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FLEXGene Repository
Platform
The FLEXGene Platform
Universal
Scientific
Excellence Access
Freedom to
Operate
Scientific Excellence
Highest quality
• Gold standard
• Fully sequence verified
Flexibility
• Genes rapidly moved to any protein expression vector
• Collections of genes moved simultaneously with ease
• Enables high-throughput functional experiments
Diligence
• World class experts have vetted the technologies
• Pilot studies confirmed robustness
Research and Development
• Continued effort to improve vectors and gene transfer
Universal Access
Broad availability
• Equal access to the entire community
• Includes both clones and cloning methodology
• Provides a level playing field
Distribution strategy promotes access
• Multiple reputable distributors
• Third party quality control
Public/private venture
• Membership open to all
• Garners the best experience from all sectors
Freedom to Operate
FLEXGene clones
• No restrictions or reach through attached to
clones
• Assembled and distributed under NIH umbrella
FLEXGene cloning methodology
• Methodology available to everyone
• Simple and open licensing structure
• Available in perpetuity
FLEXGene Repository
Organizational Plan
FLEXGene
Organizational Structure
Scientific Advisory Board
(Contributing Members)
Legal Committee
Administrative Staff
Director
Operations
NIH Foundation
Communications and Public Relations
Suppliers
Informatics
Clone Production
Sequencing site(s)
Distribution and
Quality Control
Director
Bob Strausberg
• Full time position
– CGAP
– MGC
– FLEXGene
• Responsible for:
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Managing the project
Ensuring that suppliers reach milestones
Overseeing budget
Enforcing standards
Driving and managing all key activities & processes
Communications & PR (with Harlow and LaBaer)
Governance
Scientific Advisory Board
• One representative per member
organization
• One class of membership
• Responsible for:
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Setting the scope and objectives
Approving the standards
Monitoring and guiding the operations
Defining future projects
FLEXGene Repository
Scientific Plan
Strategy
Scope of project
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One representative version for each human gene
Project limited to producing master clones
• Expression clones and proteins to be made by users
Two clones per gene: with and without stop codon
Clone production
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FLEXGene uses MGC clones as starting template
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High quality template
Fully sequenced
Fewer cycles of PCR needed  higher fidelity
MGC has agreed to continue until all genes represented
Alternate splice forms, mutant collections, etc.
considered for subsequent projects, e.g., FLEXGene II
Cloning system selection to be managed by independent
blue ribbon panel
The FLEXGene Concept-I
mRNA
5’ Untranslated
Coding Region
3’ Untranslated
Precisely copy the coding region
Add recombination sites
Move to plasmid vector
Master clones
that populate
the repository
•Precise coding region
•No 5’ stop codons, 5’ or 3’ regulatory sequences
•Ready for expression as native protein, NH2- or COOH-terminal fusions
The FLEXGene Concept-II
FLEXGene
master clone
Move the insert by recombination to:
(Now a simple automated procedure)
Any expression vector (bacteria, yeast, mammalian, viral et al.)
Native protein
or
Amino-terminal fusions
or
Carboxy-terminal fusions
or
Amino- and carboxy-terminal fusions
Pilot Study
Project Scope
GOAL:
1. Direct comparison of cloning systems
2. Assess mutation rate during clone assembly
•Used MGC clones as template for PCR
•Same set of 384 genes are cloned in each system
•Evaluate each system based on
– Efficiency (hit rate)
– Product quality (sequence)
– Ease of use (for cloners and for end users)
– Cost
Sequence Fidelity
Pilot Study
384 MGC clones converted to each of two systems
Pilot completed in 3 months
No significant differences between systems
768 clones have been fully sequenced:
• 192 genes, 2 systems, 2 separate isolates each
• Sequencing done to at least 1 in 10,000 accuracy
• Average mutation rate ~1 error every 3700 bases
• Concordance indicates <3% duplicates have same mutation
Combining the two systems:
average = 1 error in every 4-5 clones.
FLEXGene Repository
Legal and Intellectual
Property Strategy
Legal Issues Addressed
Organizational structure
• Under NIH umbrella
• FLEXGene membership open to all
• Uniform cost of membership; no special
payment terms
• Cloning system recommendations by
independent blue ribbon panel
Intellectual property
• Existing gene IP
• Cloning system IP
• No IP overhead added by FLEXGene
Intellectual Property
Existing Gene IP
FLEXGene will:
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Publish its plans broadly
Operate under the NIH umbrella
Not search for IP on individual genes
Provide a shrink wrap MTA: it is users’ responsibility to
check IP on specific genes
• Attach no IP to the clones
Intellectual Property
Cloning System
FLEXGene (through NIH) will request a contract from cloning
system provider that:
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Ensures that users will always be able to use technology
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Perpetual license
Methods for producing reagents will be placed in escrow
Ensures that there are no limitations on the use of the clones added by
cloning technology
Ensures that the cost will be the same for everyone
Encourages innovation by ensuring that third parties who develop new
technologies can make them compatible with the system
Ensures that the price will not jump as soon as the contract is signed
Ensures that clones can be distributed by multiple distributors
FLEXGene Repository
Clone Distribution and
Maintenance Strategy
Maintenance and Distribution
Overview
• Vital issue for FLEXGene
• Production  Central Archive  Distributors
• Multiple distributors is essential
• Multiple distributors ensure competitive pricing
• Multiple distributors ensure better quality control
• FLEXGene will not dictate price
• License to distribute may be contingent upon a
minimum level of quality control
• Oversight board established to monitor quality control
• Distributors can be commercial or non-profit
• Distributors must offer all FLEXGene clones for sale
• Distributors cannot provide clones to another
distributor for resale
Maintenance and Distribution
Distributor Responsibilities
Distributors must provide
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Clones on a fair, equitable and confidential basis
E-mail or web-based help desk
Clone annotation – either locally or linked to FLEXGene
E-mail or web-based complaint system with record keeping
A published and accessible list of their products, services, prices,
expected response times and guaranteed delivery times
• A completed MTA from each customer
• Feedback on aberrant clone identities to the central archive
Each distributor can determine its distribution format
• DNA, bacterial strain, or both
Distributors can offer additional services for added value
• Pre-made clone sets (cancer, kinase, etc.)
• User-specified custom sets
• Re-sequencing, T1 Phage testing, testing for cross-contamination
Maintenance and Distribution
Distribution Oversight Board
The Distribution Oversight Board will:
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Consist of 4-6 users
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Review complaints about distributors semi-annually
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Academic, commercial and geographic representation
No conflicts of interest with distributors
Agree to maintain confidentiality
Ensure adequate response and follow-up
Ensure measures established to improve systematic problems
Spot check distributors annually (Optional)
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Order 100-200 clones
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Monitor service quality and response times
Ensure clone viability
Confirm clone quality by sequencing
Help to identify problems early, before complaints come in
Continue to operate even after production is completed
Maintenance and Distribution
Distributor Qualifications
Experience distributing clones on a fee basis
• Evidence of quality service
• Positive customer references
Existing infrastructure
• For clone storage
• For distribution
• For testing
• DNA Sequencing
• Contamination monitoring
Ability to provide annotation
• Electronically
• Enclosed with shipped parcel of clones