is also required in order to ensure that true global harmony is achieved. The views of industry can be presented to the harmonization process through their involvement in the International Federation of Pharmaceutical Manufacturers Associations. This again is a useful step, but care must be taken that the voice of industry is not solely presented by the major pharmaceutical manufacturers. The risk of harmonizing regulations based on the needs of the drug sector without recognition of the special and distinct needs of other health-related sectors e.g., the biological-based health care industry and indeed the manufacturers of generic drugs, would not be helpful and needs to be both recognized and addressed in the ICH process. Many issues remain to be resolved including (i) how to harmonize national variances in Freedom of Information law applications, (ii) how to harmonize different fees for license requirements, (iii) how to assure clinical trial requirements for one region or one population equate with requirements for other regions, etc. The challenges are indeed numerous, but the fact that the initiative has been well launched and the international will to achieve success has been demonstrated by both public and private sectors are factors that will surely lead to attainment of effective global harmonization of the health care regulatory system perhaps even by the year 2000.

5. Risk assessment of environmental releases BUILDING UP A SCIENTIFIC BASE ON THE RELEASE OF GENETICALLY MODIFIED ORGANISMS IN THE ENVIRONMENT Ioannis Economidis

John R. Vose Connaught Laboratories Ltd, 1755 Steeles Avenue West, Willowdale, Ontario M2R 3T4, Canada

Global competitiveness is the theme for industry during the 1990s. Harmonization of the current patchwork of nationspecific regulations is clearly central to enhancing the ability of industry to provide the public with safe, effective and high quality health care products. Recent initiatives culminating in the program recently launched in Brussels at the International Conference on Harmonization (ICH) are helping progress toward the important and ambitious goals of

Commission of the European Communities, Directorate-General for Science Research and Development (DG XII), Rue de la Loi 200, B-1049 Brussels, Belgium

Although Biotechnology can be the solution to many problems (unsolved by traditional techniques) of medicine, the agro-food industry, agriculture and environmental clean-up, certain questions may be raised which deserve attention. It is unlikely but possible that certain risks are associated with the release in the environment of genetically modified organisms (GMOs) such as transgenic plants, or genetically modified micro-organisms including vaccines obtained by recombinant DNA techniques. As in all cases where a new biological

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system is exploited, one must take into account that the ecological equilibrium should be preserved. The Commission of the European Communities in the framework of the Biotechnology Action Programme (BAP, 1985-1990) has financed 58 European laboratories which were engaged in 16 transnational projects of risk assessment of micro-organisms under physical containment including, depollution bacteria, plant-interacting bacteria, transgenic plants and genetically engineered viruses. Currently under the framework of the BRIDGE (1990-1993) programme, the Commission is financing 62 laboratories from the European Community and the EFTA countries complementary to the earlier BAP projects. Furthermore, under the framework of a new Biotechnology programme, the Commission is planning to finance projects on aspects of molecular microbial ecology in order to advance the understanding of the multifactorial interactions which take place in the environment. This kind of research contributes to the international debate on the development and implementation of legislation and standards aiming at a proper balance between promotion of biotechnology and environmental and health safety.

GREEN ALLIANCE WORK ON BIO-TECHNOLOGY Julie Hill Green Alliance, 49 Wellington St, London WC2E 7BN, UK

The Green Alliance is an ind,ependent voluntary group working on environmental policy. The role of the Green Alliance is to help set the public and political agendas in relation to environmental issues, and in doing so it works closely with other UK public interest groups. In 1987 the Green Alliance identified bio-technology, and in particular genetic manipulation, as an issue with environmental implications that had not yet figured on the political or voluntary group agendas in the UK. The Green Alliance organized a visit by US bio-technology campaigner Jeremy Rifkin which included discussions with UK regulatory authorities, academics and environmental leaders aimed at stimulating increased debate on bio-technology. The Green Alliance maintained an interest in the development of UK regulations up to the introduction in 1989 of the Environmental Protection Bill, Part VI of which deals with genetically modified organisms (GMOs), and which partly implements the EC directives on contained use and deliberate release of GMOs. Green Alliance lobbying on the Bill has included seeking assurances that releases will be regulated on a ‘case by case’ basis, that information from the regulatory system will be available to the public, and that mechanisms will be found for securing wider public involvement in regulating GMOs. The Environmental Protection Bill became law in November 1990. In June 1990 Julie Hill, Parliamentary Officer for the Green Alliance, was asked to serve on the Advisory Committee on Release to the Environment (ACRE). ACRE is a new committee charged with advising the UK Government on the environmental implications of GMOs. Other members of ACRE include scientists, representatives of industry and representatives of workers’ organizations. This is the first appointment of someone with an enk-onmental pressure group background to such a committee. The Green Alliance has also been involved in the development of the Genetics Forum, a voluntary group which has been set up to act as a focus for all UK public interest groups concerned with bio-technology, including those working on environmental, consumer, animal welfare, health, development and social issues. Julie Hill is a member of the Genetics Forum core group.

At European level, the Green Alliance maintains contact on bio-technology issues with a range of groups, mainly through the work of the European Environment Bureau (EEB) .

ESTIMATING THE RISKS OF OUTCROSSING AND DISTRIBUTION OF OUTCROSSING DISTANCES IN TRANSGENIC CROPS Peter Kareiva Department of Zoology, University of Washington, Seattle, WA 98195, USA

William Morris Center for Population Biology, University of California, Davis, CA, USA

Gene flow and gene escape is a stochastic process and as such is best described by standard probability distributions that can be fit to outcrossing data from field tests. We illustrate this method using cotton and canola and address two fundamental biological questions: (i) to what extent are estimates of gene flow or escape a generalizable crop trait, that are approximately constant across a wide geographic range (from North Carolina to Arizona for cotton)? (ii) Can we use quantitative models and observations of pollinators to develop optimum ‘isolation strategies’ involving barren zones, trap borders and so forth? The probability distributions we examine are the exponential, Wiebuli and gamma, and the pollinator models we apply are continuous approximations of random walks with a directional bias.

6. International strategic alliances THE NETWORKS OF CENTRES OF EXCELLENCE: IMPORTANCE AND ROLE OF INTERNATIONAL STRATEGIC ALLIANCES David B. Shindler Canadian Genetic Diseases Network, Centres of Excellence Bldg at UBC, Office 348, 2125 East Mall, Vancouver, BC, V6T 124, Canada

The Federal Centres of Excellence Networks Program represents a bold attempt to engage the Canadian research and industrial communities in internationally competitive scientific efforts. Fifteen Canada-wide networks have been established, each with a 4-year mandate to conduct concerted research collaborations involving university, industry and government researchers. Using examples based on experience with the Biohedical Networks, the challenges and opportunities associated with the Networks will be analysed, including selected comparisons with European and Japanese programs. The Networks are involved in a variety of international relationships, ranging from research collaborations to international commercial joint ventures. The researchers and directors of the Networks will need to effectively manage such relationships in order to gain or maintain international leadership positions in competitive research fields and commercial sectors.

SHORT ABSTRACTS

During their first year or so of operation, networks are aggressively exploring and developing a variety of industrial relationships and international linkages, thus setting the foundations for attainment of long-term goals. Expectations must be measured against international experience with industrial sponsorship of research at institutes and universities. The time and investments necessary to achieve technologytransfer and industrial development objectives must also be taken into consideration. Early indications are that the Networks will develop close links with industry and consequently help achieve improved industrial performance in the long term.

STRATEGIC COLLABORATIONS: ESSENTIAL PARTNERSHIPS Don Kirksey Glaxo Inc., Five Moore Drive, Research Triangle Park, NC 27709, USA

In the environment of the 1990s, no pharmaceutical company is large enough or smart enough to meet all of its knowledge needs in isolation. Each business must maintain a complex network of relationships with companies, universities, federal and provincial agencies on the topics that are relevant to their own strategic focus. New knowledge and intellectual manpower from these various sources are needed to capitalize on new technologies and improve old ones. The extent and type of collaborative ventures that a company has to undertake is based on the stage of research, the maturity of the scientific field, and the size of the company R&D effort. For smaller companies, external collaborations are critical because often these companies have limited R&D budgets and therefore need to maximize research capacity by leveraging work through collaborations. The challenge for the fully integrated pharmaceutical company is to determine the adequacy of its own knowledge base, identify emerging technologies and barriers to knowledge transfer, and to define approaches to collaborations which will provide maximum input of new knowledge. This 15 min discussion will focus on Glaxo’s perspective regarding industry collaboration both in Canada and the USA, its strategic approach to the concept of partnering, and some characteristics of successful collaborations.

7. Intellectual property issues (pharmaceuticals) THE IMPACT OF PATENT ISSUES ON THE PHARMACEUTICAL INDUSTRY Heinz Redwood Consultant, 5 Links Avenue, Felixstowe, Suffolk l P l l 9HD, UK

Patent issues are vitally important for both sides of the pharmaceutical industry: research-based and generic. Without adequate patent protection, the costs, delays, and high risk of failure of research, development and marketing of new drugs cannot, in the long run, be financed. On the other hand, patent expiry provides opportunities for generic competition and opens the door to lower drug prices for health care insurers and providers. The real question is therefore: what constitutes adequate patent protection? The 1970s and 1980s saw the progressive erosion of effective patent life of pharmaceuticals, as regulatory delays ate into the span of nominal protection. As a result, the authori-

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ties in the USA (1984) and Japan (1988) accepted the need for Patent Term Restoration, and steps to follow suit are now in progress in the European Community. Underlying this trend towards restoring the patent term in countries with active and successful research-based pharmaceutical industries is the recognition of society’s need for innovative drug therapy, and the observation that countries which have failed to give adequate patent protection have also failed in discovering and developing innovative drugs. Every country is therefore faced with a choice of emphasis between an industrial strategy that provides long-term support for innovation, and a Cheap Drugs Policy that presents immediate budgetary advantages. The strength and duration of patent protection are prime factors in establishing the ground rules for such a choice. The encouragement of generic competition after patent expiry is another. The emphasis between the two conflicting priorities of industrial research and health care budgets differs, and will continue to differ, between firstly the world leaders in pharmaceutical research and development (USA, European Community, Switzerland, Japan); secondly, countries with a strong scientific infrastructure but a relatively weaker pharmaceutical industry (Canada, Australia); and the Third World where Cheap Drugs policies have until recently taken absolute and uncompromising precedence over industrial policies. What is the outlook?

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CHALLENGES FOR THE 1990s: TROPICAL FOREST PEOPLES, CONSERVATION AND PHARMACEUTICAL DISCOVERY Lisa Conte Shaman Pharmaceuticals Inc., 887 Industrial Road, Suite G, San Carlos, CA 94070-3312, USA

Nearly 500 years ago, people of the New World encountered Europeans for the first time on their soil. Since that time the global pharmacopeia has been enriched by a number of important plant-derived medicines discovered by native people in the tropics. We know that tropical forests contain numerous scientifically undescribed plant species and that tropical forest people utilize and manage a wide array of the flora as medicine. Discovering and commercializing these new compounds can, and should, be integrated into sustainable extractive reserve systems. The destruction of tropical forest ecosystems is often driven by the need for basic human requirements: food, shelter, and health care. The continuing loss of tropical forests also poses a significant threat to the world’s future sources of new medicines. Recognizing the interrelationship of the causes of destruction and future consequences for global drug discovery suggests the need for a new alliance based on reciprocity. Inhabitants of tropical forests and the pharmaceutical industry can both benefit through increased research and development of natural products. Direct benefits for local people will also provide incentive to continue managing genetic diversity.

PATENTING BIOPHARMACEUTICALS Joan M. van Zant Scott and Aylen, 34th Floor, Royal Trust Tower, Toronto-Dominion Centre, Toronto, Ontario M5K 1H6, Canada

‘Intellectual Property’ is no longer an arcane expression that only those involved in its practice should understand. The

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modernization and harmonization of Intellectual Property Laws throughout the world over the past ten years, along with some very high profile litigation, has helped to popularize these rights. Owners are now very aware that these rights constitute vital economic tools which must be used effectively to provide a competitive edge in the global economy. Every business must take an aggressive approach to ensuring its proprietary rights are properly protected and the rights of others are correctly and fully assessed for litigation potential. This applies even more so in the area of biopharmaceuticals where the costs of product development have proven to be substantial. It would be easy if all countries provided identical laws in this area, with perhaps US law being the guide, but that is not the case. Patent applicants must be active participants in the process in order to obtain effective manufacturing and licensing rights. The process and the rights need careful monitoring particularly from the cost recovery perspective. Application filing strategies must often be developed on a case by case basis in view of the rapid advances in the technology and the evolving legal standards. While it would be foolish to embark upon the process without the help of a professional, it is essential to become knowledgeable about the basics and to be alerted at the very least to the pitfalls. The basics include: (i) learning when and where to publish; (ii) knowing what can or cannot be protected; (iii) understanding the advantages and disadvantages of the patent right; (iv) deciding where to obtain protection and in the most economic manner; (v) when to expect a patent grant and how it must be maintained; (vi) when to approach a licencee or partner. Learning the jargon used by those in the profession does provide a good shorthand to being sensitized to the subtleties of the process. Some terms of great significance are: novelty, obviousness, utility, experimental data, deposit requirements, enablement, the P m , process claims, use claims, method of treatment claims, compulsory licensing, dominant patents, reverse equivalents, patent term extension. The special problems of biopharmaceuticals require a careful and considered approach to the patenting process. Patenting an invention can be extremely frustrating. The process seems at times to have a different focus from commercial reality. However, the value of the protection is ever increasing and cannot be ignored.

agricultural community, further alienating the rural population and further increasing the gap between the technologically developed and less developed nations. Furthermore, would a race to patent genetic characteristics for their economic value increase the possibility of both deteriorating genetic resources and increasing genetic uniformity? A patent is not neutral in its effect. It provides both a monopoly on the invention and the equivalent to a reward for work accomplished: in the case of patenting life forms, it rewards the conquest of the living.

PATENTING ‘CHICKEN LITTLE’: THE SKY IS NOT FALLING Stephen A. Bent Biotechnology Law Practice Group, Foley & Lardner, PO Box 299, Alexandria, VA 22313, USA

A mythology rooted in controversy dating from the turn of this century has grown up around the patenting of life forms. In modern guise this mythology focuses on supposed adverse consequences of patenting multicellular organisms, ranging from enhancing a global decline in genetic diversity to undermining the family farm. Yet the availability of patent protection cannot have the dire impact posited by the proponents of this mythology. A patent empowers its owner to do no more with the patented invention than the owner could have done before the patent was issued. Conversely, a patent compels no one to exploit the patented invention. Thus, a patent can facilitate the creation of new products, including those composed of living matter, but it cannot abrogate economic forces which determine how a patented product may be commercialized. By the same token, patenting in no way affects the dominion which the ‘creator’ of a new life form exercises over that life form, pursuant to property-law principles qualified by more recent legal constraints, such as animal rights statutes. Simply put, therefore, the availability of patent protection for life forms is not a significant factor bearing on whether a given life form will be used in a socially responsible manner.

8. Patenting life forms PATENTING LIFE FORMS Therese Leroux

9. Recognizing East European markets ~

University of Montreal, Faculty of Law, Center for Research in Public Law, C.P. 6128, succursale A , MontrCal, Quebec H3C 357, Canada

DOING BUSINESS IN EASTERN EUROPE

Patents for processes or products involving microorganisms are not usually the subject of debate. It is a different matter when we talk about patenting actual life forms, that is, modified microorganisms, plants, molluscs or mammals. Patent requests today are even made for sequencing the human genome. These developments force us to think about the relationship between human beings and nature. What is this relationship? What effects could there be if genetic resources are appropriated and controlled by private companies? Does such a concentration of power, which this development implies, increase the vulnerability and dependency of the

Bill Lifchus Apotex IRC., 150 Signet Dr., Weston, Ontario M9L 1T9, Canada

This presentation will address a series of issues. (1) Definition of Eastern Europe; (2) how to get started avoiding the pitfalls and perfidious people, the tradition of baksheesh and how to avoid it; (3) opening an office. Why? Where? (4) Is lead time required? Rent or own? (5) The importance of a good lawyer. How to obtain one; (6) consider a strategic joint venture. How to pick the right partner. Strengths and weaknesses to look for in Eastern European business people; (7) how to overcome the language barrier; (8) tips on getting your profits out. Barter opportunities.

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CLOSING ADDRESS ON THE BIO-TECHNOLOGY OF JAPAN-THE VISION

CHANGING

Fusao Tomita Faculty of Agriculture, Hokkaido University, Kita 9, Nishi 9, Kita-Ku, Sapporo 060, Japan

The progress of bio-industry depends greatly on the new knowledge and technology originated from bio-science. Bio-science is a very broad science and no single company covers all of its areas, and collaborative work among industry, academia and government nationally and also at global level is, therefore, required. Targeting government policies is extremely crucial in assisting the rapid and efficient promotion of new industry. In Japan, the Ministry of International Trade and Industry and other ministries provide various programs to subsidize the development of bio-industry. As a result of such policies and others, Japan has issued many provisional patents. In recent years, substantial new biotechnology products have appeared on the market amounting to 199.7 billion yen in 1989, 298.9 billion yen in 1990 and 385.7 billion yen in 1991. Up to now, most products are in biopharmaceutical fields, but it is expected that products related to foods (a stable supply of good quality and safe foods), health care (prophylaxis and ensuring the quality of life of patents, especially of the elderly) and environmental management (waste treatment and saving fossil energy) will follow soon. Japan’s policy on the promotion of bio-technology and bio-industry in the 1990s will be similar to the previous one, but attention will be focused on basic bio-science and the construction of global frameworks for the sound development of bio-technology and bioindustry. This is necessary because bio-industry has grown into an international industry with its products finding markets around the world and bio-technology may be the only means of ensuring our sustainable development.

Bio-Recognition--International Industrial Biotechnology Conference. Montreal, Canada, 1-4 June 1992. Abstracts.

JOURNAL O F MOLECULAR RECOGNITION, VOL. 5 , 19-39 (1992) Abstracts Bio-Recognition-International Industrial Biotechnology Conferencet Montreal, Can...
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