| May 1997 |
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NEWS FOR THE AGRICULTURAL AND ENVIRONMENTAL BIOTECHNOLOGY COMMUNITY
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| May 1997 |
|
NEWS FOR THE AGRICULTURAL AND ENVIRONMENTAL BIOTECHNOLOGY COMMUNITY
In This Issue:
Expanded Notification Rule Finalized; Public Meeting Scheduled
Australian Debate on Critical Issues for Commercialization of
Transgenic Crops
Can Hemoglobin Increase Plant Productivity?
New Insight into Chemical Signaling
Chemical Companies Look to Pharmaceuticals/Life Sciences
Court Finds That Concealment of Best Mode Invalidates Patent
Searching Patent Information on the Internet
WASHINGTON D.C., May 1,1997 
The U.S. Department of Agriculture is
amending its regulations pertaining to genetically engineered plants
introduced under USDA's notification and petition regulatory processes.
"The amendment will simplify procedures for the introduction of certain genetically engineered organisms, expedite review for certain determinations of nonregulated status, and adjust procedures for the reporting of field tests conducted under notification to the biology of the test organisms," said John Payne, director for biotechnology and scientific services with the Animal and Plant Health Inspection Service, a part of USDA's marketing and regulatory programs mission area.
Developing and commercializing new genetically engineered plant varieties most often involves field testing under APHIS oversight, followed by submission of a petition for determination of nonregulated status by the agency. APHIS grants nonregulated status to a new plant variety when it determines that the new variety has no potential to pose a plant pest risk and is as safe to grow as any other variety of the same plant.
The amended regulations will allow a broader application of existing simplified procedures for requests for movement or field testing of genetically engineered plants. They will also streamline the determination of nonregulated status for plant varieties that closely resemble other varieties that have already been through the determination process. This will enable APHIS, when appropriate, to extend the existing determination of nonregulated status for new products that do not raise new risk issues.
For plants that are being evaluated in field tests, reporting requirements have been made more consistent. For example, for trees and other long lived plants field data reports will only need to be provided upon the conclusion of the trial. However, applicants must apply to APHIS for yearly renewal to ensure appropriate measures are taken when plants become reproductively mature.
APHIS will also use appropriate guidelines to provide additional information to developers of regulated articles and other interested persons regarding procedures, methods, scientific principles, and other factors that could be considered for various aspects of its regulations. The first guidelines will provide information to help applicants on requests for extension of a determination of nonregulated status.
Payne added that USDA has the responsibility to ensure that, in releasing any bioengineered plant, no plant pest risk is presented. APHIS reviewers focus on the biology, propagation, and cultivation of the plant. The reviewers also consider the source of the engineered genes, the vector used to transfer them, and the stability of the insertion.
The original final rule which was printed in the April 24, Federal Register was retracted April 25, a month before it would have gone into effect. This final rule supersedes the previous one issued. Notice of this action is scheduled for publication in the May 2 Federal Register and becomes effective June 2.
Public Meeting
USDA/APHIS Biotechnology and Scientific Services will hold a public
meeting on May 28 and 29 to discuss the new rule. The meeting will be
operated as a workshop, and organizers request that interested persons
register and submit agenda items two weeks before the meeting date. The
meeting is in the Conference Center at the USDA Center at Riverside,
4700 River Road, Riverdale, Md., from 8 a.m. to 4 p.m. on May 28 and
from 8 a.m. from 12:30 p.m. on May 29.
A revised user's guide and guidelines are available as background materials. For a copy of this material and to register and submit agenda items for the meeting, contact Kay Peterson at 301-734-4885; fax: 301-734-8669; email: mkpeterson@aphis.usda.gov. Documents are also available on the internet at http://www.aphis.usda.gov/biotech. For further information about the agenda, contact James White at 301-734-5940.
For further information on the regulatory changes, contact John Payne, Director, Biotechnology and Scientific Services, 4700 River Road, Unit 98, Riverdale, Md. 20737-1237; 301-734-7602. For technical information, contact Michael Schechtman, Biotechnology and Scientific Services, Plant Protection and Quarantine, Unit 146, Riverdale, Md. 20737-1237, 301-734-7601.
NOTE: USDA news releases, program announcements, and media advisories are available on the Internet. Access the APHIS Home Page by pointing your Web browser to http://www.aphis.usda.gov and clicking on "APHIS Press Releases." Also, anyone with an e-mail address can sign up to receive APHIS press releases automatically. Send an e-mail message to majordomo@info.aphis.usda.gov and leave the subject blank. In the message field, type subscribe press_releases.
Intellectual Property
Discussion focused on the impact of intellectual property rights on the
conduct of research and four main concerns were identified: (1)
Frequently researchers fail to identify intellectual property rights
that could affect their "freedom to operate" but this might be solved
in future if researchers share their experience. (2) Broad claims on
fundamentally useful technologies may prohibit the development of
transgenic varieties of minor crops unless reasonable licenses can be
negotiated. However, it is unclear if intellectual property claims by
others should be used to argue against initiating a research program.
(3) There is no clear pathway for releasing new germplasm for public
good rather than for commercial benefit. (4) The research community
needs to be aware of current moves to modify Australian patent law,
e.g. there is a bill before the Australian Federal Senate to prohibit
patenting of genes.
Regulation
The release of transgenic crops in Australia is overseen by the Genetic
Manipulation Advisory Committee (http://www.dist.gov.au/science
/gmac/gmachome.htm) but the Federal Government is assessing the
possibility of forming a statutory authority. Many participants
expressed a desire for Australian legislation that would provide a
clear pathway for researchers and investors and that would "enable"
commercialization rather than prohibit it. Participants with a
specific interest in the regulatory system agreed on a more detailed
list of features. They asked for a system that was pragmatic,
efficient, logical and transparent, and that addressed health, safety,
social and environmental concerns. They suggested that the legislation
should include provision for notification, assessment, approval,
management, compliance, monitoring, and effective communication with
all interested parties. Some experts argued that ethical concerns
should be resolved at a political level and should not influence
regulation.
Herbicide-Resistant Transgenic Crops
The potential for herbicide-resistant transgenic plants to become
weeds, and the possibility that a transgene transferred to a weedy
relative of a crop species could have undesired environmental
consequences, are generally recognized as risks. However, scientists
felt that these concerns could be adequately evaluated and discussions
centered on the possibility of increased selection pressures on
existing weeds through the over-use of some herbicides. Participants
agreed that the market place should decide which herbicide-resistance
genes are used and called for minimal regulation beyond assessing
weediness potential and gene transfer. Scientists and industry
representatives emphasized the importance of integrated weed management
systems and the need to assess all contributing technologies. Basic
research on resistance mechanisms and developing and maintaining
comprehensive data on weed ecology were also thought to be important.
A national forum for examining weed control was proposed.
Insect-Resistant Transgenic Crops
Entomologists, cotton farmers and other interested experts at the
meeting agreed that the current system of monitoring, by the owners of
the technology, of on-farm compliance with release conditions was not
working optimally. They suggested that the authority with the power to
approve release of insect-resistant transgenic crop plants should also
have responsibility for this monitoring. It was stressed that, with
regard to the recently released transgenic cotton, farmers have
proportionally more at stake than the owners of the technology.
Participants called for a national insect-resistance management
advisory group to be formed from industry representatives and
researchers. It was envisaged that the group would provide advice to
the authority on appropriate management strategies for new and existing
transgenic varieties and advice on coordinating the use of transgenes
in different crops. Participants were also concerned that any potential
interactions between new traits should be assessed when transgenic
plants carrying more than one new trait are developed. For example,
plants that are both insect resistant and drought tolerant may have
greater weediness potential.
Virus-Resistant Transgenic Crops
The risks posed by viral recombination became a key issue at the
meeting after seminars from two visiting scientists showing some
recombinant viruses to cause increased disease and to have expanded
host ranges. It was suggested that the development of virus-resistant
transgenic crops had advanced ahead of understanding of some of the
possible risks. In this context there was a call by experts and non-
experts alike for further research on the risks posed by recombinant
viruses. A need for research in three other areas was also recognized:
(1) the nature of plant virus populations and interactions within these
populations, (2) the basis of transgenic protection and (3) the basis
of viral host range. Workers in the field also identified a need for
independent monitoring during transgenic development and perhaps even
after release and suggested a set of goals for the design of virus
resistance genes that, given current data, may reduce risks. These
design goals included the use of RNA-mediated protection using
untranslatable sequences of a minimal size taken from genes of known
function and using sequences that contain no subgenomic promoters or
promoter-like sequences.
Mark J. Gibbs and Peter M. Waterhouse
CRC for Plant Science
Canberra, Australia
mark.gibbs@pi.csiro.au
However, a recent article in Nature Biotechnology by Leif Bülow and coworkers (1) provides evidence that turns this notion on its head. They have generated tobacco plants that synthesize a bacterial hemoglobin molecule (VHb) and demonstrated that these transgenic plants have increased productivity compared to their non-transformed counterparts. The hemoglobin gene was taken from the obligate aerobic bacterium Vitreoscilla, which produces the hemoglobin under conditions of limiting O2, and was fused to the CaMV 35S promoter. Expression of VHb accounted for approximately 0.1% of total leaf protein in the resulting plants.
Analysis of two lines of transformants showed that transgenic plants had higher growth rates and altered activity of metabolic pathways. The VHb-containing plants germinated 3 to 4 days earlier than non- transformed control plants and developed faster, accumulating 80 to 100% more fresh weight after 35 days. In addition, the transgenic plants contained greater chlorophyll and nicotine content than non- transformed controls. The increases in chlorophyll and nicotine were attributed to a greater availability of O2 as a substrate in their biosynthetic pathways, thus leading to a shift toward metabolism requiring oxygen. For example, the transgenic plants produced more nicotine and less anabasine than control plants, but nicotine and anabasine are both derived from nicotinic acid, with the difference that nicotine synthesis requires O2 as a substrate.
The mechanism by which the VHb hemoglobin functions in the tobacco system is not clear. The authors suggest that it acts through a combination of increasing availability of O2 as a substrate for cellular metabolism and by increased O2 leading to higher levels of ATP available for powering cellular metabolism. It is also possible that the hemoglobin scavenges free O2 and its radicals, thus protecting the cell from these harmful molecules.
Whatever the mechanism, it seems that tobacco plants benefit significantly from hemoglobin. It remains to be seen whether the enhanced productivity reported here can be repeated in other crops, or how any increase in growth will translate into additional yields under field conditions, but this research is significant because it points out the importance of a previously neglected area of study and demonstrates that there is still more room for improving plant productivity. This is all the more promising because the effect was produced by the insertion of just a single gene.
Reference:
1. Holmberg, N., G. Lilius, J. E. Bailey, and L. Bülow. 1997.
Transgenic tobacco expressing Vitreoscilla hemoglobin exhibits enhanced
growth and altered metabolite production. Nature Biotechnology 15:244-
247.
Jim Westwood
International Research and Development
Virginia Tech
westwood@vt.edu
NEW INSIGHT INTO CHEMICAL SIGNALING
An interesting study from the laboratory of Ilya Raskin at Rutgers
University shows how sick plants can communicate with neighboring
plants, in a way that may help the healthy plants avoid disease. The
study, reported in the February 20, 1997 issue of Nature, found that
tobacco plants infected with tobacco mosaic virus (TMV) emit distress
signals by releasing an oil of wintergreen (volatile methyl salicylate)
into the air. When neighboring plants absorb the chemical, synthesis of
antiviral proteins is triggered making them better able to resist virus
infection.
V. Shulaev and colleagues employed a tobacco variety carrying the N gene that confers resistance to TMV at low but not high temperatures. When inoculated with TMV, these plants produce gaseous methyl salicylic acid (MeSA) and pathogenesis-related (PR-1) protein, while the uninoculated or wounded plants do not produce these chemicals. Through experiments conducted using connected gas-tight chambers, the Rutgers group observed that volatile MeSA produced by virus-inoculated plants kept in one chamber triggered a disease resistance response in recipient plants located in a separate chamber. Such recipient plants exposed to the airborne signals showed an expression of the PR-1 gene and also exhibited a moderate increase in resistance to a subsequent viral inoculation. If the MeSA produced by donor (virus-infected) plants was trapped using a resin or if the donor plants were mock-inoculated, then no PR-1 gene expression or virus resistance was observed in the recipient plants. According to the authors, MeSA is the first airborne signal known to facilitate communication between infected and healthy plants. Future studies may determine whether this signal is strong enough under field conditions to be of any practical consequence in disease development. Nevertheless, the Nature report provides an intriguing twist to what we know about the biology of plant-to-plant communication.
C. S. Prakash
Center for Plant Biotechnology Research
Tuskegee University
prakash@acd.tusk.edu
As recently as a year ago, some analysts were saying that the large chemical multi-nationals needed to separate the two areas, and create completely separate companies or sell off units to groups entrenched in one business or the other. But there is evidence this may not be the emerging model, as many of the major chem-pharm players are looking for ways to leverage synergy between the two businesses.
Major companies like Bayer concede that maintaining a presence in both areas helps to balance risk and allows for the possibility to gain competitive advantage. The integration of a pharmaceutical business is also of direct benefit to the bottom line. Healthcare pursuits represent Bayer's highest profit margin business (1). Chem-pharm company Rhone-Poulenc derived 87 percent of its income in 1996 from life sciences, which include agricultural chemicals and healthcare. Even companies like BASF, which have traditionally focused predominately on commodity chemicals, are looking to grow their pharmaceutical business as a less cyclical revenue stream (2) .
Other chem-pharm players are not inclined to integrate the two businesses, but still find value in maintaining a presence in both. Akzo Nobel prioritizes its business units starting with pharmaceuticals, followed by coatings, chemicals, and fibers, preferring to grow the pharmaceuticals business autonomously. One advantage of this strategy is that it makes divestiture of a business unit cleaner and faster, should this become desired (2).
Monsanto has been one of the more aggressive chem-pharms in terms of realigning its business, and is segregating its chemical business as part of a strategy to redefine itself as a life science company. Chem-pharm companies looking to strengthen their pharmaceutical / life science positions have turned to biotechnology firms to help build pipeline portfolios through acquisitions and the formation of strategic alliances. Monsanto's Searle pharmaceutical unit has seen significant growth in its R&D budget, allowing greater partnering flexibility. On the agricultural side, Monsanto recently entered into a definitive agreement with Calgene to acquire the remaining shares of Calgene stock that Monsanto does not already own.
Although chem-pharm companies currently appear content to embrace both their pharmaceutical/life science and chemical interests, it is clear that most are looking more to the "Pharm/Life Science" than "Chem" as the centerpiece of their growth strategies.
References:
1. Actions Database, Institute for Biotechnology Information, 1997.
2. Scott, A., Freedman, W., and Hunter, D. Chemicals vs. Drugs, Industry Wrestles with the Choice. Chemical Week, April 16, 1997, pg. 24-28.
William O. Bullock
Institute for Biotechnology Information, LLC
Research Triangle Park, NC
http://www.biotechinfo.com
One basic rationale behind U.S. patent law is to encourage invention by guaranteeing some degree of exclusivity, and in return for this limited property right, the inventor is required to file a patent application that fully describes the invention. Accordingly, a U.S. patent specification must disclose the best manner contemplated by the inventor of carrying out the claimed invention (2). To be blunt, the purpose of the best mode requirement is to prevent inventors from applying for a patent while concealing from the public preferred embodiments of their inventions (3).
The current best mode test requires two factual inquiries. First, one must ascertain whether the inventor subjectively contemplated a best mode of practicing the claimed invention at the time that the patent application had been filed. If so, then one must determine whether the specification adequately discloses that best mode so that those having ordinary skill in the art could practice it. This second inquiry is largely objective and depends upon the scope of the claimed invention and the level of skill in the art.
In Kaken Pharmaceutical Company, Ltd. v. United States International Trade Commission, the Federal Circuit noted that the patentee's own documents shed light on the inventors' state of mind prior to filing the patent application. In particular, the court noted that Hara's lab reports showed that the inventors had considered the SLS-K-7-68 strain to be the best for producing salinomycins.
With respect to the objective component of the best mode test, the Federal Circuit decided that, although the patent reveals that a strain designated as "80614" and its mutants may be used to produce salinomycins, the specification provides no information concerning the SLS-K-7-68 strain or how the strain can be obtained. Moreover, the court found that the inventors had developed the SLS-K-7-68 strain after four years of intensive research, "plagued with much unpredictability." The Federal Circuit concluded, therefore, that the inventors' failure to disclose a method for obtaining the SLS-K-7-68 strain, or to provide a public deposit of SLS-K-7-68, resulted in the effective concealment of the best mode strain.
The Kaken case raises several points worth considering. First, making a deposit of biological material is not always necessary to fulfill the best mode requirement for a biological invention. It is sufficient if the patent specification describes a method to produce the biological material that represents the best mode. In Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., for example, Chugai and Genetics Institute Inc. argued that Amgen's patent should be declared invalid for failure to deposit the best mammalian host cells (known to Amgen's inventor) for producing erythropoietin (4). However, the court decided that Amgen's patent specification disclosed a sufficient method for isolating the preferred strain of Chinese Hamster Ovary cells using only routine experimentation. This situation is distinct from the Kaken case, in which the court found that the inventors had developed their best mode strain after years of intensive research in an unpredictable field.
A final point worth remembering is that the concealment of a best mode can be an intentional concealment or an effective concealment. That is, a patent will be declared just as invalid whether the inventor deliberately or accidentally failed to reveal the best mode. This places a burden on the inventor to actively consider whether his or her patent application describes the best mode before filing.
References:
1. Kaken Pharmaceutical Company, Ltd. v. United States International
Trade Commission, No. 96-1300,-1302 (Fed. Cir. March 31, 1997).
2. 35 U.S.C. Section 112.
3. Wahl Instruments Inc. v. Acvious Inc., 21 USPQ2d 1123 (Fed. Cir. 1991).
4. Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Phillip B. C. Jones
Foley and Lardner
Madison, WI
pbcj@globaldialog.com
C. S. Prakash
Center for Plant Biotechnology Research
Tuskegee University
prakash@acd.tusk.edu
The material in this News Report is compiled by NBIAP's Information Systems for Biotechnology, a joint project of USDA/CSREES and the Virginia Polytechnic Institute and State University. It does not necessarily reflect the views of the U.S. Department of Agriculture or of Virginia Tech. The News Report may be freely photocopied or otherwise distributed without charge. P.L. Traynor, Editor.
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