PowerPoint Presentation DuPont ProductPresentation Title

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Biotechnology Update
Steve Daugherty Director, Biotechnology Affairs
The World Demands, and We Deliver
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Ag Biotechnology TerminologyWhat they mean to me

• Modern Agricultural Biotechnology Manipulating
  genes from one source to another transgenic
  technology.
• Allows farmers to grow plants that are more
  nutritious, resistant to pests and more
  productive.
• Genetic Engineering/Modification Changing an
  organisms genes using the methods of modern
  molecular biology (Modern Ag Biotechnology).
• Living Modified Organism Term used in the
  Cartagena Protocol on Biosafety to reference
  genetically modified organism.
• Recombinant DNA (rDNA) Transformed DNA.

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Ag Biotechnology TerminologyWhat they mean to me

• Gene a specific sequence of DNA .
• Protein A molecule composed of amino acids in a
  specific order. Proteins are required for the
  structure, function and regulation of metabolic
  activities in the bodys cells, tissues and
  organs, and each protein has unique function.
  Proteins are expressed by DNA.
• Event the successful result of inserting genetic
  material into another genome.
• Trait a distinguishing characteristic.

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Example Herculex I

• Herculex I insect protection for corn
• Gene Cry1F and pat
• Protein Cry1F and pat
• Event 1507 (DAS-01507-1)
• Traits insect control (pests include European
  corn borer, southwestern corn borer, black
  cutworm, western bean cutworm, lesser corn stalk
  borer, southern corn stalk borer, sugarcane
  borer, corn earworm and fall armyworm) and
  herbicide resistance to glufosinate (Liberty)
• Herculex I Insect Protection technology by Dow
  AgroSciences and Pioneer Hi-Bred. Herculex and
  the HX logo are registered trademarks of Dow
  AgroSciences LLC.

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Ag Biotechnology TerminologyWhat they mean to me

• Herbicide-Tolerant Crops Crops that are not
  damaged when sprayed with herbicide.
• Examples Roundup Ready, Liberty Link, Optimum
  GATTM
• Insect-Tolerant Crops Crops that are not damaged
  by insects.
• Examples Herculex, YieldGard, Optimum GATTM

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Ag Biotechnology TerminologyWhat they mean to me

• Stewardship Management of a product from its
  inception through to its ultimate end and
  discontinuation.
• This is how we keep the genes out of your mill
• Adventitious Presence (Low Level Presence) The
  unintended presence of genetic material in seed,
  grain, feed or food.
• Gene Flow Genes moving from one plant to
  another.
• Identity Preservation Segregation of one crop
  from another.

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Pioneers Stage-Gate System
Review Decision
Review Decision
Review Decision
Review Decision
Review Decision
StageC OptimizeGeneConstruct
StageD CreateCommercialEvent
StageE Commercial Event toRegulatory
StageF Breedingand Testing
StageG SellProduct
StageA New Ideas
StageB EvaluateGeneticApproaches
Transgene Discovery Event Development
Product Breeding Evaluation
Sales
Key Tasks
Key Tasks
Key Tasks
Key Tasks
Key Tasks
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US Coordinated Regulatory Framework for
Biotechnology a Matrix of Existing Laws
USDA - Plant Protection Act
EPA (Plants) Federal Insecticide, Fungicide and
Rodenticide Act (FIFRA)
EPA (Microbes) Toxic Substances Control Act
(TSCA)
FDA - Federal Food, Drug, and Cosmetic Act (FFDCA)
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US Coordinated Regulatory Framework for
Biotechnology Plant Products
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Rapid Global Adoption of Biotech Crops
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Global Area of Biotech Crops, 1996 to 2007 By
Crop (Million Hectares)
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Global Adoption Rates () for Principal Biotech
Crops (Million Hectares) 2007
Source Clive James, 2008
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Global Area of Biotech Crops, 1996 to 2007 By
Trait (Million Hectares)
Source Clive James, 2008
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CropLife International Industry Priority Issues

• Low Level Presence
• Biosafety Protocol
• Intellectual Property
• Regulatory Issues
• Allergenicity, stacks, new technologies/emerging
  issues, data protection, discontinued products,
  detection methods
• Biotechnology Acceptance

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BIO Quality Management ProgramExcellence Through
StewardshipSM

• BIO Food Agriculture Section Governing Body
  approved initiative for stewardship and quality
  management.
• BIO member companies pledge to
• Adopt principles and best practices
• Implement a program consistent with the QMP
• Conduct third party audits of QMP
• Failure to live up to the pledge over time would
  be viewed as conduct detrimental to BIOs best
  interests.
• Timeline
• December 2007 - QMP Guide completed, member
  companies self-certified objectives, principles
  and management practices, audit program defined
• December 2008 - Third-party audits completed for
  all US operations
• December 2009 Third-party audits completed for
  global operations

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DuPont Bioethics Guiding Principles

• Commitment to Food/Feed Safety
• Environmental Focus
• Conserving Biodiversity
• Transparency of Information
• Engaging Stakeholders
• Advocating Independent Research
• Contributing to Developing Economies
• Formalizing Access to Genetic Resources

http//www.dupont.com/biotech
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Steps to the US Market

• Laboratory research
• National Institutes of Health rDNA Guidelines
• Contained greenhouse evaluation
• USDA Guidelines for contained research
• Contained small scale field trials (crop
  destruct)
• USDA Notifications and Permits for contained
  release
• EPA Experimental Use Permit (EUP) gt 10 acres
  Plant Incorporated Protectant (PIP) (e.g. Bt)
• Pre-commercial testing (non-crop destruct)
• USDA De-regulation
• FDA Notification and Consultation
• EUP with Food/Feed Tolerance Exemption
• Commercial release
• EPA Registration

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U.S. Regulatory System

• Coordinated Framework for Biotechnology
• utilizes existing regulations
• Department of Agriculture
• Inspects greenhouses for compliance with
  guidelines
• Issues permits for small scale field trials
• Reviews petitions for De-regulation of products
• Environmental Protection Agency (fee for service)
• Issues Experimental Use Permits for Plant
  Incorporated Protectants (PIPs) (e.g., Bts)
• Grants Registrations and sets Tolerances for
  PIPs
• Food and drug Administration
• Conducts voluntary Early Food Safety Evaluations
  of gene products
• Conducts voluntary pre-market Consultation on
  food safety

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United States
Environmental Protection Agency
United StatesDepartment of Agriculture
Food and DrugAdministration
Submission to the Office of Pesticide
Programs Federal Register (FR) notice Review by
staff Questions EPA Scientific Advisory Panel
(SAP) No Further Questions Final Risk Assessment
Draft FR Notice and 30-day public comment
period Pre-acceptance letter sent Registration
and final tolerance exemption rule decision
Submission to the Biotechnology Regulatory
Services Review by staff Draft environmental
Assessment USDA Federal Register notice
(FR) Draft environmental assessment 60-day
comment period on USDA Deregulation
Submission of EFSE to the Center for Food Safety
and Nutrition Review by staff
EFSE is Optional (takes 4 months)
QuestionsRequest for additional information
No Questions(Deemed Complete)
No Questions
Questions
EFSE Consultation Complete
12 18 months
18 24 months
Submission of Biotech Notification to the Center
for Food Safety and Nutrition
Review by staff
12 months
Questions
No Questions
FDA Consultation Complete
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EPA - Approval

• Average time to complete all actions is 18 to 24
  months
• Most submitted studies are conducted under
  EPA/OECD Good Laboratory Practices (GLP) and
  subject to audit
• Internal review with use of expert Science
  Advisory Panels on case by case basis
• Notices of proposed Registrations and Tolerances
  published for public comment and final decisions
  published in Federal Register
• Fee structure for different actions Agency
  commits to timeline for specific action

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USDA and FDA Approvals

• USDA average review time for dossier is 18
  months
• Internal review Environmental Assessment (EA)
  published for public comment
• De-regulation notice published in Federal
  Register
• No fees
• FDA average time for Consultation is 12 months
• Internal review - Notice of completed
  Consultation and Memorandum to File published on
  FDA web-site
• No fees

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What is Regulated?

• Transgenic products are regulated by event
• Each time a piece of rDNA is inserted into a
  plant a new event is created
• USDA can extend de-regulation decisions to
  include additional similar events
• Combining two approved events by breeding
  (stacking) does not trigger further USDA action
• FDA requires notification of new stacks
• Could request more data (e.g., if two genes
  targeting same pathway produce altered
  nutritional profile)
• Stacking two or more approved PIPs requires new
  Registration from EPA
• Data requirements aimed at showing no alteration
  in non-target activity

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Basic Information Needs for Risk Assessment

• Knowledge of the crop and its wild relatives
• biology, distribution cultivation and uses
• Knowledge of the modification
• detailed genetic and molecular characterization
• Safety of expressed gene products
• protein characterization and toxic/allergenic
  potential
• Equivalence of the modified crop
• nutritional equivalence to unmodified crop
• environmental safety non-target impact

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Molecular Analysis

• Confirm genetic stability of the event
• Confirm expected segregation of trait over three
  generations
• Analyze the inserted DNA
• Confirm purity of event
• Analyze integration pattern of 100 progeny
• Characterize the integration event
• Complete high resolution map (Southern)
• Confirm that unwanted DNA is absent
• Show absence of unwanted vector sequences
• Develop event specific diagnostic
• Use insert/plant DNA borders

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Toxicology/Nutritional Assessment

• Toxicity evaluation
• Consider any toxic properties of gene donor
  organism
• Screen sequence for homology to known toxins
• Conduct acute mouse study with purified protein
  (plant purified or microbial equivalent) in a
  single dose (in large excess of dietary exposure)
• Allergenicity evaluation weight of evidence
  approach considering
• Determine rate of digestibility in in vitro
  gastric digestion model (pepsin)
• Screen sequence for homology to known allergens
• Perform specific IgE serum screen (if gene is
  from commonly allergenic food)
• Additional studies case by case basis to
  address specific concerns
• 42 day broiler chicken feeding study with grain
• 90 day rat feeding study with grain

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Composition, Expression and Agronomics (CEA)
Trials

• Grow modified plants at 6 sites for 1 or 2
  seasons to confirm that
• Composition of modified whole plant (silage) and
  grain is similar to unmodified counterparts and
  within normal range for that crop
• Modified plants exhibit expected agronomic
  phenotype when grown in regions typical of
  expected cultivation
• Modified plants expresses novel traits as
  anticipated under variety of field conditions
• measure gene expression in up to 12 tissue types
  over time, depending on crop

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Compositional Analysis

• Substantial equivalence - starting point for
  safety evaluation - measure more than fifty
  substances including
• amino acids
• fatty acids
• carbohydrates
• essential vitamins and minerals
• naturally occurring toxicants, anti-nutrients and
  allergens
• secondary metabolites
• Investigate nutritional significance of any
  changes from non-modified crop or normal range
  for that crop
• Leads to determination of safety relative to
  equivalent non-modified food with history of safe
  use

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Non-target Studies (Tier 1) for Cultivation of
Plant Incorporated Protectants (PIPs)
Test plant tissue (e.g., pollen) or purified
protein against appropriate representative
non-target organisms with focus on beneficial
species (e.g.)

• Avian
• quail
• Aquatic
• trout/catfish
• Waterflea
• Soil
• springtail
• earthworm

• Terrestrial
• ladybug
• lacewing
• parasitic wasp
• honeybee (adult and larva)
• butterfly

Effects seen in these Tier 1 studies may require
follow up with field observations (e.g., census
studies of non-target organisms)
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Risk Assessment for Cultivation

• Use hazard information (e.g., toxicity) and
  potential exposure by various routes to determine
  risk
• Measure pollen flow over distance
• Measure metabolism and fate in soil and water
• Calculate exposure from pollen and soil
  incorporated material
• Use information on distribution of non-targets
• Endangered species
• Out-crossing to wild and/or weedy species
• Additional studies as required to address
  specific concerns (e.g., increased fitness)

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Post Commercial Activities

• Post-registration requirements have included
• Insect Resistance Management resistance
  monitoring and refuge (non-Bt) planting
• Additional non-target studies (e.g., Monarch
  butterfly)
• Voluntary stewardship activities may be
  undertaken according to the nature of the
  modified crop
• Rapid detection methods for traceability
• Livestock performance studies e.g., dairy cows
  and pigs

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Commitment to Food/Feed Safety

• DuPont will develop products derived from
  biotechnology that are at least as safe as their
  conventionally produced counterparts for both
  human food and animal feed using the best
  scientific knowledge.

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2. Environmental Focus

• DuPont will endeavor to apply biotechnology in
  production systems so there is a net gain for the
  environment.

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3. Conserving Biodiversity

• DuPont will strive to protect and conserve
  natural resource biodiversity.

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4. Transparency of Information

• DuPont believes in the individuals right to
  information regarding product safety. DuPont
  will apply a strict and transparent standard in
  determining what product information is
  proprietary. DuPont will disclose safety
  information on its products in a clear and
  accessible manner.

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5. Engaging Stakeholders

• DuPont will routinely engage stakeholders
  (shareholders, customers, society, and employees)
  and consider their diverse viewpoints in its
  decision-making process for products derived from
  biotechnology.

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6. Advocating Independent Research

• DuPont will seek opportunities to advocate and/or
  fund biotechnology research important to its
  business at public institutions, research centers
  and non-governmental organizations that follow
  accepted science protocols and peer review
  standards.

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7. Contributing to Developing Economies

• DuPont will endeavor to be socially and
  culturally responsible as it shares knowledge and
  appropriate technology in developing economies to
  help improve food, nutrition and the quality of
  life. DuPont will seek to utilize its
  intellectual property in ways that help alleviate
  hunger.

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8. Formalizing Access to Genetic Resources

• DuPont will strive to identify the owner(s) of
  natural biological resources and knowledge
  selected for research and product development and
  will develop fair and equitable business
  arrangements that recognize the contributions of
  the involved parties. To the extent possible,
  arrangements will be made public.